ABSTRACT

Among the most important and complex systems in the human body are the endocrine and immune systems. Emerging research over the last decade has shed light on their remarkable interplay, revealing a multitude of bidirectional communication pathways and reciprocal regulation mechanisms. Endocrine diseases, such as autoimmune thyroiditis, diabetes mellitus type 1 and type 2, osteoporosis, and disorders of the hypothalamic-pituitary-adrenal (HPA) axis, as well as endocrine malignancies, such as thyroid cancer, are highly interconnected with dysregulations of the immune system. Thus, multiple cytokines, chemokines, and evolving inflammatory processes are involved in the pathogenesis of immune-related endocrine disorders, providing potential targets for immune-based therapeutic approaches. In this chapter, we provide a comprehensive overview of the molecular mechanisms underlying these complex endocrine-immune interactions, and discuss the implications of immune system function or dysfunction in endocrine disorders. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The immune system is a host defense system that comprises numerous biological structures and processes to defend the human body against potentially harmful substances and invading pathogens. It functions through a series of coordinated mechanisms, including innate and adaptive immunity. The innate immune response consists of i) phagocytosis by macrophages, neutrophils, monocytes, and dendritic cells, and ii) cytotoxicity by natural killer cells, providing an immediate, nonspecific defense against a wide range of invaders by recognizing common patterns shared by many pathogens (1).

Adaptive immunity, on the other hand, is an acquired, specially designed defense system; it develops over time and utilizes highly specialized immune cells involving antibody-dependent complement or cell-mediated cytotoxicity produced by T cells that recognize injurious agents, such as heat shock proteins or microbial antigens. During adaptive immunity, antigens taken up by antigen-presenting cells (APCs) are presented to T cells through binding with major histocompatibility complex (MHC) molecules on the surface of these cells. Activated CD4 helper T cells stimulate the release of cytokines, such as interleukin (IL)-2, which i) induce T cell proliferation and activation, ii) stimulate killer cell activity by CD8 suppressor T cells, and iii) activate B cells to differentiate into plasma cells and produce antibodies. Naïve T cells differentiate mainly into two main subsets that produce a different set of cytokines and regulate distinct immune functions. T-helper 1 (Th1) cells produce mainly interferon-γ (IFN)-γ, tumor necrosis factor-α (TNF)-, and IL-12 to regulate cell-mediated responses, while T-helper 2 (Th2) cells secrete IL-4, IL-5, and IL-13, to stimulate antibody production. In addition, three other subsets of T helper cells have been identified: Th22, which secrete IL-22, Th17, which secrete IL-17, and Treg, which secrete transforming growth factor (TGF)- b, all of which also play a role in the pathogenesis of autoimmune diseases (2).

Multiple regulatory mechanisms are involved in maintaining central and peripheral T and B cell tolerance (1). Defects in the processes that ensure immune cell tolerance may induce a maladaptive immune response to a self-antigen and lead to the development of autoimmune diseases.

Emerging research of the last few decades has shed light on the remarkable interplay between endocrine and immune systems, revealing a multitude of bidirectional communication pathways and reciprocal regulation.

Autoimmune endocrine diseases, such as Hashimoto thyroiditis, diabetes mellitus type 1 (DM1), and Addison disease, as well as endocrine malignancies, such as differentiated, anaplastic, and medullary thyroid cancer (3), and other endocrine disorders, including diabetes mellitus type 2 (DM2), osteoporosis, as well as a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis response to stress and inflammation, are highly interconnected with dysregulations of the immune system.

This chapter seeks to elucidate the interplay between the endocrine and immune systems, exploring their interconnections and highlighting the impact of their crosstalk on health and disease. We present a comprehensive overview of the molecular mechanisms underlying this interaction and discuss the potential therapeutic implications of targeting the immune system for the management of endocrine diseases.

IMMUNE SYSTEM AND THYROID DISEASE

Autoimmune Thyroid Disease

Autoimmune thyroid disease (AITD) results from a dysregulation of the immune system that leads to loss of tolerance to thyroid antigens and to an autoimmune attack on the thyroid gland. The most common clinical manifestations of AITD are Hashimoto's thyroiditis and Graves’ disease, while less prevalent manifestations are drug-induced thyroiditis, postpartum thyroiditis, or thyroiditis associated with polyglandular syndromes (i.e., autoimmune polyglandular syndromes type 1 and type 2). The underlying molecular mechanisms of AITD involve both circulating autoantibodies and T cell immune mechanisms, while genetic background, as well as cross-reactivity to external antigens (4-6), are also implicated.

There are three major thyroid autoantigens that are targeted during autoimmune thyroid attack and are critical for thyroid homeostasis, namely, thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) (Figure 1).

Figure 1.

Thyroid proteins that serve as autoantigens. Thyroglobulin (Tg) function as storage protein in thyroid cells, playing a critical role in the synthesis and release of thyroid hormones. Thyroid peroxidase (TPO) catalyzes iodination of tyrosines in thyroglobulin, which attaches one or two iodine molecules to form monoiodotyrosine (MIT) or diiodotyrosine (DIT), respectively. In addition, thyroid peroxidase catalyzes the coupling of iodotyrosine residues to form triiodothyronine (T3) and thyroxine (T4) attached to thyroglobulin. Thyrotropin receptor (TSHR) is a transmembrane G-protein coupled receptor that upon stimulation by circulating TSH activates the expression of downstream effector genes to regulate thyroid growth, thyrocyte differentiation, and thyroid hormone synthesis. Sodium/iodide symporter (NIS) is a membrane glycoprotein, which actively cotransports two sodium cations per each iodide anion, using the electrochemical sodium gradient generated by the Na+/K+-ATPase. Pendrin is involved in the apical iodide efflux in thyroid cells. It can also exchange chloride and bicarbonate. [Modified by Boguslawska et al (7)].

Thyroglobulin is a soluble glycoprotein homodimer composed of two subunits of ~330 kDa in size and is the most abundant glycoprotein in the thyroid gland. It is the scaffold for the synthesis of thyroid hormones and the storage-form of thyroid hormones inside the gland. Recently, researchers described the first atomic structure of full-length Tg and identified its hormone-forming tyrosine residues (8). Anti-Tg antibodies (TgAb) act mainly through antibody-dependent cytotoxicity cells rather than through complement fixation (7). In AITD, the prevalent TgAb species recognize native rather than denatured antigens and bind to a number of overlapping epitopic domains located mainly in the central region and C-terminal end of Tg. Of note, TgAb in the serum of healthy subjects have a different epitopic pattern (9).

Another major thyroid antigen is TPO, a glycosylated heme-containing homodimer of two 107-kDa transmembrane subunits located in the apical membrane of thyrocytes (Figure 1). It catalyzes the iodination of tyrosyl residues in Tg and the coupling of iodotyrosine residues to form iodothyronines attached to Tg (10). Both humoral and cellular immune responses are directed against TPO. TPO autoantibodies (TPOAb) occur in almost all patients with Hashimoto thyroiditis and approximately 75% of individuals with Graves’ disease (11). In addition, TPOAb may be involved in autoimmune thyroid cell death via antibody-dependent cytotoxic cells and C3 complement-mediated cytotoxicity (7). Specific patterns of TPOAb recognition remain stable in an individual over time and are genetically transmitted through family lineages (12).

Thyrotropin receptor is primarily expressed on the basolateral membrane of thyrocytes (Figure 1) and belongs to the transmembrane G protein-coupled receptor family. The intracellular signaling pathway that is activated by the interaction of TSH with TSHR is indispensable for the synthesis of thyroid hormones and the proliferation of follicular epithelial cells. TSHR-stimulating antibodies (TSAb) act as TSHR agonists and stimulate thyroid growth and production of thyroid hormone in an autonomous and unregulated manner. On the other hand, TSHR-blocking antibodies (TBAb) act as antagonists that block the intracellular signaling of TSH, leading to decrease of thyroid hormone synthesis and subsequently hypothyroidism. Neutral antibodies to TSHR, which may also be detected in the serum of patients with Graves’ disease, bind to the receptor but do not alter its activity (13). The exact antigenic sites of TSHR-specific TBAb and TSAb overlap and are mostly directed to the extracellular A subunit of the receptor (Figure 1) (14,15).

Other thyroid antigens include the iodide transporters, sodium iodide symporter (NIS), and pendrin (Figure 1). The presence of NIS antibodies is increased in AITDs, especially in patients with Graves’ disease, whereas their expression in euthyroid individuals is rare (16). Pendrin is an apical membrane-bound iodide transporter, but the diagnostic value of antibodies against pendrin is rather low (16).

Although the above-described circulating autoantibodies are useful markers of thyroid autoimmunity, it is the T cell immune mechanism, i.e., the loss of immune self-tolerance, that is the core of AITD pathophysiology. Loss of immune self-tolerance may result from either: i) the loss of central tolerance (i.e., disturbed deletion of autoreactive T cells in the thymus), ii) dysfunction of peripheral tolerance (i.e., impaired apoptosis of self-reactive T cells and inhibition of the activity of T-regulatory cells), or iii) disturbed energy (i.e., disturbance of the functional inactivation that prevents the lymphocytes from activating an immune reaction against the antigen).

Patients with AITD express IFN-γ-induced MHC class II molecules, which promotes the presentation of thyroid autoantigens and activates T cells (4). The subsequent infiltration of the thyroid gland by APCs (dendritic cells and macrophages) may be triggered by inflammation resulting from either viral or bacterial infection or exposure to toxins. The common mechanism involved in the initiation and perturbation of the inflammatory processes in AITDs and in other autoimmune endocrine diseases (e.g., type 1 diabetes and Addison disease) is the Th1-cytokine/chemokine axis (17). Upon activation, Th1 lymphocytes produce IFN-γ -and TNF-α, which stimulate thyrocytes and retroorbital cells (in Graves ophthalmopathy) to secrete chemokines (CXCL10, CXCL9, and CXCL11). Chemokines, in turn, bind and activate the CXCR3 receptor on Th1 cells and further enhance IFN-γ and TNF-α secretion in a positive feedback loop which aggravates recruitment and activation of inflammatory cells in the affected organs (Figure 2). In advanced thyroiditis, the thyroid gland is infiltrated by B cells (representing up to 50% of the infiltrating immune cells), as well as cytotoxic T lymphocytes and CD4+ cells (7).

Figure 2.

Depiction of the molecular mechanism involved in the inflammatory processes in autoimmune thyroid diseases. Activation of Th1 lymphocytes by antigen presenting cells produce INF-γ -and IL-2 and 12, which stimulate thyrocytes and retroorbital cells to secrete chemokines (CXCL10, CXCL9, and CXCL11). Chemokines bind and activate the CXCR3 receptor on Th1 cells, further enhancing IFN-γ and ILs secretion. APC, antigen presenting cells; IFΝ-γ, interferon gamma; IL-2, interleukin 2; IL-12, interleukin-12; CXCR3, C-X-C Motif Chemokine Receptor 3.

In Hashimoto thyroiditis, the humoral immune response is characterized by the presence of autoantibodies to TPO or Tg and is related to thyroid lymphocytic infiltration. These autoantibodies are themselves cytotoxic or may affect antigen processing or presentation to T cells. Th1 cells are the predominant T cell clones found in patients with Hashimoto thyroiditis: they promote apoptosis of thyrocytes through secretion of IL-12, TNF-α, and INF-γ, which activate cytotoxic T lymphocytes and macrophages (18). In addition, the Toll-like receptor-3 protein is overexpressed in human thyrocytes surrounded by immune cells in all patients with Hashimoto thyroiditis, but not in Graves’ disease or in euthyroid individuals (17).

In patients with Graves’ disease, the predominant antibodies are directed against the TSHR. T cells are activated through the presentation of TSHR peptides and, in turn, trigger B-cells and plasma cells that infiltrate the thyroid to produce autoantibodies directed against the TSHR. Activity of B-cells and plasma cells is also regulated by liver-produced insulin growth factor 1 (IGF1). In contrast to TPO and Tg, TSHR is widely expressed in extrathyroidal tissues and cells, including lymphocytes, adipose tissue, and fibroblasts. In consequence, the presence of TSHR antibodies contributes to the extrathyroidal manifestations of Graves’ disease, such as Graves ophthalmopathy, Graves dermopathy, and Graves-associated thymus hyperplasia (19).

Particularly in Graves ophthalmopathy, the TSHR autoantigen is presented by macrophages and B cells recruited to the orbit (20). Activated T cells, in turn, initiate an immunological attack on the orbital fibroblasts expressing TSHR. In response to the cytokines released by Th cells, orbital fibroblasts and adipocytes —both expressing TSHR— produce and deposit large amounts of glycosaminoglycans (e.g., hyaluronan), leading to increased osmotic pressure and water uptake, swelling of the extraorbital muscles, and increased accumulation of orbital adipose tissue. The process is enhanced by the IGF1/IGF1R signaling pathway in fibroblasts and adipocytes, as well as the crosstalk between TSHR and IGF1R intracellular signaling (21). A similar molecular pathophysiology may underlie Graves dermopathy (19).

NON-CODING RNAs

In recent years, non-coding RNAs, which are known to modulate gene transcription at the post-transcriptional level, have attracted a great deal of attention as potential biomarkers in various endocrine diseases. Although the study of microRNAs and circular RNAs is still in its infancy, these newly discovered non-coding, single-stranded RNA molecules have been implicated in the development and progression of AITDs.

A cluster of biomarkers consisting of miR-205/miR-20a-3p/miR-375/miR-296/miR-451/miR-500a/miR-326 has been reported to be differentially expressed in patients with Hashimoto thyroiditis (22,23). Similarly, multi-miRNA-based biomarkers, such as miR-762/miR-144-3p or miR-210/miR-155/miR-146, were differentially expressed in the serum of patients with Graves’ disease compared to healthy individuals. These dysregulated miRNAs can target key genes involved in the immune response and thyroid function. Regarding their prognostic role, higher miR-21-5p expression is associated with a worse prognosis for patients with Graves’ disease, whereas impaired expression of miR-155 correlates with the size of the goiter (22,24). Further understanding of the role of miRNAs in AITDs could provide valuable insights into disease mechanisms and potentially identify novel therapeutic targets. Data on other non-coding RNAs (such as long-noncoding RNAs and circular RNAs) are scarcer. Impaired expression of n335641, TCONS-00022357-xloc-010919, and n337845 was found in B cells of patients with Graves’ disease (25), while altered expression of 627 circRNAs in PBMCs of patients with Hashimoto thyroiditis has been tested for their potential prognostic value (26).

GUT MICROBIOME

Emerging evidence suggests that the composition and function of the gut microbiome may be involved in AITDs. The gut microbiome refers to the complex community of microorganisms residing in the gastrointestinal tract, which plays a vital role in various aspects of human health, such as prevention of intestinal colonization by pathogenic bacteria, fermentation/degradation of food debris, and production of nutrients. Studies have indicated that alterations in the gut microbiome can influence immune responses and contribute to the development of autoimmune diseases (7). In this context, dysbiosis, or an imbalance in the gut microbiota, has been observed in patients with Hashimoto thyroiditis and Graves’ disease, thus distinguishing them from healthy controls, while it was associated with the stage of disease, the level of thyroid autoantibodies, and the response to therapy.

Targeting the microbiome through dietary interventions or probiotics may represent a promising potential therapeutic avenue. It is therefore of interest to note that in hypothyroid patients treated with LT4, symbiotic supplementation for 8 weeks resulted in decrease of TSH concentration and LT4 dose (27). Moreover, the results of a large clinical study, INDIGO, reported a significant effect of LAB4 probiotics on the gut microbiota composition of patients with Graves’ disease and a temporary reduction in the serum level of IgG and IgA antibodies (28). Further research involving patients from different populations is required to fully understand the relationship between the gut microbiome and AITDs and to explore potential strategies for intervention.

Euthyroid Sick Syndrome

Euthyroid sick syndrome (ESS) is a condition characterized by alterations in thyroid hormone levels despite normal thyroid gland function. The characteristic laboratory abnormalities of the ESS include low T3 and/or fT3, elevated reverse T3 (rT3), normal or low TSH, and normal or low serum T4 or fT4 concentrations. Clinical conditions that trigger the development of ESS include systemic inflammation, myocardial infarction, starvation, sepsis, surgery, trauma, chronic degenerative diseases, malignancy, and every other condition associated with severe illness.

During illness or periods of severe physiological stress, the immune system releases various proinflammatory cytokines, such as in IL-6, TNF-α, IL-1β, IFN-γ, and TGF-β2. These cytokines disrupt the hypothalamic-pituitary-thyroid axis and interfere with the normal synthesis, secretion, and metabolism of thyroid hormones (Figure 3), while the more severe the illness, the more extensive the hormonal alterations.

Figure 3.

Secretion of proinflammatory cytokines during severe illness or stress inhibits the activity of hepatic deiodinase type 1- suppressing the peripheral conversion of T4 to T3. They also suppress intrathyroidal hormone synthesis, TRH release and TSH secretion from the pituitary. IL-6, interleukin-6; IL-1, interleukin-1; TNF-α, tumor necrosis factor alpha; INF-γ, interferon gamma; TGF-β, tumor growth factor beta; TG, thyroglobulin; NIS, sodium/iodide symporter; TSH, thyroid stimulating hormone; TRH, Thyrotropin-releasing hormone.

Proinflammatory cytokines suppress the peripheral conversion of T4 to T3, resulting in low T3 levels and increase rT3 levels, by inhibiting the activity of hepatic deiodinase type 1, which promotes conversion of T4 to T3 and of rT3 to diiodothyronine (32). They also suppress TRH release and inhibit TSH response to TRH stimulation, leading to a decrease in TSH levels. Thus, the cause of the decreased T3 concentration in ESS is decreased T3 production, whereas the cause of the increased rT3 concentration is the result of impaired degradation. Prolonged and severe illness is marked by a decrease in circulating total T4 along with low T3 and high rT3, with very low T4 levels displaying a poor prognosis and having been associated with an increased mortality rate (32). In addition, cytokines reduce iodine uptake by inhibiting sodium-iodine symporter protein expression (25-27), and decrease thyrocyte growth (33), iodide organification (34,35), and thyroglobulin synthesis (36,37).

The central role of cytokines in the pathophysiology of ESS has been further elucidated in studies involving cytokine administration to humans. TNF-α administration in healthy volunteers caused a decrease in serum T3 and an increase in serum rT3 concentration (38). Unlike IL-6, serum TNF-α levels did not correlate with any of the typical thyroid parameters, such as low T3, increased rT3, or decreased TSH levels seen in ESS (39,40), suggesting that the changes of thyroid hormone profile following TNF-α administration might be indirect (i.e., through TNF-α increase in circulating IL-6 levels). Furthermore, both IL-6 and TNF-α can upregulate type 2 deiodinase in the anterior pituitary, affecting TSH release and contributing to the development of the non-thyroidal illness syndrome (41,42).

Leptin, a hormone primarily known for its role in regulating appetite and energy balance, has also been implicated in the development of EES. During acute illness or chronic inflammation, leptin levels are usually elevated. A link between leptin and the proinflammatory cytokines TNF-α and IL-6 in chronic inflammatory diseases, such as chronic obstructive pulmonary disease (43) and ankylosing spondylitis (44), respectively, has also been proposed previously.

The primary effect exerted by leptin on the hypothalamic-pituitary-thyroid axis is alteration of the setpoint for feedback sensitivity of hypophysiotropic TRH-producing neurons in the paraventricular nucleus of the hypothalamus to thyroid hormones (mainly T3) by lowering of the setpoint when leptin levels are suppressed during fasting (45). Two anatomically distinct and functionally antagonistic populations of neurons in the arcuate nucleus of the hypothalamus, α-melanocortin-stimulating hormone (α-MSH)-producing neurons that co-express cocaine- and amphetamine-regulated transcript and neuropeptide Y (NPY)-producing neurons that co-express agouti-related peptide (AGRP), are responsible for the effects of leptin on hypophysiotropic TRH. It has also been proposed that leptin directly affects hypophysiotropic TRH neurons (46). Leptin has been found to inhibit the conversion of T4 to T3 in peripheral tissues and increase the activity of the enzyme type 3 deiodinase, which converts T4 to rT3. These data suggest that leptin can disturb thyroid function in seriously ill patients via two different independent mechanisms (cytokine-dependent and directly).

Thyroid Cancer

Thyroid cancer is the most common endocrine cancer, the incidence of which has steadily increased over the past few decades (57).

The association of chronic inflammation induced by Hashimoto thyroiditis and thyroid cancer has been long recognized (58). However, the immune response triggered against thyroid cancer and AITDs differs significantly. In thyroid cancer, the immune response is more tolerant and allows tumor growth, whereas in AITDs, the response is more aggressive, triggering cell destruction and reduction of the function of the gland (59). Hashimoto thyroiditis is considered both a risk factor for the development of thyroid cancer (60) and a favorable prognostic factor due to chronic lymphocytic infiltration, which can downregulate tumor aggressiveness (60,61). In Graves’ disease, the presence of a strong humoral immune response appears to be protective against thyroid cancer. Patients with increased anti-TPO and anti-Tg levels show lower distant metastasis rates than patients without thyroid autoantibodies (62,63), suggesting their potentially protective role (59).

Immune infiltrates in the tumor microenvironment differ between the different thyroid neoplasm subtypes (Figure 4). In general, differentiated thyroid cancer (DTC) has a higher number of tumor-associated lymphocytes and regulatory T cells (Tregs), while anaplastic thyroid cancer (ATC) and medullary thyroid cancer (MTC) display a high density of tumor-associated macrophages (64). The number of tumor-associated macrophages has been associated with dedifferentiation, lymph node metastases, and reduced survival (65). It is important to note, however, that most of the studies analyzing the immune milieu of DTC have used papillary thyroid cancer (PTC) tumor samples (66-69). Myeloid-derived suppressor cells are associated with aggressive characteristics of differentiated thyroid cancer and are related to poor prognosis (65).

Figure 4.

Immune infiltrates differ in different types of thyroid cancer [Modified by Garcia-Alvarez et al, (70)]. TAM, tumor-associated macrophages; MDSC, myeloid-derived suppressor cell.

The dendritic cells, which play a critical role in antigen presentation, are increased in PTC, while neutrophils are found in more aggressive thyroid cancers (such as poorly differentiated or anaplastic). In addition, natural killer cells that play an important role in immunosurveillance are also increased in PTC and are negatively correlated with tumor stage, while lymphocytic infiltration is associated with better overall survival and low recurrence rate (71,72).

Cytokines, which may be produced by thyroid follicular cells and by immune cells infiltrating thyroid tumors, are also related to tumor development. IL-1 and IL-6 stimulate thyroid cell proliferation and tumor growth, while TGF-β, which is a suppressive cytokine, is overexpressed in aggressive cancers (73). In addition, multiple chemokines may be secreted by thyroid cancer or immune cells and affect chemiotaxis, angiogenesis, and lymphangiogenesis (73).

Immunomodulatory proteins, such as programmed death-ligand 1 (PDL1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin and ITIM domain (TIGIT), which are considered major immune coinhibitory receptors and promising immunotherapeutic targets in cancer treatment, are also expressed in thyroid cancer, being associated with more aggressive tumor characteristics and a poor prognosis (64). Programmed death-ligand 1 staining by immunohistochemistry has shown higher expression in ATC than in other subtypes (70). Six cohort studies have been published to-date reporting positive PD-L1 expression, varying between 22% and 65%, this being higher compared to that detected in DTC and poorly differentiated thyroid cancer (74-79). TIM-3 expression was observed in 48% of patients with MTC, and in the majority of cases (84.4%) its expression was restricted to tumor cells (80). Other coinhibitory receptors, such as LAG-3 and T cell TIGIT, were observed in a lesser percentage of cases (approximately 3%) (80). Nevertheless, results from clinical trials with immunotherapy as monotherapy or combinations have shown limited efficacy (70). In one phase Ib KEYNOTE-028 trial assessing the efficacy of pembrolizumab in patients with PD-L1+ (membranous staining on ≥1%) locally advanced or metastatic follicular or papillary thyroid cancer, pembrolizumab achieved an objective response rate of 9% and a median progression-free survival of 7 months (81). Several clinical trials further investigating the efficacy of combination therapy of immune checkpoint inhibitors are currently ongoing.

IMMUNE SYSTEM AND DIABETES MELLITUS

The immune system plays a crucial role in the pathogenesis of both type 1 and type 2 diabetes.

Diabetes type 1, which is immune-mediated in more than 95% of cases, is an organ-specific autoimmune disease characterized by lymphocytic infiltration and inflammation that leads to pancreatic β-cell destruction and absolute insulin deficiency (82). The immune system’s attack on pancreatic β-cells is usually triggered by a number of factors, including genetic predisposition and environmental triggers such as viral infections (e.g., Coxsackie B4, mumps, and rubella) or dietary compounds (e.g., cow’s milk) (82). The process involves the activation of immune cells, particularly T cells, which recognize self-autoantigens in pancreatic β-cells and initiate an immune response.

On the other hand, in type 2 diabetes, the immune system also plays a different role from that in DM1. Chronic low-grade inflammation, often associated with obesity, leads to immune cell activation and the release of proinflammatory cytokines. These cytokines interfere with the normal functioning of insulin and promote insulin resistance. Macrophages infiltrate adipose tissue and release inflammatory molecules, further exacerbating insulin resistance with increasing adiposity. The immune system, thus, contributes to the development and progression of insulin resistance and eventually promotes the onset of DM2.

Understanding the intricate relations between the immune system and diabetes pathogenesis is essential for the development of effective treatments and interventions for the management of both types of diabetes.

Diabetes Type 1

The susceptibility to develop DM1 is associated with multiple alleles of the major histocompatibility complex MHC I and II locus. More than 90% of patients with DM1 express either HLA DR3, DQ2 or DR4, or DQ8 (83), whereas HLA haplotype DR2, DQ6 is protective against DM1 development.

The primary pathological presentation of DM1 is inflammation of the pancreatic islets, also known as insulitis, caused by infiltration of immune cells, including CD4 and CD8 T cells along with B cells (84-86). Although the initial events triggering autoreactive responses remain unclear, presentation of pancreatic islet autoantigens by the associated MHC class II molecules contribute to priming and expansion of pathogenic T cells.

CD4 T helper cells are required for the development of the autoimmune process in the pancreatic islets, while CD8 cytotoxic T cells are the cells responsible for β-cell destruction (Figure 5). T cell receptors recognize peptides bound to MHC molecules on the surface of antigen-presenting cells (B-cells, dendritic cells, and macrophages). Each T cell then generates a unique receptor for the recognition of an autoantigen presented in the MHC molecule. The interaction between T cell receptor/autoantigen/MHC leads to activation of the T cells.

Figure 5.

T cell mediated destruction of β- cells in diabetes type 1. CD4+ effector T cells recognize an insulin or islet peptide presented by diabetes-risk conferring HLA-DQ8 or DR4 on APCs, migrate to the pancreas and promote pancreatic β-cell destruction. Inside the pancreatic islets CD8+ effector T cells recognize islet antigens presented by HLA-A2 leading to the destruction of the β-cells. [Modified by Mitchel et al (87)]. TCR, T cell receptor; APC, antigen presenting cell; HLA-A2, human leukocyte antigen-A2.

Three different mechanisms have been proposed to explain T cell activation in DM1. One mechanism is thought to involve molecular mimicry-activated T cell proliferation. The hypothesis for this mechanism is based on the assumption that epitopes of proteins expressed by infectious agents can be shared by unrelated molecules encoded by host genes (88). A second mechanism that may trigger molecular mimicry-activated T cell proliferation is “bystander” T cell proliferation. This mechanism involves the stimulation of non-antigen-specific T cells by various cytokines during infection, simply because they are in the area. The cytokines thought to be involved in this nonspecific stimulation are IFN-α and IFN-β (89). The 3rd mechanism might involve a superantigen-mediated T cell proliferation mechanism: this theory proposes that autoreactive T cells can be inappropriately primed to react against self-structures through an encounter with a superantigen (90).

Multiple autoantigens in the pancreatic islets have been identified, including non-specific islet cell autoantigens (ICA), insulin, glutamic acid decarboxylase 65 (GAD65), insulinoma antigen-2 (IA-2), heat shock protein (HSP), islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), imogen-38, zinc transporter-8 (ZnT8), and the most recently identified pancreatic duodenal homeobox factor 1 (PDX1), chromogranin A (CHGA), and islet amyloid polypeptide (IAPP) (91). Autoantibodies against these autoantigens may be detected long before the onset of hyperglycemia and usually decline during the course of the disease (92).

Most patients diagnosed with DM1 have circulating islet cell autoantibodies directed against pancreatic islet autoantigens. However, although the detection of autoantibodies may be useful for DM1 diagnosis and prediction, it is the cellular immune system that eventually infiltrates the pancreatic islets and causes β-cell destruction. In turn, further β-cell destruction leads to more self-antigen presentation and ensuing amplification of the immune response (82,93,94).

Among several proinflammatory cytokines, IL-21, produced by CD8 T cells, is required for the development of DM1, while TNF-α may also be involved (95,96). IL-6 plays an important role in the pathogenesis of vitiligo-associated DM1 (97). In contrast, in vivo experiments with non-obese diabetic mice have shown that IL-4, produced by Th2 cells, may be protective against developing diabetes (95,96,98,99).

Understanding both the pathophysiology and the regulatory mechanisms involved in DM1 is a critical step towards the development of antigen-specific, β-cell-directed, immunomodulatory or cellular treatment modalities (100).

Investigations into the efficacy and safety of various immunotherapeutic strategies against the development of DM1 have been carried out in recent clinical trials and are still ongoing in current trials (101). Among them, T cell-directed therapies that aim at a favorable balance between effector T cell depletion and regulatory T cell preservation have shown the most promising results. Teplizumab, an anti-CD3-directed monoclonal antibody, was the first immunomodulatory agent to demonstrate a significant delay in disease progression in high-risk individuals before clinical onset (102) and has recently (November 17, 2022) been approved by the FDA as the first disease-modifying therapy for DM1 in adults and in children aged 8 years and older.

The Enigma of Pancreatic α-Cell Resistance in Diabetes Mellitus Type 1

Although both insulin-producing β-cells and glucagon-producing α-cells of the pancreatic islets share a similar embryonic origin and are directly exposed to the deleterious immune signals in DM1, it appears that the immune system selectively destroys β-cells, while α-cells survive even in long-term DM1 (103). α-Cells are located in close proximity to β-cells in human pancreatic islets (104), creating a closed communication loop that regulates their function and secretory capacity (105). Dysfunction of α-cells plays a significant role in the pathogenesis of both types of diabetes (106). It has long been proposed that the reduced functional β-cell mass in DM1 and the consequent hypoglycemia were the key mechanisms indirectly inducing dysfunction of α-cells in diabetes (107). Advanced molecular technology of the last decade has, however, challenged this notion, showing that dysfunction of α-cells in diabetes is not secondary to β-cell pathology but is instead directly immune-induced (108-110). Despite this dysfunction, α-cells exhibit a remarkable autoimmune resistance that enables them to survive over β-cells in long-standing diabetes (103,111). Recent studies using single-cell RNA sequencing (109,112) have demonstrated important differences between these two cell types in terms of expression of: i) anti-apoptotic genes, ii) endoplasmic reticulum (ER) stress-related genes, III) innate immune response genes, and iv) antiviral response genes, all of which render α-cells less immunogenic and more resistant to viral infections and ER stress (113). In addition, CD8+ T cells invading the islets in DM1 are reactive to preproinsulin but not to glucagon. Furthermore, although β-cells are essential to life (neither humans nor animal models can survive without them), mice with 98% α-cell ablation retain near-normal glucose homeostasis (114): this points to the knowledge gap we have, from an evolutionary point of view, regarding the question of why β-cells are more fragile than α-cells. Certainly, greater understanding of the underlying mechanisms responsible for the autoimmune resistance of α-cells is critical since it is likely to reveal intracellular pathways amenable to therapeutic interventions that would increase the resistance of the β-cells themselves to the immune attack of the host’s immune system.

Diabetes Type 2

DM2 accounts for 90% of cases of diabetes worldwide (115). The increasing prevalence of DM2 around the world has been largely attributed to an unhealthy lifestyle and resultant development of obesity and overweight (116). Obesity is strongly related to DM2 mainly through inducing insulin resistance in the insulin sensitive tissues in the periphery.

The concept that a smoldering inflammatory process plays an important part in the pathogenesis of DM2 (117) has attracted much attention and is supported by evidence of inflammation in islets, adipose tissue, liver, and muscle that can provoke insulin resistance and β-cell dysfunction (118-120). Adipose tissue is characterized by infiltration by macrophages and other immune cells that produce cytokines and chemokines and contribute to the development of local and systemic chronic low-grade inflammation, this inflammatory milieu being the link between obesity, insulin resistance, and diabetes mellitus (121,122).

Earlier in vivo studies demonstrated that levels of TNF-α (123-125), IL-6, C-reactive protein, plasminogen activator inhibitor, and other inflammation mediators were elevated in adipose tissue and plasma of obese mice (126,127). It was also observed that these inflammatory mediators, together with saturated free fatty acids and reactive oxygen species (ROS), inhibited serine phosphorylation of the insulin receptor substrates (IRS-1 and 2) (128-130) in insulin sensitive tissues, such as adipose tissue and the liver (131), promoting insulin resistance (Figure 6). TNF-α is associated with increased release of free fatty acids by adipose tissue and leads to impaired insulin secretion and signaling (123,132).

Figure 6.

Insulin resistance and inflammation in diabetes type 2. Insulin binds to insulin receptor (IR) in insulin sensitive tissues, and autophosphorylates tyrosine molecules of IRS-1 and -2 substrates. In the presence of obesity, and hyperlipidemia, the influx of free fatty acids, inflammatory cytokines and glucose activates IKKβ and JNK, which are the mediators for stress and inflammatory. In turn IKKβ and JNK inhibit tyrosine phosphorylation of IRS1 and 2 and promote transcriptional activation of genes related to inflammatory and stress responses resulting in insulin resistance. [Modified by Berbudi et al (133)]. IRS 1 -2, insulin receptor substrates; ER, Endoplasmic reticulum; IKKβ, inhibitory kappa B kinase β; JNK1 and c-Jun N-terminal kinase I.

In line with these early in vivo studies, studies in humans have shown that elevated levels of i) nonspecific indicators of inflammation, such as white cell count, fibrinogen, and CRP levels (134-136), ii) markers of reduced fibrinolysis, such as plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (tPA), iii) von Willebrand factor (vWf), which is a marker of endothelial injury, and iv) early markers of inflammation, such as monocyte chemotactic protein-1 (MCP-1), IL-8, and interferon-γ-inducible protein-10 (137), were predictive of DM2 development.

Furthermore, CRP and/or IL-6 were associated with the incidence of DM2 independently of adiposity or insulin resistance (136,138,139). Visceral adipose tissue appears to be a major source of circulating IL-6 in humans, and obese people with insulin resistance display high levels of plasma IL-6 concentration, also predictive of DM2 development (113). TNF-α is also increased in obese individuals with insulin resistance (124,140) and it plays a major role in the pathogenesis of obesity-linked DM2 (141).

At the cellular level, chronic exposure of adipocytes to low doses of TNF-α led to a dramatic decrease in insulin-stimulated auto-phosphorylation of the IRS 1-2 (142). Treatment of cultured murine adipocytes with TNF-α induced serine phosphorylation of IRS-1 and convert IRS-1 into an inhibitor of IR tyrosine kinase activity in vitro. TNF-α has also been shown to downregulate glucose transporter GLUT4 mRNA levels in adipocyte and myocyte cultures as well (125,143,144).

Oxidative stress, as a result of increased cytokine levels in DM2, is also thought to play an important role in activating inflammatory genes (145,146) (Figure 6). It is possible that oxidative stress markers do not adequately reflect the impact of increased ROS on β-cells or insulin signaling, while inflammatory, procoagulant or endothelial dysfunction markers are more specific to the pathophysiology of hyperglycemia (145,146). Hasnain et al. showed that islet-endogenous and exogenous IL-22 suppressed oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human β-cells by regulating oxidative stress pathways. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced β-cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin, and fully restored glucose homeostasis, followed by reinstitution of insulin sensitivity (147).

The chemokine system is also associated with obesity and insulin resistance. MCP-1, which acts on monocytes, macrophages, T cells and NK cells, is increased in obese compared to lean subjects and is related to non-alcoholic fatty liver disease and other lipid overload states (148-153). A short-term program of 4-month lifestyle modification significantly decreases MCP-1 levels, with favorable effects on the glycemic and lipid profile (151).

Collectively, these findings supported the investigation of new therapeutic approaches that target inflammation to ameliorate diabetes and its complications. Regarding the latter, it is important to note that multiple sources of evidence support a pathogenic connection between rheumatoid arthritis (RA) and the mechanisms of DM2, via formation of a vicious circle that is perpetuated by impaired glucose metabolism and inflammation. In this context, ongoing clinical studies have shown that the inhibition of interleukin IL-1 and IL-6 may allow the treatment of RA and concomitant T2D at the same time (154).

Treatment with anakinra, a recombinant form of human IL-1 receptor antagonist that works as a competitive inhibitor of IL-1β, achieved significant improvements of glycemia and secretory function of β-cells (155,156), which was maintained after anakinra withdrawal during a 39-week follow-up (157). Canakinumab, a monoclonal antibody against IL-1β, significantly reduced inflammatory proteins, such as CRP, IL-6, and fibrinogen, in patients with DM2 and high cardiovascular risk (158,159), while regarding glycemic control, it reduced values of HbA1c during the first 6–9 months of treatment, without, however, consistent long-term benefits (159). Antagonists of IL-6 receptor tocilizumab and sarilumab have also been investigated in patients with RA with or without concomitant DM2. Tocilizumab showed a positive effect on insulin resistance in some studies (160-162), while other studies failed to report any beneficial effect on glycemic control (163,164). The efficacy of sarilumab was assessed in a post hoc analysis (165) of three randomized clinical trials in patients with RA with or without DM2 (166-168). Sarilumab, as monotherapy or in combination, significantly reduced HbA1c compared to adalimumab monotherapy or placebo plus methotrexate/convectional DMARDs in patients with RA and DM2 (165).

Several studies have analyzed the effects of TNF inhibitors (i.e., adalimumab, etanercept, and infliximab) on glucose metabolism, demonstrating a potential favorable effect on insulin resistance and insulin sensitivity (169,170). In a meta-analysis combining data from 22 randomized controlled trials and three cohort studies (171), new-onset DM2 was delayed in RA patients treated with TNF inhibitors.

OSTEOPOROSIS AND THE IMMUNE SYSTEM

Osteoporosis is a clinical condition characterized by low bone mass and impaired bone microarchitecture associated with an increased risk of fragility fractures. Growing evidence of the last few decades has demonstrated the effect of the immune system on bone metabolism, leading to the emergence of the new field of osteoimmunology (182-185) and immunology of osteoporosis (named as immunoporosis) (184-188).

States of immune dysfunction such as immunodeficiency, inflammatory diseases, or immune response to infections are associated with increased osteoclastic bone resorption and, therefore, increased bone loss and increased fracture risk.

EFFECTS OF THE IMMUNE SYSTEM ON THE STRESS SYSTEM

ACKNOWLEDGEMENTS

This chapter is an update of a previous chapter and the authors would like to thank Professor Gregory Kaltsas, an author of the prior chapter.

REFERENCES

1.

Poland GA, Quill H, Togias A. Understanding the human immune system in the 21st century: the Human Immunology Project Consortium. Vaccine. 2013;31(28):2911-2912. [PubMed: 23648045]

2.

Li Q, Wang B, Mu K, Zhang JA. The pathogenesis of thyroid autoimmune diseases: New T lymphocytes - Cytokines circuits beyond the Th1-Th2 paradigm. J Cell Physiol. 2019;234(3):2204-2216. [PubMed: 30246383]

3.

Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21(2):137-148. [PubMed: 15308095]

4.

McLachlan SM, Rapoport B. Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity. Endocr Rev. 2014;35(1):59-105. [PMC free article: PMC3895862] [PubMed: 24091783]

5.

Colaci M, Malatino L, Antonelli A, Fallahi P, Giuggioli D, Ferri C. Endocrine disorders associated with hepatitis C virus chronic infection. Rev Endocr Metab Disord. 2018;19(4):397-403. [PubMed: 30499080]

6.

Wang B, Shao X, Song R, Xu D, Zhang JA. The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases. Front Immunol. 2017;8:396. [PMC free article: PMC5383710] [PubMed: 28439272]

7.

Boguslawska J, Godlewska M, Gajda E, Piekielko-Witkowska A. Cellular and molecular basis of thyroid autoimmunity. Eur Thyroid J. 2022;11(1). [PMC free article: PMC9142813] [PubMed: 34981746]

8.

Coscia F, Taler-Vercic A, Chang VT, Sinn L, O'Reilly FJ, Izore T, Renko M, Berger I, Rappsilber J, Turk D, Lowe J. The structure of human thyroglobulin. Nature. 2020;578(7796):627-630. [PMC free article: PMC7170718] [PubMed: 32025030]

9.

McLachlan SM, Rapoport B. Thyroid Autoantibodies Display both "Original Antigenic Sin" and Epitope Spreading. Front Immunol. 2017;8:1845. [PMC free article: PMC5742354] [PubMed: 29326719]

10.

Godlewska M, Banga PJ. Thyroid peroxidase as a dual active site enzyme: Focus on biosynthesis, hormonogenesis and thyroid disorders of autoimmunity and cancer. Biochimie. 2019;160:34-45. [PubMed: 30742860]

11.

Godlewska M, Gawel D, Buckle AM, Banga JP. Thyroid Peroxidase Revisited - What's New? Horm Metab Res. 2019;51(12):765-769. [PubMed: 31826271]

12.

Jaume JC, Burek CL, Hoffman WH, Rose NR, McLachlan SM, Rapoport B. Thyroid peroxidase autoantibody epitopic 'fingerprints' in juvenile Hashimoto's thyroiditis: evidence for conservation over time and in families. Clin Exp Immunol. 1996;104(1):115-123. [PMC free article: PMC2200393] [PubMed: 8603516]

13.

Morshed SA, Ando T, Latif R, Davies TF. Neutral antibodies to the TSH receptor are present in Graves disease and regulate selective signaling cascades. Endocrinology. 2010;151(11):5537-5549. [PMC free article: PMC2954721] [PubMed: 20844004]

14.

Sanders J, Miguel RN, Bolton J, Bhardwaja A, Sanders P, Nakatake N, Evans M, Furmaniak J, Smith BR. Molecular interactions between the TSH receptor and a Thyroid-stimulating monoclonal autoantibody. Thyroid. 2007;17(8):699-706. [PubMed: 17725428]

15.

Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, Evans M, Clark J, Wilmot J, Hu X, Roberts E, Powell M, Nunez Miguel R, Furmaniak J, Rees Smith B. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol. 2011;46(2):81-99. [PubMed: 21247981]

16.

Eleftheriadou AM, Mehl S, Renko K, Kasim RH, Schaefer JA, Minich WB, Schomburg L. Re-visiting autoimmunity to sodium-iodide symporter and pendrin in thyroid disease. Eur J Endocrinol. 2020;183(6):571-580. [PubMed: 33055303]

17.

Fallahi P, Ferrari SM, Ragusa F, Ruffilli I, Elia G, Paparo SR, Antonelli A. Th1 Chemokines in Autoimmune Endocrine Disorders. J Clin Endocrinol Metab. 2020;105(4). [PubMed: 31863667]

18.

Meeusen EN, Premier RR, Brandon MR. Tissue-specific migration of lymphocytes: a key role for Th1 and Th2 cells? Immunol Today. 1996;17(9):421-424. [PubMed: 8854560]

19.

Davies TF, Andersen S, Latif R, Nagayama Y, Barbesino G, Brito M, Eckstein AK, Stagnaro-Green A, Kahaly GJ. Graves disease. Nat Rev Dis Primers. 2020;6(1):52. [PubMed: 32616746]

20.

Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves ophthalmopathy. Lancet Diabetes Endocrinol. 2017;5(2):134-142. [PubMed: 27346786]

21.

Neumann S, Krieger CC, Gershengorn MC. Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease. Eur Thyroid J. 2020;9(Suppl 1):59-65. [PMC free article: PMC7802449] [PubMed: 33511086]

22.

Taheri M, Eghtedarian R, Dinger ME, Ghafouri-Fard S. Dysregulation of non-coding RNAs in autoimmune thyroid disease. Exp Mol Pathol. 2020;117:104527. [PubMed: 32916160]

23.

Liu Y, Cui X, Wang S, Liu J, Zhao N, Huang M, Qin J, Li Y, Shan Z, Teng W. Elevated MicroRNA-326 Levels Regulate the IL-23/IL-23R/Th17 Cell Axis in Hashimoto's Thyroiditis by Targeting a Disintegrin and Metalloprotease 17. Thyroid. 2020;30(9):1327-1337. [PubMed: 32204685]

24.

Zheng L, Zhuang C, Wang X, Ming L. Serum miR-146a, miR-155, and miR-210 as potential markers of Graves disease. J Clin Lab Anal. 2018;32(2). [PMC free article: PMC6817012] [PubMed: 28569050]

25.

Jiang X, Wang Y, Li X, He L, Yang Q, Wang W, Liu J, Zha B. Microarray profile of B cells from Graves disease patients reveals biomarkers of proliferation. Endocr Connect. 2020;9(5):405-417. [PMC free article: PMC7274554] [PubMed: 32432440]

26.

Xiong S, Peng H, Ding X, Wang X, Wang L, Wu C, Wang S, Xu H, Liu Y. Circular RNA Expression Profiling and the Potential Role of hsa_circ_0089172 in Hashimoto's Thyroiditis via Sponging miR125a-3p. Mol Ther Nucleic Acids. 2019;17:38-48. [PMC free article: PMC6579753] [PubMed: 31207490]

27.

Talebi S, Karimifar M, Heidari Z, Mohammadi H, Askari G. The effects of synbiotic supplementation on thyroid function and inflammation in hypothyroid patients: A randomized, double‑blind, placebo‑controlled trial. Complement Ther Med. 2020;48:102234. [PubMed: 31987229]

28.

Biscarini F, Masetti G, Muller I, Verhasselt HL, Covelli D, Colucci G, Zhang L, Draman MS, Okosieme O, Taylor P, Daumerie C, Burlacu MC, Marino M, Ezra DG, Perros P, Plummer S, Eckstein A, Salvi M, Marchesi JR, Ludgate M. Gut Microbiome Associated With Graves Disease and Graves Orbitopathy: The INDIGO Multicenter European Study. J Clin Endocrinol Metab. 2023;108(8):2065-2077. [PMC free article: PMC10807910] [PubMed: 36683389]

29.

Olivieri A, De Angelis S, Vaccari V, Valensise H, Magnani F, Stazi MA, Cotichini R, Gilardi E, Cordeddu V, Sorcini M, Boirivant M. Postpartum thyroiditis is associated with fluctuations in transforming growth factor-beta1 serum levels. J Clin Endocrinol Metab. 2003;88(3):1280-1284. [PubMed: 12629119]

30.

Weetman AP, Bennett GL, Wong WL. Thyroid follicular cells produce interleukin-8. J Clin Endocrinol Metab. 1992;75(1):328-330. [PubMed: 1619027]

31.

Premawardhana LD, Parkes AB, Ammari F, John R, Darke C, Adams H, Lazarus JH. Postpartum thyroiditis and long-term thyroid status: prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab. 2000;85(1):71-75. [PubMed: 10634366]

32.

Papanicolaou DA. Euthyroid Sick Syndrome and the role of cytokines. Rev Endocr Metab Disord. 2000;1(1-2):43-48. [PubMed: 11704991]

33.

Simons PJ, Delemarre FG, Drexhage HA. Antigen-presenting dendritic cells as regulators of the growth of thyrocytes: a role of interleukin-1beta and interleukin-6. Endocrinology. 1998;139(7):3148-3156. [PubMed: 9645688]

34.

Asakawa H, Hanafusa T, Kobayashi T, Takai S, Kono N, Tarui S. Interferon-gamma reduces the thyroid peroxidase content of cultured human thyrocytes and inhibits its increase induced by thyrotropin. J Clin Endocrinol Metab. 1992;74(6):1331-1335. [PubMed: 1592878]

35.

Ashizawa K, Yamashita S, Nagayama Y, Kimura H, Hirayu H, Izumi M, Nagataki S. Interferon-gamma inhibits thyrotropin-induced thyroidal peroxidase gene expression in cultured human thyrocytes. J Clin Endocrinol Metab. 1989;69(2):475-477. [PubMed: 2546966]

36.

Poth M, Tseng YC, Wartofsky L. Inhibition of TSH activation of human cultured thyroid cells by tumor necrosis factor: an explanation for decreased thyroid function in systemic illness? Thyroid. 1991;1(3):235-240. [PubMed: 1668616]

37.

Yamashita S, Kimura H, Ashizawa K, Nagayama Y, Hirayu H, Izumi M, Nagataki S. Interleukin-1 inhibits thyrotrophin-induced human thyroglobulin gene expression. J Endocrinol. 1989;122(1):177-183. [PubMed: 2788696]

38.

van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab. 1990;71(6):1567-1572. [PubMed: 2229314]

39.

Chopra IJ, Sakane S, Teco GN. A study of the serum concentration of tumor necrosis factor-alpha in thyroidal and nonthyroidal illnesses. J Clin Endocrinol Metab. 1991;72(5):1113-1116. [PubMed: 2022711]

40.

Girvent M, Maestro S, Hernandez R, Carajol I, Monne J, Sancho JJ, Gubern JM, Sitges-Serra A. Euthyroid sick syndrome, associated endocrine abnormalities, and outcome in elderly patients undergoing emergency operation. Surgery. 1998;123(5):560-567. [PubMed: 9591009]

41.

Davis PJ. Cytokines and growth factors and thyroid hormone. Curr Opin Endocrinol Diabetes Obes. 2008;15(5):428. [PubMed: 18769214]

42.

Baur A, Bauer K, Jarry H, Kohrle J. Effects of proinflammatory cytokines on anterior pituitary 5'-deiodinase type I and type II. J Endocrinol. 2000;167(3):505-515. [PubMed: 11115778]

43.

Calikoglu M, Sahin G, Unlu A, Ozturk C, Tamer L, Ercan B, Kanik A, Atik U. Leptin and TNF-alpha levels in patients with chronic obstructive pulmonary disease and their relationship to nutritional parameters. Respiration. 2004;71(1):45-50. [PubMed: 14872110]

44.

Park MC, Lee SW, Choi ST, Park YB, Lee SK. Serum leptin levels correlate with interleukin-6 levels and disease activity in patients with ankylosing spondylitis. Scand J Rheumatol. 2007;36(2):101-106. [PubMed: 17476615]

45.

Lechan RM, Fekete C. Feedback regulation of thyrotropin-releasing hormone (TRH): mechanisms for the non-thyroidal illness syndrome. J Endocrinol Invest. 2004;27(6 Suppl):105-119. [PubMed: 15481810]

46.

Harris M, Aschkenasi C, Elias CF, Chandrankunnel A, Nillni EA, Bjoorbaek C, Elmquist JK, Flier JS, Hollenberg AN. Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. J Clin Invest. 2001;107(1):111-120. [PMC free article: PMC198547] [PubMed: 11134186]

47.

Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med. 1997;126(1):63-73. [PubMed: 8992925]

48.

Cohen-Lehman J, Dahl P, Danzi S, Klein I. Effects of amiodarone therapy on thyroid function. Nat Rev Endocrinol. 2010;6(1):34-41. [PubMed: 19935743]

49.

Goundan PN, Lee SL. Thyroid effects of amiodarone: clinical update. Curr Opin Endocrinol Diabetes Obes. 2020;27(5):329-334. [PubMed: 32773570]

50.

Newman CM, Price A, Davies DW, Gray TA, Weetman AP. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart. 1998;79(2):121-127. [PMC free article: PMC1728611] [PubMed: 9538302]

51.

Narayana SK, Woods DR, Boos CJ. Management of amiodarone-related thyroid problems. Ther Adv Endocrinol Metab. 2011;2(3):115-126. [PMC free article: PMC3474631] [PubMed: 23148177]

52.

Loh KC. Amiodarone-induced thyroid disorders: a clinical review. Postgrad Med J. 2000;76(893):133-140. [PMC free article: PMC1741517] [PubMed: 10684321]

53.

Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amiodarone on the thyroid. Endocr Rev. 2001;22(2):240-254. [PubMed: 11294826]

54.

Bartalena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab. 1996;81(8):2930-2933. [PubMed: 8768854]

55.

Mosher MC. Amiodarone-induced hypothyroidism and other adverse effects. Dimens Crit Care Nurs. 2011;30(2):87-93. [PubMed: 21307683]

56.

Piga M, Serra A, Boi F, Tanda ML, Martino E, Mariotti S. Amiodarone-induced thyrotoxicosis. A review. Minerva Endocrinol. 2008;33(3):213-228. [PubMed: 18846027]

57.

Kent WD, Hall SF, Isotalo PA, Houlden RL, George RL, Groome PA. Increased incidence of differentiated thyroid carcinoma and detection of subclinical disease. CMAJ. 2007;177(11):1357-1361. [PMC free article: PMC2072986] [PubMed: 18025426]

58.

Cunha LL, Marcello MA, Ward LS. The role of the inflammatory microenvironment in thyroid carcinogenesis. Endocr Relat Cancer. 2014;21(3):R85-R103. [PubMed: 24302667]

59.

Zeng R, Lyu Y, Zhang G, Shou T, Wang K, Niu H, Yan X. Positive effect of RORgammat on the prognosis of thyroid papillary carcinoma patients combined with Hashimoto's thyroiditis. Am J Transl Res. 2018;10(10):3011-3024. [PMC free article: PMC6220227] [PubMed: 30416647]

60.

Kim EY, Kim WG, Kim WB, Kim TY, Kim JM, Ryu JS, Hong SJ, Gong G, Shong YK. Coexistence of chronic lymphocytic thyroiditis is associated with lower recurrence rates in patients with papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2009;71(4):581-586. [PubMed: 19222495]

61.

Zivancevic-Simonovic S, Mihaljevic O, Majstorovic I, Popovic S, Markovic S, Milosevic-Djordjevic O, Jovanovic Z, Mijatovic-Teodorovic L, Mihajlovic D, Colic M. Cytokine production in patients with papillary thyroid cancer and associated autoimmune Hashimoto thyroiditis. Cancer Immunol Immunother. 2015;64(8):1011-1019. [PMC free article: PMC11029755] [PubMed: 25971541]

62.

Veit F, Graf D, Momberger S, Helmich-Kapp B, Ruschenburg I, Peters A, Kussmann J, Saeger W, Schmidt KW, Toetsch M, Nestler K, Mann K. Papillary Thyroid Cancer and Coexisting Autoimmune Thyroiditis. Horm Metab Res. 2017;49(11):869-872. [PubMed: 29136676]

63.

Chowdhury S, Veyhl J, Jessa F, Polyakova O, Alenzi A, MacMillan C, Ralhan R, Walfish PG. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget. 2016;7(22):32318-32328. [PMC free article: PMC5078015] [PubMed: 27086918]

64.

Dias Lopes NM, Mendonca Lens HH, Armani A, Marinello PC, Cecchini AL. Thyroid cancer and thyroid autoimmune disease: A review of molecular aspects and clinical outcomes. Pathol Res Pract. 2020;216(9):153098. [PubMed: 32825964]

65.

Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20(11):651-668. [PMC free article: PMC7238960] [PubMed: 32433532]

66.

Na KJ, Choi H. Immune landscape of papillary thyroid cancer and immunotherapeutic implications. Endocr Relat Cancer. 2018;25(5):523-531. [PubMed: 29507047]

67.

Ryder M, Ghossein RA, Ricarte-Filho JC, Knauf JA, Fagin JA. Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer. 2008;15(4):1069-1074. [PMC free article: PMC2648614] [PubMed: 18719091]

68.

French JD, Kotnis GR, Said S, Raeburn CD, McIntyre RC, Jr., Klopper JP, Haugen BR. Programmed death-1+ T cells and regulatory T cells are enriched in tumor-involved lymph nodes and associated with aggressive features in papillary thyroid cancer. J Clin Endocrinol Metab. 2012;97(6):E934-943. [PMC free article: PMC3387418] [PubMed: 22466343]

69.

Gogali F, Paterakis G, Rassidakis GZ, Kaltsas G, Liakou CI, Gousis P, Neonakis E, Manoussakis MN, Liapi C. Phenotypical analysis of lymphocytes with suppressive and regulatory properties (Tregs) and NK cells in the papillary carcinoma of thyroid. J Clin Endocrinol Metab. 2012;97(5):1474-1482. [PubMed: 22399513]

70.

Garcia-Alvarez A, Hernando J, Carmona-Alonso A, Capdevila J. What is the status of immunotherapy in thyroid neoplasms? Front Endocrinol (Lausanne). 2022;13:929091. [PMC free article: PMC9389039] [PubMed: 35992118]

71.

Mould RC, van Vloten JP, AuYeung AWK, Karimi K, Bridle BW. Immune responses in the thyroid cancer microenvironment: making immunotherapy a possible mission. Endocr Relat Cancer. 2017;24(12):T311-T329. [PubMed: 28912377]

72.

Pan J, Ye F, Yu C, Zhu Q, Li J, Zhang Y, Tian H, Yao Y, Zhu M, Shen Y, Zhu F, Wang Y, Zhou X, Guo G, Wu Y. Papillary Thyroid Carcinoma Landscape and Its Immunological Link With Hashimoto Thyroiditis at Single-Cell Resolution. Front Cell Dev Biol. 2021;9:758339. [PMC free article: PMC8602800] [PubMed: 34805166]

73.

Galdiero MR, Varricchi G, Marone G. The immune network in thyroid cancer. Oncoimmunology. 2016;5(6):e1168556. [PMC free article: PMC4938375] [PubMed: 27471646]

74.

Ahn S, Kim TH, Kim SW, Ki CS, Jang HW, Kim JS, Kim JH, Choe JH, Shin JH, Hahn SY, Oh YL, Chung JH. Comprehensive screening for PD-L1 expression in thyroid cancer. Endocr Relat Cancer. 2017;24(2):97-106. [PubMed: 28093480]

75.

Cameselle-Garcia S, Abdulkader-Sande S, Sanchez-Ares M, Rodriguez-Carnero G, Garcia-Gomez J, Gude-Sampedro F, Abdulkader-Nallib I, Cameselle-Teijeiro JM. PD-L1 expression and immune cells in anaplastic carcinoma and poorly differentiated carcinoma of the human thyroid gland: A retrospective study. Oncol Lett. 2021;22(1):553. [PMC free article: PMC8170268] [PubMed: 34093774]

76.

Cantara S, Bertelli E, Occhini R, Regoli M, Brilli L, Pacini F, Castagna MG, Toti P. Blockade of the programmed death ligand 1 (PD-L1) as potential therapy for anaplastic thyroid cancer. Endocrine. 2019;64(1):122-129. [PubMed: 30762153]

77.

Chintakuntlawar AV, Rumilla KM, Smith CY, Jenkins SM, Foote RL, Kasperbauer JL, Morris JC, Ryder M, Alsidawi S, Hilger C, Bible KC. Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study. J Clin Endocrinol Metab. 2017;102(6):1943-1950. [PubMed: 28324060]

78.

Zwaenepoel K, Jacobs J, De Meulenaere A, Silence K, Smits E, Siozopoulou V, Hauben E, Rolfo C, Rottey S, Pauwels P. CD70 and PD-L1 in anaplastic thyroid cancer - promising targets for immunotherapy. Histopathology. 2017;71(3):357-365. [PubMed: 28383817]

79.

Wu H, Sun Y, Ye H, Yang S, Lee SL, de las Morenas A. Anaplastic thyroid cancer: outcome and the mutation/expression profiles of potential targets. Pathol Oncol Res. 2015;21(3):695-701. [PubMed: 25588542]

80.

Strickler JH, Hanks BA, Khasraw M. Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better? Clin Cancer Res. 2021;27(5):1236-1241. [PMC free article: PMC9912042] [PubMed: 33199494]

81.

Mehnert JM, Varga A, Brose MS, Aggarwal RR, Lin CC, Prawira A, de Braud F, Tamura K, Doi T, Piha-Paul SA, Gilbert J, Saraf S, Thanigaimani P, Cheng JD, Keam B. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced, PD-L1-positive papillary or follicular thyroid cancer. BMC Cancer. 2019;19(1):196. [PMC free article: PMC6399859] [PubMed: 30832606]

82.

Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464(7293):1293-1300. [PMC free article: PMC4959889] [PubMed: 20432533]

83.

Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P, Mychaleckyj JC, Todd JA, Bonella P, Fear AL, Lavant E, Louey A, Moonsamy P, Type 1 Diabetes Genetics C. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008;57(4):1084-1092. [PMC free article: PMC4103420] [PubMed: 18252895]

84.

Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol. 2009;155(2):173-181. [PMC free article: PMC2675247] [PubMed: 19128359]

85.

Vandamme C, Kinnunen T. B cell helper T cells and type 1 diabetes. Scand J Immunol. 2020;92(4):e12943. [PMC free article: PMC7583378] [PubMed: 32697399]

86.

Pugliese A. Insulitis in the pathogenesis of type 1 diabetes. Pediatr Diabetes. 2016;17 Suppl 22(Suppl Suppl 22):31-36. [PMC free article: PMC4948864] [PubMed: 27411434]

87.

Mitchell AM, Michels AW. Self-Antigens Targeted by Regulatory T Cells in Type 1 Diabetes. Int J Mol Sci. 2022;23(6). [PMC free article: PMC8954990] [PubMed: 35328581]

88.

Atkinson MA, Bowman MA, Campbell L, Darrow BL, Kaufman DL, Maclaren NK. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J Clin Invest. 1994;94(5):2125-2129. [PMC free article: PMC294659] [PubMed: 7962558]

89.

Tough DF, Borrow P, Sprent J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science. 1996;272(5270):1947-1950. [PubMed: 8658169]

90.

Katz JD, Benoist C, Mathis D. T helper cell subsets in insulin-dependent diabetes. Science. 1995;268(5214):1185-1188. [PubMed: 7761837]

91.

Han S, Donelan W, Wang H, Reeves W, Yang LJ. Novel autoantigens in type 1 diabetes. Am J Transl Res. 2013;5(4):379-392. [PMC free article: PMC3665912] [PubMed: 23724162]

92.

Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity. 2010;32(4):468-478. [PMC free article: PMC2861716] [PubMed: 20412757]

93.

Burton AR, Vincent E, Arnold PY, Lennon GP, Smeltzer M, Li CS, Haskins K, Hutton J, Tisch RM, Sercarz EE, Santamaria P, Workman CJ, Vignali DA. On the pathogenicity of autoantigen-specific T-cell receptors. Diabetes. 2008;57(5):1321-1330. [PubMed: 18299317]

94.

Serreze DV, Fleming SA, Chapman HD, Richard SD, Leiter EH, Tisch RM. B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Immunol. 1998;161(8):3912-3918. [PubMed: 9780157]

95.

Sutherland AP, Van Belle T, Wurster AL, Suto A, Michaud M, Zhang D, Grusby MJ, von Herrath M. Interleukin-21 is required for the development of type 1 diabetes in NOD mice. Diabetes. 2009;58(5):1144-1155. [PMC free article: PMC2671036] [PubMed: 19208913]

96.

Lechleitner M, Koch T, Herold M, Hoppichler F. Relationship of tumor necrosis factor-alpha plasma levels to metabolic control in type 1 diabetes. Diabetes Care. 1999;22(10):1749. [PubMed: 10526750]

97.

Farhan J, Al-Shobaili HA, Zafar U, Al Salloom A, Meki AR, Rasheed Z. Interleukin-6: a possible inflammatory link between vitiligo and type 1 diabetes. Br J Biomed Sci. 2014;71(4):151-157. [PubMed: 25562992]

98.

Zhang J, Huang Z, Sun R, Tian Z, Wei H. IFN-gamma induced by IL-12 administration prevents diabetes by inhibiting pathogenic IL-17 production in NOD mice. J Autoimmun. 2012;38(1):20-28. [PubMed: 22186068]

99.

Arif S, Moore F, Marks K, Bouckenooghe T, Dayan CM, Planas R, Vives-Pi M, Powrie J, Tree T, Marchetti P, Huang GC, Gurzov EN, Pujol-Borrell R, Eizirik DL, Peakman M. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated beta-cell death. Diabetes. 2011;60(8):2112-2119. [PMC free article: PMC3142078] [PubMed: 21659501]

100.

Jacobsen LM, Newby BN, Perry DJ, Posgai AL, Haller MJ, Brusko TM. Immune Mechanisms and Pathways Targeted in Type 1 Diabetes. Curr Diab Rep. 2018;18(10):90. [PMC free article: PMC8053389] [PubMed: 30168021]

101.

Smigoc Schweiger D. Recent Advances in Immune-based Therapies for Type 1 Diabetes. Horm Res Paediatr. 2022. [PubMed: 35533645]

102.

An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2020;382(6):586. [PubMed: 32023396]

103.

Eizirik DL, Szymczak F, Mallone R. Why does the immune system destroy pancreatic beta-cells but not alpha-cells in type 1 diabetes? Nat Rev Endocrinol. 2023;19(7):425-434. [PubMed: 37072614]

104.

Bosco D, Armanet M, Morel P, Niclauss N, Sgroi A, Muller YD, Giovannoni L, Parnaud G, Berney T. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes. 2010;59(5):1202-1210. [PMC free article: PMC2857900] [PubMed: 20185817]

105.

Campbell JE, Newgard CB. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat Rev Mol Cell Biol. 2021;22(2):142-158. [PMC free article: PMC8115730] [PubMed: 33398164]

106.

Gromada J, Chabosseau P, Rutter GA. The alpha-cell in diabetes mellitus. Nat Rev Endocrinol. 2018;14(12):694-704. [PubMed: 30310153]

107.

Brissova M, Haliyur R, Saunders D, Shrestha S, Dai C, Blodgett DM, Bottino R, Campbell-Thompson M, Aramandla R, Poffenberger G, Lindner J, Pan FC, von Herrath MG, Greiner DL, Shultz LD, Sanyoura M, Philipson LH, Atkinson M, Harlan DM, Levy SE, Prasad N, Stein R, Powers AC. alpha Cell Function and Gene Expression Are Compromised in Type 1 Diabetes. Cell Rep. 2018;22(10):2667-2676. [PMC free article: PMC6368357] [PubMed: 29514095]

108.

Shapira SN, Naji A, Atkinson MA, Powers AC, Kaestner KH. Understanding islet dysfunction in type 2 diabetes through multidimensional pancreatic phenotyping: The Human Pancreas Analysis Program. Cell Metab. 2022;34(12):1906-1913. [PMC free article: PMC9742126] [PubMed: 36206763]

109.

Fasolino M, Schwartz GW, Patil AR, Mongia A, Golson ML, Wang YJ, Morgan A, Liu C, Schug J, Liu J, Wu M, Traum D, Kondo A, May CL, Goldman N, Wang W, Feldman M, Moore JH, Japp AS, Betts MR, Consortium H, Faryabi RB, Naji A, Kaestner KH, Vahedi G. Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes. Nat Metab. 2022;4(2):284-299. [PMC free article: PMC8938904] [PubMed: 35228745]

110.

Kaestner KH, Powers AC, Naji A, Consortium H, Atkinson MA. NIH Initiative to Improve Understanding of the Pancreas, Islet, and Autoimmunity in Type 1 Diabetes: The Human Pancreas Analysis Program (HPAP). Diabetes. 2019;68(7):1394-1402. [PMC free article: PMC6609987] [PubMed: 31127054]

111.

Doliba NM, Rozo AV, Roman J, Qin W, Traum D, Gao L, Liu J, Manduchi E, Liu C, Golson ML, Vahedi G, Naji A, Matschinsky FM, Atkinson MA, Powers AC, Brissova M, Kaestner KH, Stoffers DA, Consortium H. alpha Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody-positive individuals. J Clin Invest. 2022;132(11). [PMC free article: PMC9151702] [PubMed: 35642629]

112.

Colli ML, Ramos-Rodriguez M, Nakayasu ES, Alvelos MI, Lopes M, Hill JLE, Turatsinze JV, Coomans de Brachene A, Russell MA, Raurell-Vila H, Castela A, Juan-Mateu J, Webb-Robertson BM, Krogvold L, Dahl-Jorgensen K, Marselli L, Marchetti P, Richardson SJ, Morgan NG, Metz TO, Pasquali L, Eizirik DL. An integrated multi-omics approach identifies the landscape of interferon-alpha-mediated responses of human pancreatic beta cells. Nat Commun. 2020;11(1):2584. [PMC free article: PMC7244579] [PubMed: 32444635]

113.

Chen CW, Guan BJ, Alzahrani MR, Gao Z, Gao L, Bracey S, Wu J, Mbow CA, Jobava R, Haataja L, Zalavadia AH, Schaffer AE, Lee H, LaFramboise T, Bederman I, Arvan P, Mathews CE, Gerling IC, Kaestner KH, Tirosh B, Engin F, Hatzoglou M. Adaptation to chronic ER stress enforces pancreatic beta-cell plasticity. Nat Commun. 2022;13(1):4621. [PMC free article: PMC9360004] [PubMed: 35941159]

114.

Thorel F, Damond N, Chera S, Wiederkehr A, Thorens B, Meda P, Wollheim CB, Herrera PL. Normal glucagon signaling and beta-cell function after near-total alpha-cell ablation in adult mice. Diabetes. 2011;60(11):2872-2882. [PMC free article: PMC3198058] [PubMed: 21926270]

115.

Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4-14. [PubMed: 19896746]

116.

Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271-281. [PubMed: 29496507]

117.

Donath MY, Storling J, Berchtold LA, Billestrup N, Mandrup-Poulsen T. Cytokines and beta-cell biology: from concept to clinical translation. Endocr Rev. 2008;29(3):334-350. [PubMed: 18048762]

118.

Varma V, Yao-Borengasser A, Rasouli N, Nolen GT, Phanavanh B, Starks T, Gurley C, Simpson P, McGehee RE, Jr., Kern PA, Peterson CA. Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action. Am J Physiol Endocrinol Metab. 2009;296(6):E1300-1310. [PMC free article: PMC2692398] [PubMed: 19336660]

119.

Ehses JA, Boni-Schnetzler M, Faulenbach M, Donath MY. Macrophages, cytokines and beta-cell death in Type 2 diabetes. Biochem Soc Trans. 2008;36(Pt 3):340-342. [PubMed: 18481953]

120.

Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793-1801. [PMC free article: PMC1483173] [PubMed: 16823477]

121.

Sell H, Habich C, Eckel J. Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol. 2012;8(12):709-716. [PubMed: 22847239]

122.

Nikolajczyk BS, Jagannathan-Bogdan M, Shin H, Gyurko R. State of the union between metabolism and the immune system in type 2 diabetes. Genes Immun. 2011;12(4):239-250. [PMC free article: PMC6826342] [PubMed: 21390053]

123.

Hotamisligil GS. The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Intern Med. 1999;245(6):621-625. [PubMed: 10395191]

124.

Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95(5):2409-2415. [PMC free article: PMC295872] [PubMed: 7738205]

125.

Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87-91. [PubMed: 7678183]

126.

Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548-2556. [PubMed: 15181022]

127.

Halberg N, Wernstedt-Asterholm I, Scherer PE. The adipocyte as an endocrine cell. Endocrinol Metab Clin North Am. 2008;37(3):753-768, x-xi. [PMC free article: PMC2659415] [PubMed: 18775362]

128.

Gao Z, He Q, Peng B, Chiao PJ, Ye J. Regulation of nuclear translocation of HDAC3 by IkappaBalpha is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor gamma function. J Biol Chem. 2006;281(7):4540-4547. [PMC free article: PMC1447600] [PubMed: 16371367]

129.

Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293(5535):1673-1677. [PubMed: 11533494]

130.

Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem. 2000;275(12):9047-9054. [PubMed: 10722755]

131.

Ye J. Regulation of PPARgamma function by TNF-alpha. Biochem Biophys Res Commun. 2008;374(3):405-408. [PMC free article: PMC2596979] [PubMed: 18655773]

132.

Ruan H, Miles PD, Ladd CM, Ross K, Golub TR, Olefsky JM, Lodish HF. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes. 2002;51(11):3176-3188. [PubMed: 12401708]

133.

Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type 2 Diabetes and its Impact on the Immune System. Curr Diabetes Rev. 2020;16(5):442-449. [PMC free article: PMC7475801] [PubMed: 31657690]

134.

Duncan BB, Schmidt MI, Offenbacher S, Wu KK, Savage PJ, Heiss G. Factor VIII and other hemostasis variables are related to incident diabetes in adults. The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. 1999;22(5):767-772. [PubMed: 10332679]

135.

Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet. 1999;353(9165):1649-1652. [PubMed: 10335783]

136.

Festa A, D'Agostino R, Jr., Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2002;51(4):1131-1137. [PubMed: 11916936]

137.

Herder C, Baumert J, Thorand B, Koenig W, de Jager W, Meisinger C, Illig T, Martin S, Kolb H. Chemokines as risk factors for type 2 diabetes: results from the MONICA/KORA Augsburg study, 1984-2002. Diabetologia. 2006;49(5):921-929. [PubMed: 16532324]

138.

Lee CC, Adler AI, Sandhu MS, Sharp SJ, Forouhi NG, Erqou S, Luben R, Bingham S, Khaw KT, Wareham NJ. Association of C-reactive protein with type 2 diabetes: prospective analysis and meta-analysis. Diabetologia. 2009;52(6):1040-1047. [PubMed: 19326095]

139.

Lin JD, Chao TC, Weng HF, Lin KD. The roles of cytokines and retinoic acid in the regulation of human thyroid cancer cell growth. Cytokine. 1998;10(7):536-539. [PubMed: 9702417]

140.

Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280(5):E745-751. [PubMed: 11287357]

141.

Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, Huston-Presley L, Friedman JE, Kalhan SC, Catalano PM. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51(7):2207-2213. [PubMed: 12086951]

142.

Vilcek J, Lee TH. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem. 1991;266(12):7313-7316. [PubMed: 1850405]

143.

Cornelius P, Lee MD, Marlowe M, Pekala PH. Monokine regulation of glucose transporter mRNA in L6 myotubes. Biochem Biophys Res Commun. 1989;165(1):429-436. [PubMed: 2556143]

144.

Stephens JM, Pekala PH. Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. J Biol Chem. 1991;266(32):21839-21845. [PubMed: 1939208]

145.

Meigs JB, Larson MG, Fox CS, Keaney JF, Jr., Vasan RS, Benjamin EJ. Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: the Framingham Offspring Study. Diabetes Care. 2007;30(10):2529-2535. [PubMed: 17586736]

146.

Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab Res Rev. 2001;17(3):189-212. [PubMed: 11424232]

147.

Hasnain SZ, Borg DJ, Harcourt BE, Tong H, Sheng YH, Ng CP, Das I, Wang R, Chen AC, Loudovaris T, Kay TW, Thomas HE, Whitehead JP, Forbes JM, Prins JB, McGuckin MA. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med. 2014;20(12):1417-1426. [PubMed: 25362253]

148.

Huma ZE, Sanchez J, Lim HD, Bridgford JL, Huang C, Parker BJ, Pazhamalil JG, Porebski BT, Pfleger KDG, Lane JR, Canals M, Stone MJ. Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2. Sci Signal. 2017;10(480). [PubMed: 28536301]

149.

Catalan V, Gomez-Ambrosi J, Ramirez B, Rotellar F, Pastor C, Silva C, Rodriguez A, Gil MJ, Cienfuegos JA, Fruhbeck G. Proinflammatory cytokines in obesity: impact of type 2 diabetes mellitus and gastric bypass. Obes Surg. 2007;17(11):1464-1474. [PubMed: 18219773]

150.

Franca CN, Izar MCO, Hortencio MNS, do Amaral JB, Ferreira CES, Tuleta ID, Fonseca FAH. Monocyte subtypes and the CCR2 chemokine receptor in cardiovascular disease. Clin Sci (Lond). 2017;131(12):1215-1224. [PubMed: 28566450]

151.

Gokulakrishnan K, Ranjani H, Weber MB, Pandey GK, Anjana RM, Balasubramanyam M, Prabhakaran D, Tandon N, Narayan KM, Mohan V. Effect of lifestyle improvement program on the biomarkers of adiposity, inflammation and gut hormones in overweight/obese Asian Indians with prediabetes. Acta Diabetol. 2017;54(9):843-852. [PubMed: 28620678]

152.

Townsend SA, Newsome PN. Review article: new treatments in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2017;46(5):494-507. [PubMed: 28677333]

153.

Chistiakov DA, Melnichenko AA, Grechko AV, Myasoedova VA, Orekhov AN. Potential of anti-inflammatory agents for treatment of atherosclerosis. Exp Mol Pathol. 2018;104(2):114-124. [PubMed: 29378168]

154.

Di Muzio C, Cipriani P, Ruscitti P. Rheumatoid Arthritis Treatment Options and Type 2 Diabetes: Unravelling the Association. BioDrugs. 2022;36(6):673-685. [PMC free article: PMC9649512] [PubMed: 36322327]

155.

Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517-1526. [PubMed: 17429083]

156.

Malozowski S, Sahlroot JT. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;357(3):302-303; author reply 303. [PubMed: 17634469]

157.

Larsen CM, Faulenbach M, Vaag A, Ehses JA, Donath MY, Mandrup-Poulsen T. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care. 2009;32(9):1663-1668. [PMC free article: PMC2732140] [PubMed: 19542207]

158.

Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, Thuren T, Group CPI. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012;126(23):2739-2748. [PubMed: 23129601]

159.

Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, Glynn RJ, Libby P, Ridker PM. Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes. J Am Coll Cardiol. 2018;71(21):2392-2401. [PubMed: 29544870]

160.

Otsuka Y, Kiyohara C, Kashiwado Y, Sawabe T, Nagano S, Kimoto Y, Ayano M, Mitoma H, Akahoshi M, Arinobu Y, Niiro H, Akashi K, Horiuchi T. Effects of tumor necrosis factor inhibitors and tocilizumab on the glycosylated hemoglobin levels in patients with rheumatoid arthritis; an observational study. PLoS One. 2018;13(4):e0196368. [PMC free article: PMC5918963] [PubMed: 29694426]

161.

Ogata A, Morishima A, Hirano T, Hishitani Y, Hagihara K, Shima Y, Narazaki M, Tanaka T. Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab. Ann Rheum Dis. 2011;70(6):1164-1165. [PubMed: 20980285]

162.

Castaneda S, Remuzgo-Martinez S, Lopez-Mejias R, Genre F, Calvo-Alen J, Llorente I, Aurrecoechea E, Ortiz AM, Triguero A, Blanco R, Llorca J, Gonzalez-Gay MA. Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis. Clin Exp Rheumatol. 2019;37(3):465-473. [PubMed: 30418124]

163.

Makrilakis K, Fragiadaki K, Smith J, Sfikakis PP, Kitas GD. Interrelated reduction of chemerin and plasminogen activator inhibitor-1 serum levels in rheumatoid arthritis after interleukin-6 receptor blockade. Clin Rheumatol. 2015;34(3):419-427. [PubMed: 24912961]

164.

Tournadre A, Pereira B, Dutheil F, Giraud C, Courteix D, Sapin V, Frayssac T, Mathieu S, Malochet-Guinamand S, Soubrier M. Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritis. J Cachexia Sarcopenia Muscle. 2017;8(4):639-646. [PMC free article: PMC5566648] [PubMed: 28316139]

165.

Genovese MC, Burmester GR, Hagino O, Thangavelu K, Iglesias-Rodriguez M, John GS, Gonzalez-Gay MA, Mandrup-Poulsen T, Fleischmann R. Interleukin-6 receptor blockade or TNFalpha inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials. Arthritis Res Ther. 2020;22(1):206. [PMC free article: PMC7488252] [PubMed: 32907617]

166.

Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, Rohane P, van Hoogstraten H, Garg A, Fan C, van Adelsberg J, Weinstein SP, Graham NM, Stahl N, Yancopoulos GD, Huizinga TW, van der Heijde D. Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis Rheumatol. 2015;67(6):1424-1437. [PubMed: 25733246]

167.

Burmester GR, Lin Y, Patel R, van Adelsberg J, Mangan EK, Graham NM, van Hoogstraten H, Bauer D, Ignacio Vargas J, Lee EB. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847. [PMC free article: PMC5530335] [PubMed: 27856432]

168.

Fleischmann R, van Adelsberg J, Lin Y, Castelar-Pinheiro GD, Brzezicki J, Hrycaj P, Graham NM, van Hoogstraten H, Bauer D, Burmester GR. Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol. 2017;69(2):277-290. [PMC free article: PMC6207906] [PubMed: 27860410]

169.

Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, Garcia-Porrua C, Sanchez-Andrade A, Martin J, Llorca J. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006;24(1):83-86. [PubMed: 16539824]

170.

Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305(24):2525-2531. [PubMed: 21693740]

171.

Lin C, Ji H, Cai X, Yang W, Lv F, Ji L. The association between the biological disease-modifying anti-rheumatic drugs and the incidence of diabetes: A systematic review and meta-analysis. Pharmacol Res. 2020;161:105216. [PubMed: 33007415]

172.

Tessaro FHG, Ayala TS, Nolasco EL, Bella LM, Martins JO. Insulin Influences LPS-Induced TNF-alpha and IL-6 Release Through Distinct Pathways in Mouse Macrophages from Different Compartments. Cell Physiol Biochem. 2017;42(5):2093-2104. [PubMed: 28810254]

173.

Kumar M, Roe K, Nerurkar PV, Orillo B, Thompson KS, Verma S, Nerurkar VR. Reduced immune cell infiltration and increased pro-inflammatory mediators in the brain of Type 2 diabetic mouse model infected with West Nile virus. J Neuroinflammation. 2014;11:80. [PMC free article: PMC4001407] [PubMed: 24750819]

174.

Martinez N, Ketheesan N, Martens GW, West K, Lien E, Kornfeld H. Defects in early cell recruitment contribute to the increased susceptibility to respiratory Klebsiella pneumoniae infection in diabetic mice. Microbes Infect. 2016;18(10):649-655. [PMC free article: PMC10687709] [PubMed: 27256462]

175.

Gupta S, Maratha A, Siednienko J, Natarajan A, Gajanayake T, Hoashi S, Miggin S. Analysis of inflammatory cytokine and TLR expression levels in Type 2 Diabetes with complications. Sci Rep. 2017;7(1):7633. [PMC free article: PMC5550417] [PubMed: 28794498]

176.

Chao WC, Yen CL, Wu YH, Chen SY, Hsieh CY, Chang TC, Ou HY, Shieh CC. Increased resistin may suppress reactive oxygen species production and inflammasome activation in type 2 diabetic patients with pulmonary tuberculosis infection. Microbes Infect. 2015;17(3):195-204. [PubMed: 25528597]

177.

Stegenga ME, van der Crabben SN, Blumer RM, Levi M, Meijers JC, Serlie MJ, Tanck MW, Sauerwein HP, van der Poll T. Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia. Blood. 2008;112(1):82-89. [PMC free article: PMC2435690] [PubMed: 18316629]

178.

Joshi MB, Lad A, Bharath Prasad AS, Balakrishnan A, Ramachandra L, Satyamoorthy K. High glucose modulates IL-6 mediated immune homeostasis through impeding neutrophil extracellular trap formation. FEBS Lett. 2013;587(14):2241-2246. [PubMed: 23735697]

179.

Restrepo BI, Twahirwa M, Rahbar MH, Schlesinger LS. Phagocytosis via complement or Fc-gamma receptors is compromised in monocytes from type 2 diabetes patients with chronic hyperglycemia. PLoS One. 2014;9(3):e92977. [PMC free article: PMC3966862] [PubMed: 24671137]

180.

Berrou J, Fougeray S, Venot M, Chardiny V, Gautier JF, Dulphy N, Toubert A, Peraldi MN. Natural killer cell function, an important target for infection and tumor protection, is impaired in type 2 diabetes. PLoS One. 2013;8(4):e62418. [PMC free article: PMC3636194] [PubMed: 23638076]

181.

Mauriello CT, Hair PS, Rohn RD, Rister NS, Krishna NK, Cunnion KM. Hyperglycemia inhibits complement-mediated immunological control of S. aureus in a rat model of peritonitis. J Diabetes Res. 2014;2014:762051. [PMC free article: PMC4293792] [PubMed: 25610878]

182.

Ponzetti M, Rucci N. Updates on Osteoimmunology: What's New on the Cross-Talk Between Bone and Immune System. Front Endocrinol (Lausanne). 2019;10:236. [PMC free article: PMC6482259] [PubMed: 31057482]

183.

Huang F, Wong P, Li J, Lv Z, Xu L, Zhu G, He M, Luo Y. Osteoimmunology: The correlation between osteoclasts and the Th17/Treg balance in osteoporosis. J Cell Mol Med. 2022;26(13):3591-3597. [PMC free article: PMC9258696] [PubMed: 35633138]

184.

Srivastava RK, Dar HY, Mishra PK. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Front Immunol. 2018;9:657. [PMC free article: PMC5895643] [PubMed: 29675022]

185.

Ahmad SS, Ahmed F, Ali R, Ghoneim MM, Alshehri S, Najmi AK, Ahmad S, Ahmad MZ, Ahmad J, Khan MA. Immunology of osteoporosis: relevance of inflammatory targets for the development of novel interventions. Immunotherapy. 2022;14(10):815-831. [PubMed: 35765988]

186.

Srivastava RK, Sapra L. The Rising Era of "Immunoporosis": Role of Immune System in the Pathophysiology of Osteoporosis. J Inflamm Res. 2022;15:1667-1698. [PMC free article: PMC8906861] [PubMed: 35282271]

187.

Saxena Y, Routh S, Mukhopadhaya A. Immunoporosis: Role of Innate Immune Cells in Osteoporosis. Front Immunol. 2021;12:687037. [PMC free article: PMC8374941] [PubMed: 34421899]

188.

Zhang W, Gao R, Rong X, Zhu S, Cui Y, Liu H, Li M. Immunoporosis: Role of immune system in the pathophysiology of different types of osteoporosis. Front Endocrinol (Lausanne). 2022;13:965258. [PMC free article: PMC9487180] [PubMed: 36147571]

189.

Xiong J, Piemontese M, Onal M, Campbell J, Goellner JJ, Dusevich V, Bonewald L, Manolagas SC, O'Brien CA. Osteocytes, not Osteoblasts or Lining Cells, are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone. PLoS One. 2015;10(9):e0138189. [PMC free article: PMC4578942] [PubMed: 26393791]

190.

Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21(2):115-137. [PubMed: 10782361]

191.

Walsh MC, Choi Y. Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond. Front Immunol. 2014;5:511. [PMC free article: PMC4202272] [PubMed: 25368616]

192.

Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Foger-Samwald U, Ellinger I. Immunology of Osteoporosis: A Mini-Review. Gerontology. 2016;62(2):128-137. [PMC free article: PMC4821368] [PubMed: 26088283]

193.

Lorenzo J. Cytokines and Bone: Osteoimmunology. Handb Exp Pharmacol. 2020;262:177-230. [PubMed: 32006259]

194.

Amarasekara DS, Yun H, Kim S, Lee N, Kim H, Rho J. Regulation of Osteoclast Differentiation by Cytokine Networks. Immune Netw. 2018;18(1):e8. [PMC free article: PMC5833125] [PubMed: 29503739]

195.

Rauner M, Sipos W, Pietschmann P. Osteoimmunology. Int Arch Allergy Immunol. 2007;143(1):31-48. [PubMed: 17191007]

196.

Weitzmann MN, Cenci S, Rifas L, Brown C, Pacifici R. Interleukin-7 stimulates osteoclast formation by up-regulating the T-cell production of soluble osteoclastogenic cytokines. Blood. 2000;96(5):1873-1878. [PubMed: 10961889]

197.

Titanji K, Vunnava A, Sheth AN, Delille C, Lennox JL, Sanford SE, Foster A, Knezevic A, Easley KA, Weitzmann MN, Ofotokun I. Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection. PLoS Pathog. 2014;10(10):e1004497. [PMC free article: PMC4231117] [PubMed: 25393853]

198.

Manolagas SC, Jilka RL, Girasole G, Passeri G, Bellido T. Estrogen, cytokines, and the control of osteoclast formation and bone resorption in vitro and in vivo. Osteoporos Int. 1993;3 Suppl 1:114-116. [PubMed: 8461536]

199.

Klein B, Wijdenes J, Zhang XG, Jourdan M, Boiron JM, Brochier J, Liautard J, Merlin M, Clement C, Morel-Fournier B, et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood. 1991;78(5):1198-1204. [PubMed: 1715218]

200.

Roodman GD, Kurihara N, Ohsaki Y, Kukita A, Hosking D, Demulder A, Smith JF, Singer FR. Interleukin 6. A potential autocrine/paracrine factor in Paget's disease of bone. J Clin Invest. 1992;89(1):46-52. [PMC free article: PMC442817] [PubMed: 1729280]

201.

Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Yamaguchi A, Kishimoto T, Suda T, Kashiwazaki S. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res. 1996;11(1):88-95. [PubMed: 8770701]

202.

Devlin RD, Bone HG, 3rd, Roodman GD. Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease. J Clin Endocrinol Metab. 1996;81(5):1893-1897. [PubMed: 8626854]

203.

Martin TJ, Allan EH, Evely RS, Reid IR. Leukaemia inhibitory factor and bone cell function. Ciba Found Symp. 1992;167:141-150; discussion 150-145. [PubMed: 1425010]

204.

Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL. IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest. 2005;115(2):282-290. [PMC free article: PMC544608] [PubMed: 15668736]

205.

Ruscitti P, Cipriani P, Carubbi F, Liakouli V, Zazzeroni F, Di Benedetto P, Berardicurti O, Alesse E, Giacomelli R. The role of IL-1beta in the bone loss during rheumatic diseases. Mediators Inflamm. 2015;2015:782382. [PMC free article: PMC4410538] [PubMed: 25954061]

206.

D'Amelio P. The immune system and postmenopausal osteoporosis. Immunol Invest. 2013;42(7):544-554. [PubMed: 24004058]

207.

Cenci S, Toraldo G, Weitzmann MN, Roggia C, Gao Y, Qian WP, Sierra O, Pacifici R. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci U S A. 2003;100(18):10405-10410. [PMC free article: PMC193574] [PubMed: 12923292]

208.

Miyaura C, Onoe Y, Inada M, Maki K, Ikuta K, Ito M, Suda T. Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: similarity to estrogen deficiency. Proc Natl Acad Sci U S A. 1997;94(17):9360-9365. [PMC free article: PMC23193] [PubMed: 9256487]

209.

Jabbar S, Drury J, Fordham JN, Datta HK, Francis RM, Tuck SP. Osteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosis. J Clin Pathol. 2011;64(4):354-357. [PubMed: 21307155]

210.

Fischer V, Haffner-Luntzer M. Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin Cell Dev Biol. 2022;123:14-21. [PubMed: 34024716]

211.

Zha L, He L, Liang Y, Qin H, Yu B, Chang L, Xue L. TNF-alpha contributes to postmenopausal osteoporosis by synergistically promoting RANKL-induced osteoclast formation. Biomed Pharmacother. 2018;102:369-374. [PubMed: 29571022]

212.

Onal M, Xiong J, Chen X, Thostenson JD, Almeida M, Manolagas SC, O'Brien CA. Receptor activator of nuclear factor kappaB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J Biol Chem. 2012;287(35):29851-29860. [PMC free article: PMC3436192] [PubMed: 22782898]

213.

Wu D, Cline-Smith A, Shashkova E, Perla A, Katyal A, Aurora R. T-Cell Mediated Inflammation in Postmenopausal Osteoporosis. Front Immunol. 2021;12:687551. [PMC free article: PMC8278518] [PubMed: 34276675]

214.

Lai N, Zhang Z, Wang B, Miao X, Guo Y, Yao C, Wang Z, Wang L, Ma R, Li X, Jiang G. Regulatory effect of traditional Chinese medicinal formula Zuo-Gui-Wan on the Th17/Treg paradigm in mice with bone loss induced by estrogen deficiency. J Ethnopharmacol. 2015;166:228-239. [PubMed: 25824592]

215.

Duque G, Troen BR. Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome. J Am Geriatr Soc. 2008;56(5):935-941. [PubMed: 18454751]

216.

De Maeyer RPH, Chambers ES. The impact of ageing on monocytes and macrophages. Immunol Lett. 2021;230:1-10. [PubMed: 33309673]

217.

Li CJ, Xiao Y, Sun YC, He WZ, Liu L, Huang M, He C, Huang M, Chen KX, Hou J, Feng X, Su T, Guo Q, Huang Y, Peng H, Yang M, Liu GH, Luo XH. Senescent immune cells release grancalcin to promote skeletal aging. Cell Metab. 2022;34(1):184-185. [PubMed: 34986333]

218.

Sandmand M, Bruunsgaard H, Kemp K, Andersen-Ranberg K, Pedersen AN, Skinhoj P, Pedersen BK. Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans? Clin Exp Immunol. 2002;127(1):107-114. [PMC free article: PMC1906284] [PubMed: 11882040]

219.

Siddiqi A, Monson JP, Wood DF, Besser GM, Burrin JM. Serum cytokines in thyrotoxicosis. J Clin Endocrinol Metab. 1999;84(2):435-439. [PubMed: 10022397]

220.

Sun L, Zhu LL, Lu P, Yuen T, Li J, Ma R, Baliram R, Moonga SS, Liu P, Zallone A, New MI, Davies TF, Zaidi M. Genetic confirmation for a central role for TNFalpha in the direct action of thyroid stimulating hormone on the skeleton. Proc Natl Acad Sci U S A. 2013;110(24):9891-9896. [PMC free article: PMC3683712] [PubMed: 23716650]

221.

Baliram R, Sun L, Cao J, Li J, Latif R, Huber AK, Yuen T, Blair HC, Zaidi M, Davies TF. Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling. J Clin Invest. 2012;122(10):3737-3741. [PMC free article: PMC3461920] [PubMed: 22996689]

222.

Grey A, Mitnick MA, Shapses S, Ellison A, Gundberg C, Insogna K. Circulating levels of interleukin-6 and tumor necrosis factor-alpha are elevated in primary hyperparathyroidism and correlate with markers of bone resorption--a clinical research center study. J Clin Endocrinol Metab. 1996;81(10):3450-3454. [PubMed: 8855783]

223.

Grey A, Mitnick MA, Masiukiewicz U, Sun BH, Rudikoff S, Jilka RL, Manolagas SC, Insogna K. A role for interleukin-6 in parathyroid hormone-induced bone resorption in vivo. Endocrinology. 1999;140(10):4683-4690. [PubMed: 10499526]

224.

Hory BG, Roussanne MC, Rostand S, Bourdeau A, Drueke TB, Gogusev J. Absence of response to human parathyroid hormone in athymic mice grafted with human parathyroid adenoma, hyperplasia or parathyroid cells maintained in culture. J Endocrinol Invest. 2000;23(5):273-279. [PubMed: 10882144]

225.

Bedi B, Li JY, Tawfeek H, Baek KH, Adams J, Vangara SS, Chang MK, Kneissel M, Weitzmann MN, Pacifici R. Silencing of parathyroid hormone (PTH) receptor 1 in T cells blunts the bone anabolic activity of PTH. Proc Natl Acad Sci U S A. 2012;109(12):E725-733. [PMC free article: PMC3311391] [PubMed: 22393015]

226.

Weitzmann MN. Bone and the Immune System. Toxicol Pathol. 2017;45(7):911-924. [PMC free article: PMC5749254] [PubMed: 29046115]

227.

Song L, Cao L, Liu R, Ma H, Li Y, Shang Q, Zheng Z, Zhang L, Zhang W, Han Y, Zhang X, Yang H, Wang Y, Melino G, Shao C, Shi Y. The critical role of T cells in glucocorticoid-induced osteoporosis. Cell Death Dis. 2020;12(1):45. [PMC free article: PMC7791068] [PubMed: 33414409]

228.

Ponnapakkam T, Katikaneni R, Nichols T, Tobin G, Sakon J, Matsushita O, Gensure RC. Prevention of chemotherapy-induced osteoporosis by cyclophosphamide with a long-acting form of parathyroid hormone. J Endocrinol Invest. 2011;34(11):e392-397. [PubMed: 21750397]

229.

Wang W, Gao Y, Liu H, Feng W, Li X, Guo J, Li M. Eldecalcitol, an active vitamin D analog, effectively prevents cyclophosphamide-induced osteoporosis in rats. Exp Ther Med. 2019;18(3):1571-1580. [PMC free article: PMC6676093] [PubMed: 31410111]

230.

Zhao D, Wang C, Zhao Y, Shu B, Jia Y, Liu S, Wang H, Chang J, Dai W, Lu S, Shi Q, Yang Y, Zhang Y, Wang Y. Cyclophosphamide causes osteoporosis in C57BL/6 male mice: suppressive effects of cyclophosphamide on osteoblastogenesis and osteoclastogenesis. Oncotarget. 2017;8(58):98163-98183. [PMC free article: PMC5716721] [PubMed: 29228681]

231.

Chen X, Wang S, Chen G, Wang Z, Kan J. The immunomodulatory effects of Carapax Trionycis ultrafine powder on cyclophosphamide-induced immunosuppression in Balb/c mice. J Sci Food Agric. 2021;101(5):2014-2026. [PubMed: 32949169]

232.

Filippa MG, Tektonidou MG, Mantzou A, Kaltsas GA, Chrousos GP, Sfikakis PP, Yavropoulou MP. Adrenocortical dysfunction in rheumatoid arthritis: Alpha narrative review and future directions. Eur J Clin Invest. 2022;52(1):e13635. [PubMed: 34097322]

233.

Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation. 2015;22(1-2):6-19. [PubMed: 25227402]

234.

Laflamme N, Lacroix S, Rivest S. An essential role of interleukin-1beta in mediating NF-kappaB activity and COX-2 transcription in cells of the blood-brain barrier in response to a systemic and localized inflammation but not during endotoxemia. J Neurosci. 1999;19(24):10923-10930. [PMC free article: PMC6784955] [PubMed: 10594073]

235.

Nadeau S, Rivest S. Regulation of the gene encoding tumor necrosis factor alpha (TNF-alpha) in the rat brain and pituitary in response in different models of systemic immune challenge. J Neuropathol Exp Neurol. 1999;58(1):61-77. [PubMed: 10068315]

236.

Perlstein RS, Whitnall MH, Abrams JS, Mougey EH, Neta R. Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in the adrenocorticotropin response to bacterial lipopolysaccharide in vivo. Endocrinology. 1993;132(3):946-952. [PubMed: 8382602]

237.

Chrousos GP, Kaltsas G. Post-SARS sickness syndrome manifestations and endocrinopathy: how, why, and so what? Clin Endocrinol (Oxf). 2005;63(4):363-365. [PMC free article: PMC7162060] [PubMed: 16181227]

238.

Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA. 1992;267(9):1244-1252. [PubMed: 1538563]

239.

Papanicolaou DA, Tsigos C, Oldfield EH, Chrousos GP. Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency? J Clin Endocrinol Metab. 1996;81(6):2303-2306. [PubMed: 8964868]

240.

Bethin KE, Vogt SK, Muglia LJ. Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation. Proc Natl Acad Sci U S A. 2000;97(16):9317-9322. [PMC free article: PMC16865] [PubMed: 10922080]

241.

Silverman MN, Miller AH, Biron CA, Pearce BD. Characterization of an interleukin-6- and adrenocorticotropin-dependent, immune-to-adrenal pathway during viral infection. Endocrinology. 2004;145(8):3580-3589. [PubMed: 15044377]

242.

Franchimont D, Bouma G, Galon J, Wolkersdorfer GW, Haidan A, Chrousos GP, Bornstein SR. Adrenal cortical activation in murine colitis. Gastroenterology. 2000;119(6):1560-1568. [PubMed: 11113077]

243.

Path G, Bornstein SR, Ehrhart-Bornstein M, Scherbaum WA. Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis. J Clin Endocrinol Metab. 1997;82(7):2343-2349. [PubMed: 9215317]

244.

Path G, Scherbaum WA, Bornstein SR. The role of interleukin-6 in the human adrenal gland. Eur J Clin Invest. 2000;30 Suppl 3:91-95. [PubMed: 11281377]

245.

Filippa MG, Tektonidou MG, Mantzou A, Kaltsas GA, Chrousos GP, Sfikakis PP, Yavropoulou MP. Adrenocortical dysfunction in rheumatoid arthritis: Alpha narrative review and future directions. Eur J Clin Invest. 2021:e13635. [PubMed: 34097322]

246.

Yavropoulou MP, Filippa MG, Mantzou A, Ntziora F, Mylona M, Tektonidou MG, Vlachogiannis NI, Paraskevis D, Kaltsas GA, Chrousos GP, Sfikakis PP. Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations. Endocrine. 2022;75(2):317-327. [PMC free article: PMC8765492] [PubMed: 35043384]

247.

de Kloet ER. Stress in the brain. Eur J Pharmacol. 2000;405(1-3):187-198. [PubMed: 11033326]

248.

Lightman SL, Wiles CC, Atkinson HC, Henley DE, Russell GM, Leendertz JA, McKenna MA, Spiga F, Wood SA, Conway-Campbell BL. The significance of glucocorticoid pulsatility. Eur J Pharmacol. 2008;583(2-3):255-262. [PubMed: 18339373]

249.

Stavreva DA, Wiench M, John S, Conway-Campbell BL, McKenna MA, Pooley JR, Johnson TA, Voss TC, Lightman SL, Hager GL. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat Cell Biol. 2009;11(9):1093-1102. [PMC free article: PMC6711162] [PubMed: 19684579]

250.

Hochberg Z, Pacak K, Chrousos GP. Endocrine withdrawal syndromes. Endocr Rev. 2003;24(4):523-538. [PubMed: 12920153]

251.

Yavropoulou MP, Filippa MG, Panopoulos S, Spanos E, Spanos G, Tektonidou MG, Sfikakis PP. Impaired adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases who relapse upon tapering of low glucocorticoid dose. Clin Exp Rheumatol. 2022. [PubMed: 35699085]

252.

Yavropoulou MP, Tsokos GC, Chrousos GP, Sfikakis PP. Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID. Clin Immunol. 2022;245:109133. [PMC free article: PMC9519365] [PubMed: 36182048]

253.

Kirschbaum C, Hellhammer DH. Salivary cortisol in psychobiological research: an overview. Neuropsychobiology. 1989;22(3):150-169. [PubMed: 2485862]

254.

Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92(12):994-1000. [PubMed: 10861311]

255.

Pervanidou P, Kolaitis G, Charitaki S, Margeli A, Ferentinos S, Bakoula C, Lazaropoulou C, Papassotiriou I, Tsiantis J, Chrousos GP. Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident. Psychoneuroendocrinology. 2007;32(8-10):991-999. [PubMed: 17825995]

256.

Bougea AM, Spandideas N, Alexopoulos EC, Thomaides T, Chrousos GP, Darviri C. Effect of the emotional freedom technique on perceived stress, quality of life, and cortisol salivary levels in tension-type headache sufferers: a randomized controlled trial. Explore (NY). 2013;9(2):91-99. [PubMed: 23452711]

257.

Lopez-Acevo CA, Arrendondo-Loza E, Salinas-Carmona MC, Rendon A, Martinez-Castilla AM, Vazquez-Marmolejo AV, Munoz-Maldonado G, Rosas-Taraco AG. Cortisol and perceived stress are associated with cytokines levels in patients infected with influenza B virus. Cytokine. 2021;138:155400. [PubMed: 33338918]

258.

Cutolo M, Villaggio B, Otsa K, Aakre O, Sulli A, Seriolo B. Altered circadian rhythms in rheumatoid arthritis patients play a role in the disease's symptoms. Autoimmun Rev. 2005;4(8):497-502. [PubMed: 16214085]

259.

Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum. 2007;56(2):399-408. [PubMed: 17265475]

260.

Cutolo M, Masi AT. Circadian rhythms and arthritis. Rheum Dis Clin North Am. 2005;31(1):115-129, ix-x. [PubMed: 15639059]

261.

Cutolo M. Circadian rhythms and rheumatoid arthritis. Joint Bone Spine. 2019;86(3):327-333. [PubMed: 30227223]

262.

Sothern RB, Roitman-Johnson B, Kanabrocki EL, Yager JG, Fuerstenberg RK, Weatherbee JA, Young MR, Nemchausky BM, Scheving LE. Circadian characteristics of interleukin-6 in blood and urine of clinically healthy men. In Vivo. 1995;9(4):331-339. [PubMed: 8555432]

263.

Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum. 1992;35(11):1281-1288. [PubMed: 1445443]

264.

Gudbjornsson B, Skogseid B, Oberg K, Wide L, Hallgren R. Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis. Effect of glucocorticoids. J Rheumatol. 1996;23(4):596-602. [PubMed: 8730111]

265.

Crofford LJ, Kalogeras KT, Mastorakos G, Magiakou MA, Wells J, Kanik KS, Gold PW, Chrousos GP, Wilder RL. Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol Metab. 1997;82(4):1279-1283. [PubMed: 9100607]

266.

Gutierrez MA, Garcia ME, Rodriguez JA, Mardonez G, Jacobelli S, Rivero S. Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation. J Rheumatol. 1999;26(2):277-281. [PubMed: 9972958]

267.

Cutolo M, Foppiani L, Prete C, Ballarino P, Sulli A, Villaggio B, Seriolo B, Giusti M, Accardo S. Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids. J Rheumatol. 1999;26(2):282-288. [PubMed: 9972959]

268.

Cutolo M, Foppiani L, Minuto F. Hypothalamic-pituitary-adrenal axis impairment in the pathogenesis of rheumatoid arthritis and polymyalgia rheumatica. J Endocrinol Invest. 2002;25(10 Suppl):19-23. [PubMed: 12508908]

269.

Straub RH, Paimela L, Peltomaa R, Scholmerich J, Leirisalo-Repo M. Inadequately low serum levels of steroid hormones in relation to interleukin-6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis. Arthritis Rheum. 2002;46(3):654-662. [PubMed: 11920401]

270.

Imrich R, Vigas M, Rovensky J, Aldag JC, Masi AT. Adrenal plasma steroid relations in glucocorticoid-naive premenopausal rheumatoid arthritis patients during insulin-induced hypoglycemia test compared to matched normal control females. Endocr Regul. 2009;43(2):65-73. [PubMed: 19856711]

271.

De Silva M, Binder A, Hazleman BL. The timing of prednisolone dosage and its effect on morning stiffness in rheumatoid arthritis. Ann Rheum Dis. 1984;43(6):790-793. [PMC free article: PMC1001537] [PubMed: 6395813]

272.

Buttgereit F, Doering G, Schaeffler A, Witte S, Sierakowski S, Gromnica-Ihle E, Jeka S, Krueger K, Szechinski J, Alten R. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet. 2008;371(9608):205-214. [PubMed: 18207016]

273.

Buttgereit F, Doering G, Schaeffler A, Witte S, Sierakowski S, Gromnica-Ihle E, Jeka S, Krueger K, Szechinski J, Alten R. Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis. Ann Rheum Dis. 2010;69(7):1275-1280. [PMC free article: PMC2946119] [PubMed: 20542963]

274.

Buttgereit F, Mehta D, Kirwan J, Szechinski J, Boers M, Alten RE, Supronik J, Szombati I, Romer U, Witte S, Saag KG. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis. 2013;72(2):204-210. [PMC free article: PMC3553491] [PubMed: 22562974]

275.

Nicolaides NC, Chrousos GP. Impact of Stress on Health in Childhood and Adolescence. Horm Res Paediatr. 2023;96(1):5-7. [PubMed: 36380633]

276.

Tzelepi I, Bacopoulou F, Chrousos GP, Sotiropoulou L, Vlachakis D, Darviri C. Mindfulness and Academic Performance of College and University Students: A Systematic Review. Adv Exp Med Biol. 2023;1425:207-215. [PubMed: 37581795]

277.

Redwine L, Mills PJ, Sada M, Dimsdale J, Patterson T, Grant I. Differential immune cell chemotaxis responses to acute psychological stress in Alzheimer caregivers compared to non-caregiver controls. Psychosom Med. 2004;66(5):770-775. [PubMed: 15385705]

278.

Rosenkranz MA, Lutz A, Perlman DM, Bachhuber DR, Schuyler BS, MacCoon DG, Davidson RJ. Reduced stress and inflammatory responsiveness in experienced meditators compared to a matched healthy control group. Psychoneuroendocrinology. 2016;68:117-125. [PMC free article: PMC4851883] [PubMed: 26970711]

279.

Fancourt D, Perkins R, Ascenso S, Carvalho LA, Steptoe A, Williamon A. Effects of Group Drumming Interventions on Anxiety, Depression, Social Resilience and Inflammatory Immune Response among Mental Health Service Users. PLoS One. 2016;11(3):e0151136. [PMC free article: PMC4790847] [PubMed: 26974430]

280.

Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000;21(1):55-89. [PubMed: 10696570]

281.

Kiss A, Aguilera G. Participation of alpha 1-adrenergic receptors in the secretion of hypothalamic corticotropin-releasing hormone during stress. Neuroendocrinology. 1992;56(2):153-160. [PubMed: 1328915]

282.

Bunn SJ, Ait-Ali D, Eiden LE. Immune-neuroendocrine integration at the adrenal gland: cytokine control of the adrenomedullary transcriptome. J Mol Neurosci. 2012;48(2):413-419. [PMC free article: PMC3488108] [PubMed: 22421803]

283.

Ait-Ali D, Turquier V, Tanguy Y, Thouennon E, Ghzili H, Mounien L, Derambure C, Jegou S, Salier JP, Vaudry H, Eiden LE, Anouar Y. Tumor necrosis factor (TNF)-alpha persistently activates nuclear factor-kappaB signaling through the type 2 TNF receptor in chromaffin cells: implications for long-term regulation of neuropeptide gene expression in inflammation. Endocrinology. 2008;149(6):2840-2852. [PMC free article: PMC2408812] [PubMed: 18292192]

284.

Douglas SA, Bunn SJ. Interferon-alpha signalling in bovine adrenal chromaffin cells: involvement of signal-transducer and activator of transcription 1 and 2, extracellular signal-regulated protein kinases 1/2 and serine 31 phosphorylation of tyrosine hydroxylase. J Neuroendocrinol. 2009;21(3):200-207. [PubMed: 19207826]

285.

Rosmaninho-Salgado J, Araujo IM, Alvaro AR, Mendes AF, Ferreira L, Grouzmann E, Mota A, Duarte EP, Cavadas C. Regulation of catecholamine release and tyrosine hydroxylase in human adrenal chromaffin cells by interleukin-1beta: role of neuropeptide Y and nitric oxide. J Neurochem. 2009;109(3):911-922. [PubMed: 19309436]

286.

Jenkins DE, Sreenivasan D, Carman F, Samal B, Eiden LE, Bunn SJ. Interleukin-6-mediated signaling in adrenal medullary chromaffin cells. J Neurochem. 2016;139(6):1138-1150. [PMC free article: PMC5177545] [PubMed: 27770433]

287.

Fan J, Zhang B, Shu HF, Zhang XY, Wang X, Kuang F, Liu L, Peng ZW, Wu R, Zhou Z, Wang BR. Interleukin-6 increases intracellular Ca2+ concentration and induces catecholamine secretion in rat carotid body glomus cells. J Neurosci Res. 2009;87(12):2757-2762. [PubMed: 19396873]

288.

Sharma D, Farrar JD. Adrenergic regulation of immune cell function and inflammation. Semin Immunopathol. 2020;42(6):709-717. [PMC free article: PMC7678770] [PubMed: 33219396]

289.

Takenaka MC, Guereschi MG, Basso AS. Neuroimmune interactions: dendritic cell modulation by the sympathetic nervous system. Semin Immunopathol. 2017;39(2):165-176. [PubMed: 27800584]

290.

Guyot M, Simon T, Panzolini C, Ceppo F, Daoudlarian D, Murris E, Macia E, Abelanet S, Sridhar A, Vervoordeldonk MJ, Glaichenhaus N, Blancou P. Apical splenic nerve electrical stimulation discloses an anti-inflammatory pathway relying on adrenergic and nicotinic receptors in myeloid cells. Brain Behav Immun. 2019;80:238-246. [PubMed: 30885844]