Introduction

Evolution has allowed the development of myriads of species from very simple to highly complex ones. Initially unicelular microorganisms appeared without a nucleus (prokarytes) and later the organisms with a nucleus similar to amoebas. These ancestral amoebas developed in groups and have been called “social amoebas” (1). Some amoebaes specialized in receiving food and fending off other organisms, as a result of which, phagocytosis appeared. This may have been the origin of the immune system as we know it. These unicellular organism developed forms of signaling and adhesion molecules which allowed them to aggregate. Then, multicellular organisms (metazoans) appeared after unicellular organisms migrated from the sea (2). The vertebrate animals with their remarkable diversification appeared 500 million years ago. Both the immune system and its regulatory mechanisms evolved in parallel in a form of evolutionary accumulation (3) (Figure 1).

Figure 1

Phylogeny of animals and their immune system. Left: Phylogenic tree of animals. Right: component of immune system that develops an accumulative mechanism of defense. From Cañas & Cañas (3).

Evolutionary theories that may explain autoimmune phenomena development in humans

Life began when deoxyribonucleic acid (DNA) acquired the ability to replicate and mutate (4). This made the transmission of genetic information to offspring and the generation of biodiversity possible. Several theories have been formulated to try to explain the biological changes that, over time, determine the evolutionary phenomena of living. These theories may be applicable to the understanding of human biology, including that of diseases. Evolutionary theories can help us understand the origin of autommune diseases beginning with the concepts of genetic drift that refer to the change in the frequency of a gene variant (allele) in a population due to random sampling (5) to the concepts of classic Darwinian natural morphological selection and, concluding for now, with the most modern of molecular selection (6). The synthetic theory of evolution developed by Theodosius Dobzhansky (7) and Ernst Mayr (8), which initially combined Darwin’s theory of evolution by natural selection and Mendelian genetics and, lately, has included modern genetic concepts, has also incorporated relevant knowledge. David Hull tries to cover these concepts in the phrase: “genes mutate, individuals are selected, and species evolve” (9). Recently, Richard Dawkins (10) showed us that the different forms of memory were the most relevant foundation for evolution. Information required for handling the present so as to survive into the future is necessarily obtained from the past. In fact, he proposed four levels of information gathering, which he called the “four memories,” which would be the foundation of evolution. The “first memory” is DNA, the inherited database each species has and which is the result of non-random evolution. The “second memory” is the adaptive immune system, which is information accumulated during the life of an individual. The “third memory” is the nervous system. Our brain records past experiences and uses a trial-and-error process. The “fourth memory” is the collective memory of the social and cultural aspects of the human species. So, evolution, far from being a tautology as analyzed by the philosopher Karl Popper, is a complex process (11). However, what is clear is that evolution is a law of nature that has been scientifically proven in many ways.

Thus, based on the theories and thoughts presented here, we provide the key elements for understanding the biological significance of evolution in autoimmune phenomena.

Influence of the first form of evolutionary memory on the autoimmune phenomena

Innate immunity is a system that does not create a new form of memory and should be included in the first memory of evolution. The innate immunity is natural, non-specific, non-anticipatory, and does not generate an accumulation of information. This system contains cells that resemble phagocytes which have generic receptors that recognize conserved patterns of pathogens and lectine-like soluble proteins, and they are essential in arthropods, nematodes, sipunculids, mollusks, annelids, platyhelminths, echinoderms, cephalochordates, and urochordates. Adaptive immunity, which has a highly diverse repertoire of lymphocytes, was added in agnathas (vertebrates without jaws) and gnathostomes (vertebrates with jaws). In fact, in the most complex species, e.g., mammals, the immune system consists of innate and adaptive immunities which include T and B lymphocytes and the production of cytokines and antibodies.

Chemokines and their receptor

Chemokines are involved in cell interactions and tropism in situations that are frequently associated with inflammation. Recently, the importance of chemokines and chemokine receptors in inflammation associated with autoimmunity has been highlighted. The molecular mechanisms that control these fundamental aspects of chemotaxis appear to be evolutionarily conserved, and studies in lower eukaryotic model systems have allowed us to form concepts, uncover molecular components, develop new techniques, and test models of chemotaxis. Some receptors of chemokines are also receptors for other molecules which include exogen agents such as microorganisms.

In the case of infections caused by P. vivax, the most widely studied evolutionary change that determines resistance is the genetic polymorphism of the parasite receptor known as Duffy Antigen Receptor for Chemokines (DARC) (27,28). In this receptor, the form lacking alleles does not allow the red blood cell to receive the parasite and let it enter. There are two kinds of alleles related to the DARC receptors: Fya and Fyb, which identify four possible phenotypical presentations: homozygous Fy (ab−) (absence of the receiver or null), homozygous Fy (a+ b+) and heterozygous Fy (a− b+) and Fy (a+ b−). These receptors belong to the family of seven transmembrane molecules, which were initially recognized as receptors for the P. vivax in human red blood cells and the simian P. Knowlesi. Later they were recognized as “promiscuous” receptors which were able to bind both CC and CXC chemokines and have a cleaning role in these molecules (29). Several chemokines related to the inflammatory process of RA are DARC ligands. These ligands include the CXC type chemokine, the interleukin-8 (IL-8) and neutrophil-activating protein derived from epithelial cells (ENA-78: epithelial cell-derived neutrophil-activating protein-78), the CC type, e.g., monocyte chemoattractant protein (MCP-1 monocyte chemoattractant protein-1), and the regulated T lymphocyte protein expressed and secreted in normal activation (RANTES: regulated on activation normal T-cell expressed and secreted). The DARC expressed on endothelial cells of the synovium is important for the recruitment of neutrophils in patients with RA (30).

However, the role of DARC in the pathogenesis of RA is unknown. As has already been mentioned, the DARC in this location plays a role in the clearance of circulating chemokines, a condition that could have an implication in the regulation of inflammatory processes. The DARC phenotypes have been studied in Caucasian patients from Italy with Behçet’s disease, where the IL-8 and MCP-1 are pathogenics. In this study, there was no association between the genetic polymorphisms of these genes and the presence of the disease. It can be assumed that the absence or deficiency of DARC would be related to more severe forms of RA (31). Diverse mechanisms of resistence to malaria which may be implicated in the immune system regulation and RA pathogenesis are showed in Table 1.

Table 1

Summary of the mechanisms of protection from malaria and their possible association with rheumatoid arthritis pathogenesis.

Influence of the second form of evolutionary memory in autoimmune phenomena

Adaptive immunity is a form of second evolutionary memory and stores molecular information about micro-organisms in order to develop a faster and more effective defense against them in future exposures through cytokines and specific antibodies. The most important mechanism that nature has used to obtain and retain this type of information has been the immunoglobulin superfamily gene system. The adaptive immune system, as defined by rearranging antigen receptor genes in the immunoglobulin superfamily and by the major histocompatibility complex, has only been found in the jawed vertebrates (gnathostomes). The mechanism of recombination-activating gene (RAG)-mediated rearrangement exists in all jawed vertebrates, but the organization and structure of immunoglobulin (Ig) genes differ between species and reveal their capability for rapid evolution. (44). Other groups of proteins that belong to the immunoglobulin superfamily with a common ancestral origin are FcγR and the immunoglobulin-like receptor (KIR) which have an important function in the inflammatory response. The antibodies directed against their own structures (autoantibodies) play a primary role in autoimmunity being pathogenic in diseases caused by an attack on cell or tissue antigens (autoantigens) or in immune complex-mediated diseases. The autoantigens may originate from different sources.

Proteins that are hidden in some tissues and by external factors such as trauma begin to be recognized by the immune system as foreign. The immune system recognizes the new antigen and tries to eliminate it by innate immunity mechanisms, and later, by induction of acquired immunity mechanisms. An example of this condition is sympathetic ophthalmia (SO) where breaching of systemic ocular barriers compromises the relative immune privilege of the eye and causes sensitization to previously sequestered uveoretinal antigens (45). A similar mechanism is observed in relapsing polychondritis which begins with cartilage trauma and is triggered by an immune response to other cartilaginous or non-cartilaginous tissues (46,47).

Even Though There Are Proteins That Are Not Present in the Human Structure, the Genetic Information Is Present. These genes are ancestrally repressed and hidden. As a result of different causes, they start protein synthesis and this “foreign” protein is attacked by the immune system. One example of this is the endogenous retrovirus (ERV) which belongs to the large family of retrotransposable elements of human genoma (48). ERV may be activated by radiation, bacteria, chemicals, or recombination with an exogenous retrovirus and start the “autoantigen” protein synthesis that is the source for autoimmune processes implicated in the pathogenesis of SLE (49).

In vertebrates, allorecognition depends on proteins encoded by MHC genes. A MHC-like region is certainly very ancient and is believed to be present in the common ancestor of proto- and deuterostomes (50). The function of MHC is to present antigens to T-cell receptors. It has been suggested that the MHC region arose as a result of chromosomal duplications. In higher vertebrates, MHC is represented by two distinct classes, MHC I and MHC II. Class II MHC polymorphisms have been studied and their presence is a risk factor for various autoimmune diseases, for example, diverse HLA DRB1-04 alleles in RA, HLA DRB1-0301 in SLE, or HLA DR1-0301-DQB1-0201 in SS (51). Sometimes the risk is caused by the combination of polymorphisms (haplotypes) such as the 8.1 ancestral haplotype (52).

The HLA-DRB1 polymorphisms are ancient and, based on an estimate of the nucleotide substitution rate for MHC coding sequences, it has been argued that most of the alleles at the class II DRB1 loci predate the separation of hominoid species (53-55). However, the phylogenetic trees for primate exon-2 sequences are consistent with the notion that most of the alleles at some class II loci, e.g., DRB1 and DPB1, may have a more recent origin (56,57). Additionally, studies of human population groups with a defined degree and time of isolation have provided support for the view that new DRB1 alleles have been generated over the last 10,000 – 20,000 years (58,59). Thus, there are indications that the allelic variation at HLA loci may be much more recent than previously assumed (60). These alleles appear to be, on average, 250,000 years old thus implying that the vast majority (greater than 90%) of the more than 135 contemporary human HLA- DRB1 alleles were generated after the separation of Homo and Pan (61). This could be related to differences in these species in the prevalence of autoimmune diseases (62).

Influence of the third form of evolutionary memory in the autoimmune phenomena

Memory related to neuronal function in relation to autoimmune phenomena is a crucial factor for storing diverse experiences during life.

Neuroimmunoendocrine Network. An emotion such as stress or pain triggers endocrine responses which, in turn, affect the immune system and cause its activation and inappropriate response in the setting of autoimmune and infectious diseases. It is a vicious cycle because stress not only causes disease but the disease itself causes the patients considerable stress (63). Neuroendocrine hormones triggered during stress may lead to immune dysregulation and cytokine liberation resulting in autoimmflamatory/autoimmune disease risk. The stress response and induction of a disregulation in the cytokine balance can trigger the hypothalamic-pituitary-adrenal axis and sympathetic nervous system (64).

Neuron-Glial Relationship. A type of information stored in the brain which is related to the experience of pain. Somatic pain induces an immediate response that generates the reflex which moves the injured body part and prevents additional damage. A second form of pain is the subacute or chronic somatic pain that is caused by the rest of the affected area during the repair process. Another form of pain is the neuropathic pain which is due to the persistent response that is generated after an injury to peripheral nerve structures (65). In this condition, the microglia, which are the resident macrophages of the brain and spinal cord, plays an important role. It seems that the nerve injury activates the TLR4 which is only expressed on microglia in the central nervous system. Genetically altered mice lacking TLR4 showed markedly reduced microglial activation after nerve injury as well as reduced sensitivity to pain (66). Another candidate for microglial activation after nerve injury is fractalkine, a CX3C chemokine expressed on the surface of neurons (67). Ontogenetically, both microglia and other glial cells are important in the process of migration and location of neurons in the central nervous system and the nutrient supply (68). Not only glial cells but also neurons respond to the presence of several cytokines (69). The concept of integrated neuroendocrine-immune regulation has now been widely accepted although the physiological impacts on normal development and homeostasis or conditions of mental stress or physical disease are still poorly understood (70).

Influence of the fourth form of evolutionary memory in the autoimmune phenomena

The fourth form of mankind’s evolutionary memory is culture, and with this, there are many conditions that are related to the genesis of autoimmune phenomena. Dietary modifications for humans that led to protein-calorie malnutrition or otherwise to weight excess have been assessed and taken into account when seeking nutritional factors associated with development of autoimmunity (71,72). The lack of exposure to various antigens in early childhood, including the newly born and those growing up in an “aseptic” environment results in a very low exposure to antigens required for the development of cell-mediated immunity (leading to better and safer protection) and, at later stages, requires an antibody-mediated protection which can lead to allergy and autoimmunity phenomena (73). It is well known that industrialization decreases exposure to sunlight with the consequent development of vitamin D deficiency, now a well-studied factor related to autoimmunity (74). At the other extreme, the overexposure to sunlight due to working conditions or the cultural practice of changing the color of the skin (tanning) increases UV radiation. This is related to the development or exacerbation of cutaneous lupus and SLE by different mechanisms (75,76). Some jobs are related to risks of SLE. For example, school teachers are exposed to many viruses that could be the basis for an abnormal immune response in a genetically predisposed individual (77). Various habits such as smoking (78) or exposure to smog-related particles (79) are also associated with a similar outcome. With the evolution of human culture, pharmacology also developed and diverse drugs could induce autoimmune phenomena through various factors including epigenetic ones (Example: procainamide, hydralazine, chlorpromazine, isoniazid, phenytoin, and penicillamine) (80). Women have a greater predisposition to developing autoimmunity, in part, as a result of the effect of estrogen, which, when used for therapeutic or contraceptive reasons, increases the risk (81). It has been postulated that older factors such as migration and exposure for long periods of time to different forms of environment were determining factors for the development of different human races which have different risks for the development of autoimmune diseases (82). More recently there has been a genetic mixing of races due to migration and risk conditions for developing diseases have changed for each race. Race can also be modified without requiring migration; for instance, by religious or political influences that encourage the choice of partner for reproduction in order to ensure a race with certain characteristics which are more related to beauty and purity (83).

Conclusion

One way to understand autoimmunity is through knowledge of the biological significance of evolution. Since a specialized system for defense against microorganisms was set up, living things have theoretically been vulnerable to developing autoimmune phenomena. The existence of different regulatory mechanisms can only be explained as strategies that were developed to avoid these phenomena of self-destruction. The human species have a cumulative evolution of the most complex mechanisms of innate and acquired immunity which makes it very vulnerable to autoimmunity.

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