A number sign (#) is used with this entry because of evidence that infantile-onset multisystem autoimmune disease-3 (ADMIO3) is caused by homozygous mutation in the CBLB gene (604491) on chromosome 3q13.

Infantile-onset multisystem autoimmune disease-3 (ADMIO3) is an autosomal recessive disorder of immune dysregulation characterized by the onset of various systemic autoimmune manifestations in the first months or years of life. Features may include hypothyroidism, type 1 diabetes mellitus, systemic inflammatory manifestations (fever, hepatomegaly), and autoimmune cytopenias. Laboratory studies show normal levels of T, B, and NK cells, but CD4+ (see 186940) T cells demonstrate hyperproliferation when stimulated in vitro (Janssen et al., 2022).

For a discussion of genetic heterogeneity of ADMIO, see ADMIO1 (615952).

Janssen et al. (2022) reported 3 unrelated patients, ranging from 4 to 16 years of age, with onset of autoimmune features in infancy or in the first years of life. P1 was a 16-year-old girl, born of consanguineous Saudi parents, who developed hypothyroidism at 1 year of age followed by type 1 diabetes mellitus and vitiligo at age 6 and recurrent urticaria in the absence of atopy. She also had recurrent upper and lower respiratory tract infections associated with hypogammaglobulinemia, which responded to IV Ig treatment. Immunologic work-up showed normal T, B, and NK cell levels, but levels of IgG autoantibodies were increased. Her plasma strongly activated normal basophils, suggesting the presence of an activator in her serum. Accordingly, plasma levels of IL6 (147620), TNFA (191160), IL10 (124092), CXCL9 (601704), and CXCL10 (147310) were substantially elevated compared to controls. Janssen et al. (2022) suggested that the hypogammaglobulinemia and recurrent infections in P1 may have been due to additional variants in other genes. P2 was a 11-year-old boy, born of unrelated Saudi parents, who presented at 3 years of age with fever, lung infiltrates, hepatomegaly, and ascites responsive to medical treatment, including corticosteroids. He was later diagnosed with hypothyroidism and type 1 diabetes. At age 7, he again developed fevers and arthralgias, and bone marrow aspiration showed hemophagocytosis. Immunologic work-up showed normal T, B, and NK cells with increased IgG autoantibodies and elevated plasma cytokines, similar to that observed in P1. P3 was a 4-year-old boy, born of consanguineous Omani parents, who developed autoimmune hemolytic anemia at 6 months of age, followed by idiopathic thrombocytopenia purpura (ITP) at age 1. T and B cell numbers were normal, and serum cytokines were increased. Testing for autoantibodies was not performed due to lack of sample.

The transmission pattern of ADMIO3 in the families reported by Janssen et al. (2022) was consistent with autosomal recessive inheritance.

In 3 unrelated patients with ADMIO3, Janssen et al. (2022) identified homozygous mutations in the CBLB gene (604491.0001-604491.0003). There were 2 missense variants and 1 nonsense variant. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None were present in the gnomAD database. CD4+ T cells derived from 2 of the patients showed hyperproliferation in response to CD3 (186740) and CD3 plus CD28 (186760) stimulation. Studies of mice carrying 1 of the mutations (H285L; 604491.0001) showed similar immune dysregulation, with hyperproliferation of CD4+ T cells and activation of B cells after stimulation (see ANIMAL MODEL). Janssen et al. (2022) concluded that the combination of CD4+ T cell hyperproliferation, resistance to Treg suppression, and possibly increased BCR signaling may contribute to the development of autoimmunity in CBLB-deficient patients.

Janssen et al. (2022) found that mice homozygous for a missense H257L mutation in the CBLB gene (which corresponds to the human H285L mutation, 604491.0001) generated by CRISPR/Cas9 gene editing showed immune dysregulation. T cells from these mice had an approximately 50% decrease in mutant protein expression. CD4+ T cells demonstrated hyperproliferation and increased IL2 (147680) secretion after anti-CD3 stimulation, although this was not associated with increased intracellular signaling. Treg cells were increased in the spleen, but mutant CD4+ T cells were resistant to suppression. B cells and bone marrow-derived mast cells also showed increased proliferation and hyperactivation when stimulated. Importantly, mutant mice did not develop autoimmune disease under pathogen-free conditions, indicating that environmental factors, including infection, may be necessary for triggering an autoimmune response.