CD3G Gene Defects in Familial Autoimmune Thyroiditis

Abstract

The patients with CD3c deficiency can present with different clinical findings despite having the same homozygous mutation. We report three new CD3gamma-deficient siblings from a consanguineous family with a combined TÀB+NK+ immunodeficiency and their variable clinical and cellular phenotypes despite the same homozygous mutation of the CD3G gene (c.80-1G>C). We also re-evaluate a previously reported non-consanguineous family with two CD3gamma-deficient siblings with the same mutation. The median age at diagnosis was 11 years (14 months-20 years). We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2). While CD3 + TCRab+T cell percentages were low in all patients, only one had lymphopenia and 3 had CD3 + T cell lymphopenia. Strikingly, we report frequent and multiple autoimmunity in tested heterozygous carriers in both families (n = 6; in 67%), and frequent autoimmunity in family members not available for testing (n = 5, in 80%). The results suggest that CD3G should be studied as a candidate gene for autoimmunity and that CD3gamma deficiency should be considered among other primary immunodeficiencies with predominantly autoimmune manifestations.

Role of IgE in autoimmunity

“…d IgE autoantibodies specific for retinal S antigen in patients with uveitis 80 ; d granulocyte-and organ-specific antinuclear IgE autoantibodies in patients with rheumatoid arthritis 4 ; d increased IgE levels in patients with CD3g deficiency 81 and anti-IgE autoantibodies in patients with systemic sclerosis 82 ; d IgE autoantibodies targeting thyroid peroxidase in patients with Hashimoto thyroiditis and Graves disease 83,84 ; d IgE reactive with myelin-derived peptides in patients with multiple sclerosis 85 ; and d anti-SS-A IgE in mothers with fetal loss. 86 The potential functional contributions of IgE autoantibodies to pathologic expressions of any of the above autoimmune diseases remain poorly understood.…”

Human congenital T-cell receptor disorders

“…Autoimmune phenomena have been described in several patients, mainly when T cells are present. Most CD3γ-deficient patients showed autoimmune hemolytic anemia (AHA) or vitiligo (Arnaiz-Villena et al 1992) and also autoimmune thyroiditis, thrombocytopenia, or autoimmune hepatitis (Gokturk et al 2014). Two (Table 1).…”

“…Two (Table 1). -Villena et al 1992;Sanal et al 1996;Allende et al 2000;Recio et al 2007;Ozgur et al 2008;Tokgoz et al 2013;Gokturk et al 2014 -5 1 0 Dadi et al 2003;de Saint Basile et al 2004;Takada et al 2005;Marcus et al 2011Gil et al 2011 TCRα-deficient patients presented with vitiligo, AHA, or autoantibodies (Morgan et al 2011). These results indicate that both positive selection and negative selection, which are TCR-dependent events, can be impaired in TCRID.…”

A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting With the CVID Phenotype Free of Autoimmunity—Analysis of all Genotypes and Phenotypes

“…The complete absence of CD3δ or CD3ε chain expression has been shown to block the development of TCRα/β T cells in both humans and mice (1), and human CD3ζ deficiency has been shown to reduce the number of circulating T cells, bearing a non-functional and restricted T-cell repertoire, and thereby causing severe combined T and B immune deficiency (SCID) (3-6). CD3γ-deficient mice have a severe block in T-cell development 7, whereas the loss of the CD3γ protein in humans has been shown to allow the development of polyclonal T cells, maintain TCR/CD3 signaling, and be associated with a less severe phenotype, characterized by a varying degree of susceptibility to infection and the frequent occurrence of autoimmune disorders (8)(9)(10). Autoimmune disorders are associated with an insufficient number of Treg cells and a reduced suppression function, as well as restricted TCR diversity (11).…”

“…To the best of our knowledge, this was the first patient of Chinese ethnicity to be identified with this novel CD3G mutation. In order to optimize his clinical management, a comprehensive review of previous phenotypes, genotypes, treatments, and prognoses was conducted by searching PubMed (8)(9)(10)(11)(12)(13). The current study presents the results of this search and also discusses the effect of this novel CD3G deletion mutation on cellular and humoral immunity.…”