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Table 1 Interplay of autoimmunity and immunodeficiency regarding Graves’ disease

From: Is Graves’ disease a primary immunodeficiency? New immunological perspectives on an endocrine disease

Primary immunodeficiency Phenotype Involved cell types Protein/Synapse Gene Mechanism Association with Graves’ disease Reference
Selective IgA deficiency Celiac disease, type 1 diabetes mellitus, impaired mucosal defense, most common PID B cells
Ligation with its receptor (FcαRI) leads to ADCC, granulocyte degranulation, phagocytosis and neutrophil oxidative burst Most commonly HLA haplotype 8.1 Ligation with its receptor (FcαRI) leads to ADCC, granulocyte degranulation, phagocytosis and neutrophil oxidative burst ++ [95, 96]
Severe combined immunodeficiency Recurrent infections, vitiligo, atopic dermatitis, ITP, AH, AITD T cells Low expression of T cell receptor CD3γ gene Impaired negative selection in thymus + [59]
Autoimmune lymphoproliferative syndrome Autoimmunity and polyclonal lymphocyte accumulation with lymphadenopathy and splenomegaly T cells Intra-thymic apoptosis via FASL to its receptor FAS (CD95) and subsequent activation of caspases 8 and 3 with impaired T cell apoptosis Heterogeneous mutations of FAS signaling pathway (1) Molecular mimicry or
(2) Slowing down of apoptosis and/or exposure of apoptosis related autoantigens
+ [62,63,64]
IPEX syndrome Immune dysregulation (eczema), polyendocrinopathy (T1DM), enteropathy Treg cells Thymus Loss of essential transcription factor FOXP3 on X chromosome Greatly reduced Treg cell number ++ [65]
IPEX-like IPEX-like phenotype Treg cells IL-2-receptor-α chain (CD25) CD25 deficiency due to autosomal recessive mutations Normal Treg in numbers but deficient stimulation by defective IL-10 expression +/– [67,68,69,70]
Common variable immunodeficiency Various autoimmune diseases (ITP, AIHA, psoriasis, AITD, arthritis) and antibody deficiencies,organ infiltration (bone marrow, kidney, brain, liver, spleen) by granulomatous-lymphocytic infiltration APCs
Treg cells
B cells
Naïve T cells
CTLA-4 binds to CD80/CD86 (B7) on APCs, leading to lower levels of co-stimulatory B7, failure to activate CD28 (the ligand for B7) on T cells CTLA-4 germline mutations with incomplete penetrance Treg cells increased, but dysfunctional (decreased CTLA-4 ligand binding) + [71, 75]
Systemic lupus erythematosus -like Recurrent infections; cutaneous, discoid lupus most common presentation, malar rash, oral ulcers, recurrent fever and vasculitis Macrophages
Apoptotic B cells
MFG-E8 (mice) and complement factor C1q Homozygous nonsense and missense mutations on chromosome 1p (C1q) Impaired debris removal,
autoantibodies against C1q correlates with thyroid function in AITD
+ [76,77,78,79]
Common variable immunodeficiency See above APCs
Treg cells
B cells
naïve T cells
BAFF-R P21R variant
BAFF (SNPs rs1041569 & rs2893321)P21R (TNF-RSF13C allele) Higher levels stimulate B cell survival, increase of TR antibody levels ++ [102,103,104, 106, 107]
Hyper-IgM syndrome Elevated serum IgM, but deficiency in IgG/A/E, recurrent respiratory and gastrointestinal infections with pyogenic bacteria and opportunistic organisms (e.g., P. jirovecii) APCs
T cells
B cells
CD40 Autosomal recessive CD40 gene mutations Upregulation of CD40 on thyrocytes, increased co-stimulatory effects and immunoglobulin class switching + [5, 14, 54, 108]
Common variable immunodeficiency See above APCs
Treg cells
B cells
Naïve T cells
Miscellaneous Decreased methylation of various genes Higher ICAM-1, decreased B cell class switching +/– [109, 120, 121]
Skewed X-chromosome inactivation Wiskott–Aldrich syndrome: PID with eczema, thrombocytopenia, and diarrhea Thymus
T cells
B cells
Miscellaneous Genes for Wiskott–Aldrich syndrome protein, CD40L or the IL-2 receptor-\( \gamma \) chain Reduced thymic expression of X chromosome-dependent self-antigens primes inadequate T cell apoptosis ++ [118, 119]
Trisomy 21 Down syndrome: increased susceptibility to leukemia, but reduced incidence of solid tumors Thymus T cells IFN-γ AIRE and FOXP3 on X chromosome Increased production of IFN-γ with augmented Th1 responses
Reduced activity of Treg cells
++ [51, 53, 66]
  1. ADCC antibody dependent cellular cytotoxicity, AIHA autoimmune hemolytic anemia, AITD autoimmune thyroid disease, AH autoimmune hepatitis, APC antigen presenting cell, BAFF B-lymphocyte activating factor, CD cluster of differentiation, CTLA cytotoxic T-lymphocyte-associated protein, FasL type-II transmembrane protein of TNF family, FOXP3 forkhead box P3, HLA human leukocyte antigen, IL interleukin, IFN interferon, IPEX immunodysregulation polyendocrinopathy enteropathy X-linked, ITP immune thrombocytopenic purpura, MFG-E8 Milk fat globule epidermal growth factor 8, PID primary immunodeficiency, T1DM type 1 diabetes mellitus, TR thyrotropin related