Table 1 Interplay of autoimmunity and immunodeficiency regarding Graves’ 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 Granulocytes | 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 | ++ | |
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 | + | |
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 | +/– | |
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) | + | |
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 | + | |
Common variable immunodeficiency | See above | APCs Treg cells B cells naïve T cells | BAFF BAFF-R P21R variant | BAFF (SNPs rs1041569 & rs2893321)P21R (TNF-RSF13C allele) | Higher levels stimulate B cell survival, increase of TR antibody levels | ++ | |
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 Thyrocytes | CD40 | Autosomal recessive CD40 gene mutations | Upregulation of CD40 on thyrocytes, increased co-stimulatory effects and immunoglobulin class switching | + | |
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 | +/– | |
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 | ++ | |
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 | ++ |