Table 1.
Immune dysregulation in CIDs: mechanisms and manifestations
| Disease | Gene defect | Mechanism of immune dysregulation/immune dysfunction | Clinical features of immune dysregulation |
|---|---|---|---|
| RAG deficiency | Hypomorphic RAG1 and RAG2 mutations | Restricted T-cell repertoire; impaired thymic architecture and mTEC maturation; decreased AIRE and TRA expression; decreased elimination of autoreactive T cells; Treg abnormalities (reduced number, restricted repertoire, decreased suppressive function); restricted B-cell repertoire; impaired receptor editing; increased levels of BAFF | Autoimmune cytopenias (AIHA, ITP, AIN); granulomas of skin and internal organs; IBD, enteropathy; skin disease (vitiligo, dermatitis); endocrinopathy (hypo/hyperthyroidism); vasculitis; alopecia; liver disease; autoimmune neuropathy; autoimmune myopathy; renal disease; interstitial lung disease; CRMO |
| CD3γ deficiency | CD3G | Decreased TCR signaling strength causing impaired thymic-positive and -negative selection; increased frequency of self-reactive clonotypes; decreased pool of Tregs with impaired suppressor function | Autoimmune cytopenias; hypothyroidism; enteropathy; atopic dermatitis; vitiligo; interstitial lung disease |
| ZAP-70 deficiency | ZAP70 | Decreased TCR signaling strength causing impaired thymic positive and negative selection | Wheezing; erythroderma; IBD; bullous pemphigoid; nephrotic syndrome; autoantibody-induced hemophilia |
| LAT deficiency | LAT | Decreased TCR signaling strength causing impaired thymic positive and negative selection | Autoimmune cytopenias; lymphoproliferative disease |
| LCK deficiency | LCK | Decreased TCR signaling strength causing impaired thymic-positive and -negative selection | Nodular skin lesions with inflammatory infiltrates; autoimmune thrombocytopenia; retinal vasculitis |
| CARD11 deficiency | Heterozygous dominant negative CARD11 variants | Th2 skewing; impaired NF-κB activation; decreased glutamine uptake in response to TCR stimulation; reduced mTORC1 signaling | Severe atopic disease; colitis; necrotizing granulomas; alopecia |
| MALT1 deficiency | MALT1 | Expansion of Th1, Th2, and Th17 cells; high levels of inflammatory cytokines; decreased number of IL-10–producing B cells; decreased Treg number | Eczema; inflammatory gastrointestinal disease |
| CD40 ligand deficiency | CD40LG | Skewing of the IgM repertoire toward self-antigens; decreased number of circulating Tfh cells, Tregs, and Tfr cells | Sclerosing cholangitis; biliary tract and neuroendocrine tumors; autoimmune cytopenia; seronegative arthritis; hypothyroidism; cutaneous granulomas; IBD |
| MHC class I deficiency | TAP1, TAP2, TAPBP, B2M | Impaired peptide binding and presentation to developing thymocytes; impaired positive and negative selection; autoreactive NK and TCRγδ+ T cells | Vasculitis; pyoderma gangrenosum; cutaneous and internal organ granulomas |
| MHC class II deficiency | CIITA, RFXANK, RFX5, RFXAP | Impaired peptide binding and presentation to developing thymocytes, impaired positive and negative selection | Autoimmune cytopenias, liver and biliary tract disease, other autoimmune manifestations |
| STK4 deficiency | STK4 | Increased proportion of transitional B cells; reduced number of memory B cells. In STK4-deficient mice: low number of splenic Tfh cells, follicular helper B cells, and peritoneal B1a cells and absence of marginal zone B cells | Lymphoproliferative disease; autoimmune cytopenias; B- and T-cell lymphoma |
| IL-21 deficiency | IL21 | Impaired Tfh cell and Breg development and plasma blast generation | Severe early-onset colitis |
| ICOS deficiency | ICOS | Treg dysfunction; impaired migration of Tfh cells into the follicles; defective production of IL-10 and IL-21; impaired generation of long-lived memory B cells and plasma cells | Enteropathy; psoriasis; arthritis; autoimmune cytopenias; eczema; granulomas; interstitial lymphocytic pneumonitis |
| APDS1, APDS2 | PIK3CD, PIK3R1 | Increased mTOR signaling; decreased number of naive and memory T cells; increased number of effector/exhausted T cells; decreased Treg homeostasis and function; increased FOXO1 degradation; impaired B-cell migration during GC reaction and maturation | Autoimmune cytopenias; lung nodular hyperplasia; enteropathy; eosinophilic GI disease; thyroiditis; glomerulonephritis; type 1 diabetes; brain inflammatory lesions; autoimmune hepatitis; lymphoproliferation; lymphoma |
AIHA, autoimmune hemolytic anemia; AIN, autoimmune neutropenia; AIRE, autoimmune regulator; BAFF, B-cell activating factor; Breg, regulatory B cell; CRMO, chronic recurrent multifocal osteomyelitis; GC, germinal center; GI, gastrointestinal; IBD, inflammatory bowel disease; IgM, immunoglobulin M; IL, interleukin; ITP, immune thrombocytopenic purpura; mTEC, medullary thymic epithelial cell; NK, natural killer; TCR, T-cell receptor; Tfh, follicular helper T; Tfr, T follicular regulatory; TRA, tissue-restricted antigen; Treg, regulatory T cell.