Table 1.
Newly reported primary immune dysregulation diseases.
| Disease | Gene defect | Number of patients/families | Consanguinity (numbers of consanguineous families/numbers of non-consanguineous families) | Mode of inheritance | Molecular manifestation | Cellular manifestation | Clinical symptoms | Immune labs | Treatment | Outcomes (alive/dead) | Reference | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Immunodeficiency | Autoimmunity | Inflammation | Malignancy | Lymphoproliferation | Others | HSCT | Target treatment | Others | ||||||||||
| SLC7A7 Deficiency | SLC7A7 | 16/9, 28/NR | 6/3 | AR | Deficiency in y+LAT-1 causes manifested amino acid transport | Impaired absorption of CAAs in intestinal epithelium cells, impaired resorption in renal tubular epithelium cells, increased cell apoptosis of epithelial cells, impaired macrophage phagocytosis, aberrant TLRs pathways | Yes, Organ: pulmonary diseases | Yes, especially lupus nephritis, vitiligo and immune thrombocytopenic purpura | Yes, HLH | NR | Yes, HM, SM | LPI, cardiovascular diseases | Cationic amino-acids levels ↓; BS ↑, D-dimer↑, PAP↑, F1+2 ↑; Leukocyte ↓, thrombocyte ↓, anemia | NR | Anti-cytokines drugs | Prevention of hyperammonemia; nutritional supplementation; prevention of specific complications, such as renal and cardiovascular manifestations | 38/6 | (5–7) |
| CD122 Deficiency | IL2RB | 10/5 | 5/0 | AR | Dysfunctional IL-2R causes dysregulated IL-2/15 signaling, elevated plasma IL-2/15 levels | Dysregulated innate and adaptive immune function | Yes, Organ: pneumonitis, otitis media, urinary tract infection, gastroenteritis and dermatitis Infectious microbes: EBV, CMV |
Yes, AIHA, autoimmune enteropathy | Yes, Early onset IBD | NR | Yes, LAD, HM, SM, large tonsils | Food allergy, eczema, failure to thrive | CD8+ T cells ↑, memory T cells ↑, Tregs ↓, NK cells ↑, Ig ↑, Coombs test + | Yes, 2 alive and 2 dead | Hyper-stimulate residual surface IL-2Rβ using IL-2 anti–IL-2 antibody complexes, IL-2 superkine, orthoIL-2 analogues or IL-2 Fc fusion proteins | Methylprednisolone for management of autoimmunity | 3/7 | (8, 9) |
| DEF6 Deficiency | DEF-6 | 7/3 | 3/0 | AR | Disruption in CTLA-4 traffic | Over-activation of T cells | Yes, Organ: sepsis, respiratory Infectious microbe: CMV, EBV, respiratory syncytial virus, rotavirus, rhinovirus, influenza B; S. pneumoniae, S. aureus, S. epidermis, E. aerogenes, E. cloacae, E. faecalis, E. aerogenes, K. oxytoca, S. epidermis, E. faecalis |
Yes, AIHA | Yes, recurrent fevers, IBD | Yes, EBV+ nodular sclerosis classic Hodgkin lymphoma | Yes, HM, SM | Dilated cardiomyopathy in some patients | CD4+ T cells ↓, thrombocytes ↓, ANCA and autoantibodies + | Yes, Auto-HSCT 1alive | CTLA-4-Ig therapy, | Immunosuppressants, plasma exchanges | 6/1 | (10, 11) |
| FERMT1 Deficiency | FERMT1 | 19/10 | 2/1, 7 NR | AR | Reduced integrin activation, higher ROS concentration | Reduced keratinocyte- ECM adhesion, reduced epidermal keratinocytes proliferation, fibroblasts stimulated. | NR | NR | Yes, colonic inflammation, gingivitis, periodontitis and mucosal inflammation | Higher risk of SCC | NR | Skin atrophy, blistering, poikiloderma, photosensitivity, mucosal stenosis | Immunofluorescence shows structure abnormality | NR | NR | Gene therapy and protein replacement may be useful | 19/2 | (12–14) |
| SOCS1 Deficiency | SOCS1 | 12/7 | NR | AD | Enhanced STAT1 phosphorylation and a proapoptotic transcriptional signature | Increased sensitivity to interferons | Only two of the patients are reported to have severe infection history, one with COVID-19 and one with bronchopulmonary | Yes, AIHA, ITP, polyarthritis, psoriasis | Yes, multisystem inflammation like fever | NR | Yes, lymphoproliferation | NR | Neutrophils ↓, lymphocytes ↓, Ig ↓, autoantibodies +, | NR | SOCS1 mimetic peptide and JAK1/2 inhibitor baricitinib | Corticosteroids, mycophenolate mofetil | 12/0 | (15, 16) |
| TGFB1 Deficiency | TGFB1 | 3/2 | 1/1 | AR | Defective TGFB1 signaling and reduced phosphorylation of SMAD2/3 in lamina propria mononuclear CD45+ CD19+ and CD3+ cells | T cells fail to activate and proliferate properly after anti-CD3/anti-CD28 or specific antigens stimulation | Yes, Organ: LRTI, URTI, retinitis Infectious microbe: CMV |
NR | Yes, infantile IBD | NR | NR | CNS disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy | T cell proliferation under stimulation of CD3 ↓ | NR | Recombinant TGF-β1 replacement | Surgery, nutritional therapy and fecal microbiota transplantation targeting early onset IBD; anti-inflammatory therapy | 1/2 | (17) |
| RIPK1 Deficiency | RIPK1 | 13/10 | 3/1, 6 NR | AR | Impaired proinflammatory signaling | Dysregulated cytokine releases such as increased IL-1β and decreased IL-10, higher levels of inflammasome activity upon stimulation, enhanced necroptosis | Yes, Organ: thrush mycotic stomatitis, enteritis, pneumonia, conjunctivitis. Infectious microbe: candida albicans, |
NR | Yes, recurrent fever, early-onset IBD | NR | Yes, HM, SM | NR | Naïve CD4+ T and naïve CD8+ T, B and NK cells ↓, IL-1β ↑ | Controversial, 1 alive | NR | Surgery for IBD, improvement pulmonary hypertension, drugs protecting liver, intravenous injection of globulin and antibiotics to resist the bacterial infection | 7/6 | (18–20) |
| CD137 Deficiency | TNFRSF9 | 6/6 | 5/1 | AR | Impaired cositmulation, mitochondrial respiration, biogenesis and function | Impaired T-cell survival, proliferation, and cytotoxicity; Diminished NK cell function; Reduced B cell activation, proliferation, and class switch recombination | Yes, Organ: sinopulmonary infections, bronchiectasis, Infectious microbes: EBV | Yes, AIHA | Yes, persistent fevers, HLH | Yes, high predisposition to EBV-related B-cell lymphoma | Yes, HM, SM, LAD | NR | Proportions of transitional and immature B ↑, memory B cells and plasmablasts ↓, NK cells ↓, TFHs ↓, proportion of Tregs ↓, Ig ↓, | Yes, 1 alive | Other costimulators like CD28 | Immunosuppression, antibiotic prophylaxis, regular immunoglobulin substitution, anti-CD20 mAb (rituximab) and chemotherapy | 6/0 | (21–23) |
| TET2 Deficiency | TET2 | 6/3 | 2/0, 1 NR | AR | Increased level of DNA methylation causes failure of transcription factors binding | Impediment in GC exit, antigen presentation and differentiation of GCB cells | Yes, Organ: LRTI Infectious microbe: RSV, CMV, EBV |
Yes, autoimmune cytopenias | Yes, HLH | Yes, remarkable predisposition to lymphoma | Yes, LAD, HM, SM | Growth impairment, variable thyroid diseases | DNT ↑, class-switch memory B cell ↓, sFasL ↑, | Yes, 2 alive, 2 dead | Inflammatory signals inhibition | Vitamin C treatment, infection prevention; Intravenous immunoglobulin, rituximab (anti-CD20 antibody) and corticosteroid | 4/2 | (24, 25) |
AD, autosomal dominant; AIHA, autoimmune hemolytic anemia; ANCA, anti-neutrophil cytoplasmic antibodies; AR, autosomal recessive; BS, bleeding score; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HLH, hemophagocytic lymphohistiocytosis; HM, hepatomegaly; IBD, Inflammatory bowel disease; LAD, lymphadenopathy; LPI, lysinuric protein intolerance associates; LRTI, lower respiratory tract infection; NR, none reported; F1+2, circulating prothrombin fragment 1 and 2; PAP, plasmin-α2-antiplasmin; SCC, squamous cell carcinoma; SM, splenomegaly; URTI, upper respiratory tract infection.