Phenocopies of IEIs associated with autoantibodies or somatic variants
| Disease . | Genetic defect/presumed pathogenesis . | Circulating T cells . | Circulating B cells . | Serum Ig . | Associated features/similar IEI . |
|---|---|---|---|---|---|
| 1. Phenocopies of IEIs | |||||
| Associated with somatic mutations | |||||
| Autoimmune lymphoproliferative syndrome (ALPS-SFAS) | Somatic mutation in TNFRSF6 | Increased CD4−CD8−double-negative (DN) αβ T cells | Normal, but increased, number of CD5+ B cells | Normal or increased | Splenomegaly, lymphadenopathy, autoimmune cytopenias, defective lymphocyte apoptosis/ALPS-FAS (=ALPS) |
| RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in KRAS (GOF) | Normal | B-cell lymphocytosis | Normal or increased | Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like |
| RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in NRAS (GOF) | Increased CD4−CD8− DN T αβ cells | Lymphocytosis | Normal or increased | Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like |
| Cryopyrinopathy, (Muckle–Wells/CINCA/NOMID-like syndrome)a | Somatic mutation in NLRP3 | Normal | Normal | Normal | Urticaria-like rash, arthropathy, neurological signs |
| Hypereosinophilic syndrome due to somatic mutations in STAT5b | Somatic GOF mutation in STAT5B | Normal | Normal | Normal | Eosinophilia, atopic dermatitis, urticarial rash, diarrhea |
| VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome | Somatic GOF mutation in UBA1 (XL) | Lymphopenia | Reduced | Normal | Late-onset treatment-refractory inflammatory syndrome (fevers, neutrophilic dermatosis, macrocytic anemia, dysplastic bone marrow, interstitial nephritis, chondritis, vasculitis) |
| TLR8 GOF | Somatic GOF mutation in TLR8 | ↑ (mild) CD4+, CD8+ T cells, effector/memory subsets; ↓NK cells | Normal B cells/subsets, ↓ pDCs | Normal/lo IgG, ↑ IgM/IgA | Severe cytopenias, hepatosplenomegaly, lymphadenopathy; recurrent infections; hypocellular bone marrow, elevated proinflammatory serum cytokines |
| JAK1 GOF (S703I)a | Somatic GOF mutation in JAK1 | Upregulated STAT3 phosphorylation in T cells | Upregulated STAT6 phosphorylation | Asymmetric pustular rash (inflammatory linear verrucous epidermal nevus) chronic GI tract inflammation, eosinophilic colitis. Peripheral eosinophilia. Membranous glomerulonephritis, asthma | |
| Associated with autoantibodies | |||||
| Chronic mucocutaneous candidiasis | AutoAb to IL-17A and/or IL-17F | Normal | Normal | Normal | Endocrinopathy, chronic mucocutaneous candidiasis/CMC |
| Adult-onset immunodeficiency with susceptibility to environmental mycobacteria | AutoAb to IFN-γ | Decreased naïve T cells | Normal | Normal | Susceptibility to intramacrophagic pathogens (mycobacteria, fungi, Talaromyces marneffei, Salmonella), VZV infections/MSMD, or CID |
| Recurrent staphylococcal skin infection | AutoAb to IL-6 | Normal | Low | Normal | Staphylococcal infections/STAT3 deficiency |
| Pulmonary alveolar proteinosis | AutoAb to GM-CSF | Normal | Normal | Normal | Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency |
| Acquired angioedema | AutoAb to C1 inhibitor | Normal | Normal | Normal | Angioedema/C1 INH deficiency (hereditary angioedema) |
| Atypical hemolytic uremic syndrome | AutoAb to complement factor H (CFH) | Normal | Normal | Normal | aHUS = spontaneous activation of the alternative complement pathway |
| Thymoma with hypogammaglobulinemia (Good’s syndrome) | AutoAb to various cytokinesb including type I IFNs | Decreased CD4+ T cells, increased CD8+ T cells | No B cells | Decreased | Invasive bacterial, viral, or opportunistic infections, autoimmunity, PRCA, lichen planus, cytopenia, colitis, chronic diarrhea |
| Critical viral infections | AutoAb to type 1 IFNs (IFN-α, IFN-ω) | • Severe, life-threatening SARS-CoV-2 infection • Critical/“breakthrough” COVID-19 pneumonia • Adverse reactions to yellow fever YFV-17D live-attenuated viral vaccine • Critical influenza pneumonia • Critical Middle East respiratory syndrome (MERS) pneumonia • West Nile virus (WNV) encephalitis | |||
| Sporadic infectious mononucleosis and chronic EBV infection | AutoAb to IL-27 | Infectious mononucleosis, chronic EBV active infection/IL-27RA deficiency | |||
| Disease . | Genetic defect/presumed pathogenesis . | Circulating T cells . | Circulating B cells . | Serum Ig . | Associated features/similar IEI . |
|---|---|---|---|---|---|
| 1. Phenocopies of IEIs | |||||
| Associated with somatic mutations | |||||
| Autoimmune lymphoproliferative syndrome (ALPS-SFAS) | Somatic mutation in TNFRSF6 | Increased CD4−CD8−double-negative (DN) αβ T cells | Normal, but increased, number of CD5+ B cells | Normal or increased | Splenomegaly, lymphadenopathy, autoimmune cytopenias, defective lymphocyte apoptosis/ALPS-FAS (=ALPS) |
| RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in KRAS (GOF) | Normal | B-cell lymphocytosis | Normal or increased | Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like |
| RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in NRAS (GOF) | Increased CD4−CD8− DN T αβ cells | Lymphocytosis | Normal or increased | Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like |
| Cryopyrinopathy, (Muckle–Wells/CINCA/NOMID-like syndrome)a | Somatic mutation in NLRP3 | Normal | Normal | Normal | Urticaria-like rash, arthropathy, neurological signs |
| Hypereosinophilic syndrome due to somatic mutations in STAT5b | Somatic GOF mutation in STAT5B | Normal | Normal | Normal | Eosinophilia, atopic dermatitis, urticarial rash, diarrhea |
| VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome | Somatic GOF mutation in UBA1 (XL) | Lymphopenia | Reduced | Normal | Late-onset treatment-refractory inflammatory syndrome (fevers, neutrophilic dermatosis, macrocytic anemia, dysplastic bone marrow, interstitial nephritis, chondritis, vasculitis) |
| TLR8 GOF | Somatic GOF mutation in TLR8 | ↑ (mild) CD4+, CD8+ T cells, effector/memory subsets; ↓NK cells | Normal B cells/subsets, ↓ pDCs | Normal/lo IgG, ↑ IgM/IgA | Severe cytopenias, hepatosplenomegaly, lymphadenopathy; recurrent infections; hypocellular bone marrow, elevated proinflammatory serum cytokines |
| JAK1 GOF (S703I)a | Somatic GOF mutation in JAK1 | Upregulated STAT3 phosphorylation in T cells | Upregulated STAT6 phosphorylation | Asymmetric pustular rash (inflammatory linear verrucous epidermal nevus) chronic GI tract inflammation, eosinophilic colitis. Peripheral eosinophilia. Membranous glomerulonephritis, asthma | |
| Associated with autoantibodies | |||||
| Chronic mucocutaneous candidiasis | AutoAb to IL-17A and/or IL-17F | Normal | Normal | Normal | Endocrinopathy, chronic mucocutaneous candidiasis/CMC |
| Adult-onset immunodeficiency with susceptibility to environmental mycobacteria | AutoAb to IFN-γ | Decreased naïve T cells | Normal | Normal | Susceptibility to intramacrophagic pathogens (mycobacteria, fungi, Talaromyces marneffei, Salmonella), VZV infections/MSMD, or CID |
| Recurrent staphylococcal skin infection | AutoAb to IL-6 | Normal | Low | Normal | Staphylococcal infections/STAT3 deficiency |
| Pulmonary alveolar proteinosis | AutoAb to GM-CSF | Normal | Normal | Normal | Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency |
| Acquired angioedema | AutoAb to C1 inhibitor | Normal | Normal | Normal | Angioedema/C1 INH deficiency (hereditary angioedema) |
| Atypical hemolytic uremic syndrome | AutoAb to complement factor H (CFH) | Normal | Normal | Normal | aHUS = spontaneous activation of the alternative complement pathway |
| Thymoma with hypogammaglobulinemia (Good’s syndrome) | AutoAb to various cytokinesb including type I IFNs | Decreased CD4+ T cells, increased CD8+ T cells | No B cells | Decreased | Invasive bacterial, viral, or opportunistic infections, autoimmunity, PRCA, lichen planus, cytopenia, colitis, chronic diarrhea |
| Critical viral infections | AutoAb to type 1 IFNs (IFN-α, IFN-ω) | • Severe, life-threatening SARS-CoV-2 infection • Critical/“breakthrough” COVID-19 pneumonia • Adverse reactions to yellow fever YFV-17D live-attenuated viral vaccine • Critical influenza pneumonia • Critical Middle East respiratory syndrome (MERS) pneumonia • West Nile virus (WNV) encephalitis | |||
| Sporadic infectious mononucleosis and chronic EBV infection | AutoAb to IL-27 | Infectious mononucleosis, chronic EBV active infection/IL-27RA deficiency | |||
Abbreviations for all tables: XL, X-linked; AR, autosomal recessive; AD, autosomal dominant; LOF, loss of function; GOF, gain of function; PRCA, pure red cell aplasia; autoAb, autoantibody; aHUS, atypical hemolytic–uremic syndrome; ALPS, autoimmune lymphoproliferative syndrome; CID, combined immunodeficiency.
Total number of conditions for Table 10: 17 (8 due to somatic mutations; 9 due to autoantibodies).
New phenocopies: 2, 1 due to somatic mutation in JAK1 (100) and 1 due to autoantibodies against IL-27 (68). Antibodies against type I interferons previously described for patients with severe COVID-19 were now also described in patients with other severe viral infections; hence, this entry was modified to include SARS-CoV-2 breakthrough infections and others (123, 124).
Phenocopies of germline disease.
Autoantibodies against IL-23 were described in the context of thymoma (125).