Introduction
Novel gene defects underlying IEI—2020 | ||||||||
Genetic defect | Inheritance/mechanisms | T/NK cells | B cells | Ig levels | Clinical features, cellular defects, and evidence of variant pathogenicity | Table (for classication)[2, 3] | Refs | |
PAX1 (8 patients, 3 families; 2 papers with overlapping patients) | AR (LOF) | • T−B+NK+ SCID • Severe T lymphopenia, low TRECs, | • Normal | • ~ Normal IgM, low IgA, normal to ↑ IgE, | • Omenn’s-like syndrome (erythroderma, lymphocytosis, eosinophilia, ↓ proliferation to PHA, severe/recurrent infections), • No thymus, T cell deficiency not corrected by HSCT despite donor chimerism • Also: otofaciocervical syndrome type 2 (OTFCS2) Validation • Reporter assays established hypomorphic LOF of mutant alleles • Patients’ derived iPSCs differentiated to thymic epithelial cells demonstrated abnormalities in thymic epithelial progenitors, consistent with failure of HSCT to reconstitute T cells • Similar to mouse model | Table 1 Subtable 1 | ||
SLP76 (1 patient) | AR (LOF) | • T cells reduced, • ↓↓ CD4+, ↑ CD8+ T cell proportions • Low naïve, ↑ TCM CD4+ T cells; • CD8+ T cell mostly clonally expanded TEMRA • Low TRECs • NK normal numbers | • Normal numbers but ↓ class-switched memory and transitional B cells, • ↑ naïve and immature B cells | • High IgM, low IgA | • Combined immunodeficiency, • Early-onset skin abscesses, rash recurrent infections, autoimmunity, • Neutrophil dysfunction, platelets dysfunction • ↓ T cell proliferation to PHA, anti-CD3/CD28 stimulation, partially restored by IL-2 • ↓ NK cell degranulation • ↓ Actin polymerization Validation • Generation of SLP76-deficient Jurkat T cells; expressing WT or mutant SLP76 allele, mimicking patient cellular phenotypes; • Partial rescue of some of the functional defects by expression of WT SLP76 | Table 1 Subtable 1 | [7] | |
MCM10 (1 patient) | AR (LOF) | • Mild lymphopenia • ↓ TCM, TEM cells • ↓↓↓ NK cells (↑ CD56bright, nearly absent CD56dim mature NK) | • ↓ B cells | • slightly ↓ IgG, normal IgM/A | • Severe (fatal) CMV infection • HLH-like (based on biomarkers, not clinical features • Phenocopies GINS1 and MCM4 deficiencies • ↓ NK function Validation • Detailed functional analysis of MCM10 variant in primary fibroblasts, transfectants, iPSC, and CRISPR/Cas9-gene-edited NK92 human NK cell line • assessed mutant allele on NK cell development in humanized mice reconstituted with CD34+ HSC generated from the patients or healthy donor IPSCs | Table 2 Subtable 2 | [8] | |
IL6ST (gp130; 12 patients, 8 families) | AD (DN) | • Normal T cell numbers • ↑ naïve CD4 and CD8 T cell proportions • ↓ TCM CD4+ and CD8+ T cells and TEM CD8 T cells; • ↓ MAIT, Tfh cells, • ↑ Th2, • Low to normal NK cell counts | Normal numbers of B cells, low memory B cell proportions | • Normal/low IgG, A, • Normal IgM, • Hyper IgE. • vaccine IgG normal | • HIES – STAT3-like; • Dermatitis/eczema, eosinophilia, recurrent skin infections, pneumonia, bronchiectasis, pneumatoceles with severe secondary pulmonary aspergillosis, connective tissue defects (scoliosis, face, joints, fractures, palate, tooth retention) • Phenocopies aspects of IL6R and IL11R deficiencies (due to unresponsiveness to these cytokines) Validation • LOF and DN alleles shown by overexpression in GP130 deficient HEK293T cells; • Impaired GP130/STAT3 signaling (mostly downstream of IL-6) in patients’ fibroblasts and leukocytes | Table 2 Subtable 5 | [9] | |
IL6ST (complete deficiency; 6 patients, 4 families) | AR (LOF) | ND (death in utero or in neonatal period occurred for most affected individuals) | • Fatal Stuve-Wiedemann-like syndrome; skeletal dysplasia, lung dysfunction, renal abnormalities, thrombocytopenia, dermatitis, eczema • Defective acute phase response • Complete unresponsiveness to IL-6 family cytokines Validation • Complete LOE (for one allele) and LOF for two alleles tested by overexpression in GP130 deficient HEK293T to all cytokines tested of the IL-6 family. • Effects of variants well-characterized, including a partial rescue of patient amniocytes | Table 2 Subtable 5 | ||||
FNIP1 (6 patients; 5 families) | AR (LOF) | Mild T cell lymphocytosis | B cell lymphopenia (absent/low; BM block [few immature B cells]) | agamma/hypogammaglobulinemia | • Early onset recurrent infections (sinopulmonary) • Bronchiectasis • Congenital heart defects (e.g., hypertrophic cardiomyopathy) • Variable neutropenia (severe or intermittent) Crohn disease (one patient) • Developmental delay • Increased AMPK activity Validation | Table 3 Subtable 1 | ||
PIK3CG (2 patients; 2 families) | AR (LOF) | • Normal CD4, • ↓ Treg, ↓ CD8 | • Normal but ↓ memory B cells | • Hypogamma • Intact vaccine responses | • Cytopenia/lymphopenia, eosinophilia, lymphadenopathy, splenomegaly, • recurrent infections • HLH-like; ↑ inflammatory markers Validation • ↓ T cell proliferation, activation in vitro • Cellular defects recapitulated in PIK3CG targeted Jurkat T cell line and Pik3cg ko mice | Table 3 Subtable 2 | ||
CTNNBL1 (1 patient) | AR (LOF) | ↓ T cells | • Reduced memory B cells; • Impaired CSR, SHM | • Progressive severe hypogamma | CVID, autoimmune cytopenias, hypogamma, recurrent infections, hyperplastic GC’s; (mutation reduces binding of CTNNBL1 to AID, resulting in less nuclear translocation of AID) Validation • detailed functional analysis of CTNNBL1 variant in EBV B lines, and engineered RAMOS cell lines; • mutant allele reduces the binding of CTNNBL1 to AID, with impaired nuclear translocation of AID; • defective SHM rescued in mutant Ramos cells by WT CTNNBL1 | Table 3 Subtable 3 | [18] | |
TNFSF13 (APRIL; 1 patient) | AR (LOF) | • Normal T/NK cells | Normal total B cell counts, ↑ IgM+ marginal zone /↓ sw memory B cells, ↓ blood plasmablasts | • Hypogamma | CVID, chronic but mild infections Validation • LOE and LOF allele, • Functional analysis of the variant in PBMCs and overexpression; • Impaired function of iPSC-moDC in promoting B cell differentiation could be rescued with exogenous APRIL | Table 3 Subtable 3 | [19] | |
SOCS1 (15 patients; 10 families) | AD (by haploinsufficiency) | • ↓CD4, CD8 T cells | • Predom naïve B cells • ↓ sw memory, ↑ CD21lo B | • ↓ IgM, G, A but protective specific Abs; • ANA’s, autoAbs • ↑ serum BAFF | • Recurrent bacterial infections, • Severe multisystemic autoimmunity (flared in context of infection-induced inflammation), ITP, AIHA, SLE, GN, hepatosplenomegaly, psoriasis, arthritis, thyroiditis, hepatitis • Evan’s syndrome • 1 patient developed COVID19/MIS-C • neutropenia, lymphopenia • incomplete penetrance Validation • ↑ pSTAT1, ↑ type I/II IFN signature • Reporter assays confirmed impaired inhibition of mutant SOCS • Jakinib effective in vitro and in vivo. | Table 4 Subtable 4 | ||
TET2 (3 patients, 2 families) | AR (LOF) | • ↑ DN T cells • ↓ Th1, Th17, Tfh cells | • ↓ Memory B cells • Impaired B cell diff in vitro to plasma cells | • Variable (hyper−/ hypogamma, ↓ response to pneumococcal vaccine | • ALPS-like (↑ sCD25, sFasL, IL10) • Recurrent viral infections, lymphadenopathy, hepatosplenomegaly, autoimmunity (cytopenias, B cell lymphoma (EBV+ HL-like) • Failure to thrive, developmental delay • EBV viremia • DNA hypermethylation • Defective FAS-mediated apoptosis | Table 4 Subtable 7 | [23] | |
CEBPE (3 patients, 1 family) | AR (GOF) | • Mild lymphopenia •↓ naive, ↑ TEMRA cells | ND | ND | • Recurrent abdominal pain, aseptic fever, systemic inflammation; abscesses, ulceration, infections; mild bleeding diathesis • Autoinflammasome activation/↑ IFN gene expression (autoinflammation, immunodeficiency, neutrophil dysfunction) Validation • homozygous CEBPE variant affecting DNA binding domain, associated with autoinflammation/immunodeficiency • showed altered chromatin occupancy of mutant CEBPE, and transcriptional changes, in patient cells targeting inflammasome and IFN-related genes | Table 5 Subtable 2 | [24] | |
TBX21 (T-bet; 1 patient) | AR (LOF) | • Normal %’s total, CD4 and CD8 T cells, naïve and memory subsets, low frequencies of NK cells • ↓ CXCR3+ CCR6− Th1 cells, CXCR3+ Tfh and CXCR3+ Treg CD4+T cells • ↑ immature NK • ↓ iNKT, MAIT, Vδ2+ γδ T cells | • Normal | • Normal | • MSMD • ↓IFN-γ and TNF-α production by T cell subsets (γδ T cells, MAIT cells, iNKT cells, NK cells,, Vδ2+γδ, Vδ1+γδ, and CD4+ T cells Validation • Biochemical and molecular analysis established the impact of this variant on Tbet function; • Impaired production of IFNγ, TNFα by TBX21-mutant naïve CD4+ T cells under Th1 polarizing cultured in vitro • Tbet-dependent functions restored in patient cells and cell lines by WT TBX21 | Table 6 Subtable 1 | [25] | |
IFNG (2 patients [cousins]) | AR (LOF) | • Normal frequencies of T and NK cells; • ↑ proportions of naive CD4+ and CD8+ T cells; • ↓ frequency of invariant iNKT | • Normal B cell frequencies; • ↓ memory B cells (↓ IgA+ / IgM+, ↑ IgG+ memory B cells) | • Normal | MSMD/BCG-osis • No IFN-γ producing cells Validation • LOE and LOF allele • Biochemical and molecular analysis established impact of this variant on IFN-γ production from patients’ cells • No IFN-γ production by T and NK cells; • Impaired IFN-γ production by patient-derived Herpesvirus saimiri–immortalized T cells restored by introduction of WT IFNG | Table 6 Subtable 1 | [26] | |
NOS2 (1 patient) | AR | • ↓ CD4+ T cells; • ↓ NK cells (mostly all immature cells) • normal CD8+ T | ↓ B cells | ND (specific Ab levels normal) | • Severe susceptibility to CMV-induced disease; fatal • Pneumocystis pneumonia secondary to CMV • Apparent intact responses to infection with other herpes viruses (EBV, VZV, HSV) Validation: • Confirmed functional defect in transfected cells; truncated NOS2 failed to induce nitrous oxide • Recapitulates susceptibility of Nos2 deficient mice to murine CMV infection [27] (these mice are also susceptible to numerous other pathogens) | Table 6 Subtable 3 | [28] | |
SNORA31 (5 patients, unrelated) | AD | • Normal | • Normal | • Seropositive for IgG against many viruses | • Forebrain herpes simplex virus-1 (HSV-1) encephalitis Validation: susceptibility of human pluripotent stem cell (hPSC)–derived cortical neurons from patients or hPSC-derived neurons from healthy donors but engineered to express variant SNORA31 to HSV1 infection, corrected by exogenous IFN-β • Incomplete penetrance | Table 6 Subtable 4 | [29] | |
ATG4A (1 patient) | AD | Normal | Normal | Normal | • Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2 • History of multiple episodes of meningitis; HSV2+ Validation • Impaired HSV2-induced autophagy → increased viral replication and apoptosis of patient fibroblasts • These defects were rescued by introduction of WT ATG4 or LC3B2 into patient fibroblasts | Table 6 Subtable 4 | [30] | |
MAP1LC3B2 (1 patient) | ||||||||
MAPK8 (3 patients, 1 family) | AD (haploinsufficiency) | • Normal total T cells, CD4+ and CD8+ T subsets, NK cells • ↓ Th17 cells | • Normal total B cells and subsets | • Normal | • Chronic mucocutaneous candidiasis (CMC) • Connective tissue disorder (similar to Ehlers-Danlos syndrome) • ↓ Th17 cells ex vivo, in vitro • ↓ Responses of fibroblasts to IL-17A, IL-17F • ↓ c-Jun/ATF-2-dependant TGF β signaling Validation • MAKP8 variant LOE in HEK293 T, heterozygous patients’ cells (↓ Th17 cells ex vivo, in vitro; ↓ fibroblast responses to IL-17A, IL-17F; ↓ TGFβ signaling) • Defective responses of fibroblasts restored by WT MAPK8 | Table 6 Subtable 6 | [31] | |
LSM11 (2 siblings, 1 family) | AR (LOF) | Not reported | • Aicardi-Goutieres syndrome (type 1 IFN-opathy) | Table 7 Subtable 1 | [32] | |||
RNU7–1 (16 patients, 11 kindreds) | ||||||||
CDC42 (15 patients; numerous kindreds reported in 7 papers) | AD | • Normal/decreased T cell numbers, • normal %CD4/CD8 but skewed differentiation | • Normal/B-lymphopenia | • Variable (↑↓) IgM, G, A, E | • Neonatal onset: pancytopenia, fever, rash, hepatosplenomegaly, systemic inflammation, myelofibrosis/proliferation, HLH, multisystemic inflammatory disease. • ↑ serum levels of IL1, IL18, IFN-γ, ferritin, sCD25, CRP etc. • Recurrent GIT/RT infection; • Neurodevelopmental delay, FTT • Mutation affects actin function; • Treated with Anakinra/ IFN-γ mAb ↓NK function (cytox), | Table 7 Subtable 1 | ||
STAT2 (GOF, 3 patients; all deceased; 2 additional deceased sibs but not genotyped; 2 unrelated families) | AR (GOF) | • Low frequency of NK, ↑ frequency of T cells (esp naïve), normal NK degranulation | • Total B cell frequencies within age-matched controls’ ranges • slight ↑ transitional and naïve B cells %‘s | • Low/normal | • Severe fatal early-onset autoinflammation (skin ulceration, fever, seizures, intracranial calcification, multiorgan dysfunction, abnormal neurodevelopment; phenocopy of USP18 deficiency) • ↑ serum IFN-α, IL6, TNFα • IFN-opathy gene signature (impaired regulation of late cellular responses to type 1 IFN), Validation • Study of the mutant STAT2 alleles in STAT2 deficient human cell line, and patient’s immortalized fibroblasts • Patient cells hyper-sensitive to IFN-α → prolonged JAK/STAT signaling/transcriptional activation • Biochemical confirmation that mutant allele is GOF in homozygous, but not heterozygous, combination • Impaired interaction of GOF STAT2 protein with USP18, a negative regulator of type 1 IFN responses | Table 7 Subtable 1 | ||
RIPK1 (12 patients; 5 families, 2 papers) | AD | • Normal T and NK cell numbers • Low/normal CD4+ T cells • Normal/hi CD8+ T cells • ↑ DN T cells | • Normal B cells | ND | • Autoinflamm disorder: regular/prolonged fevers, lymphadenopathy, spleno/hepatomegaly, ulcers, arthralgia, GI features, • ↑ inflamm markers, ↑ pro-inflamm cytokines/gene signature; • Responsive to Tocilizumab (not IL1/TNF blockade) | Table 7 Subtable 2 | ||
NCKAP1L (9 patients; 7 families, 3 papers) | AR (LOF) | • Normal T cell numbers • ↑TCM, exhausted cells; • Possibly immature NK cells but intact function | • Normal B cells and naïve/memory subsets • ↑ CD21lo cells | • Normal/ ↑ Ig levels • autoAbs | • Recurrent URTI, skin rashes/abscesses, ulcers, • Anti dsDNA Abs, SLE-like, lymphadenopathy, fever, HLH-like • FTT • Immunodeficiency coupled with atopy, lymphoproliferation, hyperinflammation ,and cytokine overproduction (↑ Th1) • ↓ T cell proliferation, cytoskeletal defects; | Table 7 Subtable 3 | ||
UBA1 (25 patients) | XL (somatic LOF mutations) | • ↓ Peripheral lymphocyte counts • Loss of immature B cells, nonclassical and intermediate monocyte populations | • Late adulthood onset treatment-refractory inflammatory syndrome • Fevers, cytopenias, dysplastic bone marrow, • Neutrophilic cutaneous and pulmonary inflammation, chondritis and vasculitis • Most patients have an inflammatory syndrome (relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, giant-cell arteritis) or a hematologic condition (MDS, multiple myeloma) • Often fatal Dysregulated proinflammatory neutrophil activation, high inflammatory markers in patients’ serum Validation: • Overexpression of mutant allele favored the production of a catalytically deficient UBA1 • Defective ubiquitylation of patients’ mutant monocytes • CRISPR-Cas9 Uba1–deficient zebrafish model recapitulates the phenotype of systemic inflammation | Table 7 | [47] | |||
Novel phenocopies of inborn errors of immunity | ||||||||
Disease | Mechanisms of disease pathogenesis | Associated/clinical features | Table | Refs | ||||
Severe COVID-19 | • High levels of neutralizing autoAbs against type 1 IFNs (primarily IFNα, IFNω) | • Severe, life-threatening infection with SARS-CoV-2 | Table 10 | [48] |