Human inborn errors of immunity resulting in severe EBV-induced disease
| Mutated gene . | Clinical features . | Viral infections . | Outcomes . | Cellular phenotype . | Treatment . | Mechanism of disease . | References . |
|---|---|---|---|---|---|---|---|
| SH2D1A (SAP) (n > 100) | Age of onset, 0.5-40 y EBV viremia (75%), FIM/HLH (∼50-60%), hypogammaglobulinemia (40-50%), B lymphoma (Burkitt/NHL; EBV+ and EBV−; ∼25%) | EBV | ∼30-80% mortality | ↓ memory B cells, no NKT cells, ↑ TEMRA (exhausted-type) CD8+ T cells | IV Ig, B-cell depletion (rituximab), chemotherapy for lymphoma, HSCT (curative in >90% of cases) | ↓SLAM/SAP-dependent activation of NK and Ag-specific CD8+ T cells by Ag-presenting or transformed B cells | 26-34 |
| ITK (n = 22) | Age of onset, 3-44 y EBV viremia (100%), EBV-induced lymphoproliferation (∼70%), EBV+ B-cell lymphoma (mostly Hodgkin; 1 NHL, 1 Burkitt lymphoma) (∼80%), other infections (epidermodysplasia verruciformis; 2 patients), CD4+ T-cell lymphopenia (∼65%), splenomegaly (∼60%), progressive hypogammaglobulinemia (>50%), some autoimmunity (25%) | EBV,CMV, VZV,HPV | 45% mortality | Normal % CD3+ T cells but ↓ naive CD4+ T cells, ↓ NKT cells | Rituximab, chemotherapy for lymphoma, IV Ig (not particularly effective), HSCT (5/7 alive and well post-HSCT) | ↓T cell activation (↓PLCγ activation) | 35-47 |
| MAGT1 (n = 22) | Age of onset, 3-45 y, chronic EBV viremia (>90%), EBV-induced lymphoproliferation (not HLH), EBV+ B lymphoma (Burkitt/Hodgkin/DLBCL; 70%), CD4+ T-cell lymphopenia (∼50%), splenomegaly, progressive hypogammaglobulinemia (>50%), intellectual/developmental disability (2/3 patients), autoimmunity (cytopenia, Guillain-Barre syndrome, hepatitis), recurrent infections (80%), Kaposi sarcoma (1 patient), Castleman disease (1 patient) | EBV,VZV, HSV, CMV, KSHV; molluscum contagiosum | ∼25% mortality | ↑ B cells, ↓ memory B cells, inverted CD4/CD8 ratio, ↓ NKG2D expression on NK and CD8+ T cells | Rituximab, R-CHOP; IV Ig; HSCT (2/4 patients died post HSCT); risk of hemorrhage pre-/post-HSCT; Mg supplementation (though variable effect) | ↓T cell activation (↓ TCR-induced Mg2+/Ca2+ flux, PLCγ activation); ↓ NKG2D impairs NK/CD8+ T cells cytotoxicity toward B cells; glycosylation defect (likely impairs expression of NKG2D, and other important immunoregulatory glycoproteins, as well as potentially affecting stability of serum Ig) | 46-56 |
| CTPS1 (n = 18) | Age of onset: 0-5 y EBV viremia (> 90%) EBV-lymphoproliferative diseases (30-50%) Severe IM (∼50%) Recurrent viral/bacterial infections (100%) Poor Ab responses to vaccines/infections; hypogammaglobulinemia (∼30%) | EBV,VZV (∼50%), HSV, CMV, HHV6 (∼20%); norovirus, adenovirus | ∼40% mortality | ↓ NKT, NK, MAIT cells; ↓ memory B and CD8+ T cells | Rituximab, adoptive EBV-specific CD8+ T cell therapy, IV Ig, HSCT (11/14 alive and well) | ↓ activation/proliferation of T and B cells (↓ de novo pyrimidine synthesis), CD27/CD70-induced T cell proliferation may be impaired, ↓IFN-γ production | 57-60 |
| RASGRP1 (n = 9) | Age of onset, 0-7 y EBV viremia (>70%) EBV+ B-lymphoma (Hodgkin), smooth muscle tumor (∼70%) CD4+ T cell lymphopenia Poor Ab responses to some vaccines/infections (∼20%) Epidermodysplasia verruciformis (1 patient) Lymphadenopathy Autoimmunity (cytopenias, ANA, hepatitis; ∼50%) Recurrent bacterial/viral infections (pneumonia) (100%) HLH (1 patient) | EBV,CMV, VZV, HSV1,HPV;molluscum contagiosum | ∼30-35% mortality (3/9 patients deceased) | ↓ naive CD4+ and CD8+ T cells, ↓ TCR αβ/↑ TCR γδ cells; ↑ CD21lo B cells; ↓ NK, MAIT cells; no NKT cells; ↓ EBV-specific CD8+ T cells | Rituximab, IV Ig, allogeneic HSCT (1 patient) | ↓ ERK activation in T cells; ↓ T cell proliferation to mitogen, Ags; ↓ CD27/CD70-induced T cell proliferation; ↓ CTPS1 expression in activated T cells; ↓ NK cell function | 61-65 |
| CD27 (n = 18) | Age of onset, 1-22 y EBV viremia (∼90%), severe HLH (∼25%), EBV-induced lymphoproliferation (∼50%), EBV+ B lymphoma (∼40%; Hodgkin, DLBCL), lymphadenopathy, hypogammaglobulinemia, poor Ab responses to some vaccines/infections (∼70%), autoimmunity (20-25%) | EBV,VZV, CMV; recurrent bacterial/viral infections | ∼30% mortality (5/18 patients deceased) | Normal/↓ NKT, MAIT cells; ↓ EBV-specific CD8+ T cells; ↓ 2B4 expression on CD8+ T cells | Rituximab, R-CHOP, steroids; IV Ig; 3/3 patients successfully treated with HSCT | ↓ CD27/CD70-induced T cell proliferation; ↓ EBV Ag-induced T cell proliferation/expansion; ↓ CD8+ T cell cytotoxicity toward B cells; ↓ NKG2D, 2B4 may impair CD8+ T cell cytotoxicity toward B cells | 66-69 |
| CD70 (n = 6) | Age of onset, 1-5 y EBV viremia (100%), EBV lymphoproliferation (80%), EBV+ B lymphoma (Hodgkin; 80%), lymphadenopathy, hypogammaglobulinemia, poor Ab responses to some vaccines/infections (60-80%), autoimmunity (20-25%, eg Behçet) | EBV,VZV, CMV (50%);recurrent bacterial/viral infections | All patients currently alive | ↑ naive CD4+, CD8+ T cells; ↓ memory B cells; normal/↓ EBV-specific CD8+ T cells but impaired functionality; ↓ NKG2D, 2B4 on CD8+ T cells | IV Ig, prophylactic antibiotics; chemotherapy for lymphoma; rituximab; 2 patients successfully treated with HSCT | 69-71 | |
| TNFRSF9* (n = 8) | Age of onset, 3-6 y EBV viremia (75%), HLH (25%), EBV lymphoproliferation (50%), EBV+ B lymphoma (3 patients), EBV T-cell lymphoproliferation (CAEBV), recurrent sinopulmonary infections (Candida, Staphylococcus, pneumonia; 90%), lymphadenopathy. hypogammaglobulinemia, poor Ab responses to some vaccines/infections (∼60%) | EBV, HSV | 7 patients currently alive, 1 died (HLH) | ↓ naive, ↑ effector memory CD4+, CD8+ T cells (post-chemo/rituximab); ↓ memory B cells; ↓ NK, NKT, MAIT cells | IV Ig; rituximab; chemotherapy for lymphoma; HSCT (1 patient) | ↓ T cell proliferation, IFN-γ secretion; ↓ EBV-specific CD8+ T-cell cytotoxicity | 72-74 |
| Mutated gene . | Clinical features . | Viral infections . | Outcomes . | Cellular phenotype . | Treatment . | Mechanism of disease . | References . |
|---|---|---|---|---|---|---|---|
| SH2D1A (SAP) (n > 100) | Age of onset, 0.5-40 y EBV viremia (75%), FIM/HLH (∼50-60%), hypogammaglobulinemia (40-50%), B lymphoma (Burkitt/NHL; EBV+ and EBV−; ∼25%) | EBV | ∼30-80% mortality | ↓ memory B cells, no NKT cells, ↑ TEMRA (exhausted-type) CD8+ T cells | IV Ig, B-cell depletion (rituximab), chemotherapy for lymphoma, HSCT (curative in >90% of cases) | ↓SLAM/SAP-dependent activation of NK and Ag-specific CD8+ T cells by Ag-presenting or transformed B cells | 26-34 |
| ITK (n = 22) | Age of onset, 3-44 y EBV viremia (100%), EBV-induced lymphoproliferation (∼70%), EBV+ B-cell lymphoma (mostly Hodgkin; 1 NHL, 1 Burkitt lymphoma) (∼80%), other infections (epidermodysplasia verruciformis; 2 patients), CD4+ T-cell lymphopenia (∼65%), splenomegaly (∼60%), progressive hypogammaglobulinemia (>50%), some autoimmunity (25%) | EBV,CMV, VZV,HPV | 45% mortality | Normal % CD3+ T cells but ↓ naive CD4+ T cells, ↓ NKT cells | Rituximab, chemotherapy for lymphoma, IV Ig (not particularly effective), HSCT (5/7 alive and well post-HSCT) | ↓T cell activation (↓PLCγ activation) | 35-47 |
| MAGT1 (n = 22) | Age of onset, 3-45 y, chronic EBV viremia (>90%), EBV-induced lymphoproliferation (not HLH), EBV+ B lymphoma (Burkitt/Hodgkin/DLBCL; 70%), CD4+ T-cell lymphopenia (∼50%), splenomegaly, progressive hypogammaglobulinemia (>50%), intellectual/developmental disability (2/3 patients), autoimmunity (cytopenia, Guillain-Barre syndrome, hepatitis), recurrent infections (80%), Kaposi sarcoma (1 patient), Castleman disease (1 patient) | EBV,VZV, HSV, CMV, KSHV; molluscum contagiosum | ∼25% mortality | ↑ B cells, ↓ memory B cells, inverted CD4/CD8 ratio, ↓ NKG2D expression on NK and CD8+ T cells | Rituximab, R-CHOP; IV Ig; HSCT (2/4 patients died post HSCT); risk of hemorrhage pre-/post-HSCT; Mg supplementation (though variable effect) | ↓T cell activation (↓ TCR-induced Mg2+/Ca2+ flux, PLCγ activation); ↓ NKG2D impairs NK/CD8+ T cells cytotoxicity toward B cells; glycosylation defect (likely impairs expression of NKG2D, and other important immunoregulatory glycoproteins, as well as potentially affecting stability of serum Ig) | 46-56 |
| CTPS1 (n = 18) | Age of onset: 0-5 y EBV viremia (> 90%) EBV-lymphoproliferative diseases (30-50%) Severe IM (∼50%) Recurrent viral/bacterial infections (100%) Poor Ab responses to vaccines/infections; hypogammaglobulinemia (∼30%) | EBV,VZV (∼50%), HSV, CMV, HHV6 (∼20%); norovirus, adenovirus | ∼40% mortality | ↓ NKT, NK, MAIT cells; ↓ memory B and CD8+ T cells | Rituximab, adoptive EBV-specific CD8+ T cell therapy, IV Ig, HSCT (11/14 alive and well) | ↓ activation/proliferation of T and B cells (↓ de novo pyrimidine synthesis), CD27/CD70-induced T cell proliferation may be impaired, ↓IFN-γ production | 57-60 |
| RASGRP1 (n = 9) | Age of onset, 0-7 y EBV viremia (>70%) EBV+ B-lymphoma (Hodgkin), smooth muscle tumor (∼70%) CD4+ T cell lymphopenia Poor Ab responses to some vaccines/infections (∼20%) Epidermodysplasia verruciformis (1 patient) Lymphadenopathy Autoimmunity (cytopenias, ANA, hepatitis; ∼50%) Recurrent bacterial/viral infections (pneumonia) (100%) HLH (1 patient) | EBV,CMV, VZV, HSV1,HPV;molluscum contagiosum | ∼30-35% mortality (3/9 patients deceased) | ↓ naive CD4+ and CD8+ T cells, ↓ TCR αβ/↑ TCR γδ cells; ↑ CD21lo B cells; ↓ NK, MAIT cells; no NKT cells; ↓ EBV-specific CD8+ T cells | Rituximab, IV Ig, allogeneic HSCT (1 patient) | ↓ ERK activation in T cells; ↓ T cell proliferation to mitogen, Ags; ↓ CD27/CD70-induced T cell proliferation; ↓ CTPS1 expression in activated T cells; ↓ NK cell function | 61-65 |
| CD27 (n = 18) | Age of onset, 1-22 y EBV viremia (∼90%), severe HLH (∼25%), EBV-induced lymphoproliferation (∼50%), EBV+ B lymphoma (∼40%; Hodgkin, DLBCL), lymphadenopathy, hypogammaglobulinemia, poor Ab responses to some vaccines/infections (∼70%), autoimmunity (20-25%) | EBV,VZV, CMV; recurrent bacterial/viral infections | ∼30% mortality (5/18 patients deceased) | Normal/↓ NKT, MAIT cells; ↓ EBV-specific CD8+ T cells; ↓ 2B4 expression on CD8+ T cells | Rituximab, R-CHOP, steroids; IV Ig; 3/3 patients successfully treated with HSCT | ↓ CD27/CD70-induced T cell proliferation; ↓ EBV Ag-induced T cell proliferation/expansion; ↓ CD8+ T cell cytotoxicity toward B cells; ↓ NKG2D, 2B4 may impair CD8+ T cell cytotoxicity toward B cells | 66-69 |
| CD70 (n = 6) | Age of onset, 1-5 y EBV viremia (100%), EBV lymphoproliferation (80%), EBV+ B lymphoma (Hodgkin; 80%), lymphadenopathy, hypogammaglobulinemia, poor Ab responses to some vaccines/infections (60-80%), autoimmunity (20-25%, eg Behçet) | EBV,VZV, CMV (50%);recurrent bacterial/viral infections | All patients currently alive | ↑ naive CD4+, CD8+ T cells; ↓ memory B cells; normal/↓ EBV-specific CD8+ T cells but impaired functionality; ↓ NKG2D, 2B4 on CD8+ T cells | IV Ig, prophylactic antibiotics; chemotherapy for lymphoma; rituximab; 2 patients successfully treated with HSCT | 69-71 | |
| TNFRSF9* (n = 8) | Age of onset, 3-6 y EBV viremia (75%), HLH (25%), EBV lymphoproliferation (50%), EBV+ B lymphoma (3 patients), EBV T-cell lymphoproliferation (CAEBV), recurrent sinopulmonary infections (Candida, Staphylococcus, pneumonia; 90%), lymphadenopathy. hypogammaglobulinemia, poor Ab responses to some vaccines/infections (∼60%) | EBV, HSV | 7 patients currently alive, 1 died (HLH) | ↓ naive, ↑ effector memory CD4+, CD8+ T cells (post-chemo/rituximab); ↓ memory B cells; ↓ NK, NKT, MAIT cells | IV Ig; rituximab; chemotherapy for lymphoma; HSCT (1 patient) | ↓ T cell proliferation, IFN-γ secretion; ↓ EBV-specific CD8+ T-cell cytotoxicity | 72-74 |
Ag, antigen; CAEBV, chronic active EBV; DLBCL: diffuse large B-cell lymphoma; HPV, human papillomavirus; Ig, immunoglobulin; KSHV, Kaposi sarcoma herpesvirus; MAIT, mucosal-associated invariant T; Mg, magnesium; NHL, non-Hodgkin lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone.
Eleven individuals with recessive mutations in TNFRSF9 have been identified, but 4 were asymptomatic. However, 1 of these unaffected individuals is included in the table, as the patient did have chronic EBV viremia.