Table 1.
Lymphoma subtypes in primary immunodeficiencies associated with high susceptibility to develop EBV-driven lymphoproliferative diseases.
| Mutated gene number of patients (n) | Age of onset (years) | EBV-associated diseases | Infections | Other clinical features | Immunological features | Outcome | Defective pathways/functions | |||
|---|---|---|---|---|---|---|---|---|---|---|
| T-cells | B-cells | NK-cells | ||||||||
|
SH2D1A (XLP-1) n > 100 |
0.5–40 | SIM/HLH 50–60% (neurological inv. 25%) B lymphoma 25–30% Vasculitis 3–4% |
EBV 60–70% HHV-6 (1) HHV-7 (1) LCMV (1) |
Lung infections 15% Diss. aspergillosis (1) E. coli sepsis (1) |
Aplastic anemia 3–4% EBV-negative lymphoma EBV-negative vasculitis |
Absence iNKT | Dys-γ, hypo-γ 50% | ↓ NK | HSCT 10–40% Mortality 20–50% |
SLAMR/SAP pathway (T and NK cytotoxicity and AICD) |
|
XIAP (XLP-2) n > 100 |
0.5–40 | SIM/HLH 50% |
EBV 35–40% CMV 10–20% HHV-6 (1) |
IBD 25–40% Inflammatory disorders 5% (uveitis, skin abcesses, etc.) Cholangitis 1–2% |
↓ MAIT ↓ iNKT |
Hypo-γ 15–20% | HSCT 10–30% Mortality 5–30% |
Excess of apoptosis (AICD, TRAIL-R, Fas) NOD1/2 signaling/function |
||
|
ITK n = 13 |
2.5–18 | LPD/B lymphoma 13/13 HLH 1/13 SMT 1/13 |
EBV 13/13 CMV 1/13 VZV 1/13 BK-virus 2/13 |
Lung infections 9/13 PCP 2/13 |
Lung involvement 11/13 Kidney involvement 3/13 Al cytopenias 3/13 |
↓ CD4+ 8/13 ↓ iNKT 5/5 |
Hypo-γ 8/13 | HSCT 4/13 Death 7/13 |
TCR induced calcium flux T-cell proliferation |
|
|
MAGT1 n = 11 |
3–45 | LPD/B lymphoma 7/11 |
EBV 11/11 HSV 2/11, VZV 1/11 JC virus (PML) 1/11 HHV-8 (KS) 1/11 |
Lung infections 9/11 | Al cytopenias 3/11 | ↓ CD4+ ↓ NKG2D |
Dys-γ, hypo-γ 8/11 Lymphocytosis |
HSCT 2/11 Death 3/11 |
NKG2D-dependent cytotoxicity | |
|
CORO1A n = 9 |
0.5–7 | LPD/B lymphoma 5/9 |
EBV 5/9 HPV 4/9, VZV 5/9 HSV 2/9 Parvovirus B19 1/9 |
Lung infections 7/9 Cutaneous leprosy 1/9 Visceral leishmaniasis 1/9 |
Neurological involvement (cognitive impairment) 3/9 | ↓ CD4+ 8/9 ↓ MAIT 1/1 ↓ iNKT 1/1 |
High IgE level 4/5 | HSCT 2/9 Death 4/9 |
Actin regulation T-cell survival NK cytotoxicity |
|
|
CD27 n = 18 |
1–22 | LPD/B lymphoma 12/18 T-cell lymphoma 1/18 SIM/HLH 5/18 Meningitis 1/18 |
EBV 18/18 VZV 2/18 CMV 1/18 |
Lung infections 4/18 Gram-positive sepsis 1/18 Giardiasis 1/18 |
Aplastic anemia 1/18 Uveitis 5/18 Oral anal ulcers 5/18 |
↓ iNKT 3/10 | Hypo-γ 13/18 | ↓ NK | HSCT 4/18 Death 3/18 |
CD27–CD70 pathway (T-cell proliferation) NK cytotoxicity |
|
CTPS1 n = 12 |
0–5 | LPD/B lymphoma 5/12 SIM 5/12 |
EBV 11/12 VZV 6/12 Norovirus 3/12 CMV 2/12, HHV-6 2/12 |
Lung infections 7/12 Meningitis 3/12 |
Eczema 2/12 | ↓ MAIT ↓ iNKT |
↓ lgG2 5/5 ↓ CD27+ B-cells |
↓ NK | HSCT 9/12 Death 3/12 |
De novo pyrimidine synthesis T- and B-cell proliferation |
|
RASGRP1 n = 6 |
5–12 | LPD/B lymphoma 4/6 SMT 2/6 |
EBV 5/6 HSV 1/6 HPV (EV) 1/6 CMV 1/6 |
Lung infections 5/6 Diss. tuberculosis 1/6 LN tuberculosis 1/6 PCP 1/6 |
Al cytopenias 3/6 EBV-negative LPD 2/6 |
↓ CD4+ 4/6 ↓ MAIT 2/2 ↓ iNKT 2/2 |
Hypo-γ 1/6 Hyper-γ 2/6 ↓ CD27+ B-cells 2/4 |
↓ NK 3/6 | HSCT 2/6 Death 2/6 |
MAPK pathway (ERK1/2, T-, B-cell proliferation) Actin/cytoskeleton dynamics NK cytotoxicity |
| CD70 n = 6 |
1–5 | LPD/B-cell lymphoma 5/6 | EBV 6/6 VZV 1/6 |
Lung infections 3/6 | PFAPA 1/6 Hypersensitivity to mosquito bites 1/6 |
↓ MAIT 1/1 ↓ iNKT 1/1 |
Hypo-γ 5/6 ↓ CD27+ B-cells 3/6 |
HSCT 1/6 All alive |
CD27–CD70 pathway (T-cell proliferation) | Decreased 2B4 and NKG2D on memory T CD8+ |
SIM, severe infectious mononucleosis; HLH, hemophagocytic lymphohistiocytosis; LPD, lymphoproliferative disorder; inv., involvement; Diss., disseminated; PCP, pneumocytosis pneumoniae; IBD, inflammatory bowel disease; Al, autoimmunity; Dys-γ, dysgammaglobulinemia; Hypo-γ, hypogammaglobulinemia; KS, Kaposi sarcoma; PFAPA, perdiodic fever, aphtous stomatitis, pharyngitis and cervical adenitis; EV, epidermodysplasia verruciformis; SMT, smooth muscle tumor; PML, progressive multifocal leukoencephalopathy; HSCT, hematopoietic stem cell transplantation; LN, lymph node; EBV, Epstein–Barr virus; LCMV, lymphocytic choriomeningitis virus; CMV, cytomegalovirus; HHV, human herpes virus; VZV, varicella zoster virus; MAIT, mucosal-associated invariant T; AICD, activation-induced cell death; TCR, T-cell receptor; SAP, SLAM-associated protein; SLAMR, SLAM receptor.