Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations

Abstract

Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients’ B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4 + T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.

TRAF3 enhances type I interferon receptor signaling in T cells by modulating the phosphatase PTPN22

“…Mice lacking TRAF3 in all mature T cells (T-Traf3 −/− ) have normal T, B, and myeloid cell numbers but mount poor CD4 + and CD8 + T cell responses to infection by the intracellular bacterium Listeria monocytogenes and cannot produce a T cell-dependent humoral response to immunization (22). Many of the functional defects exhibited by TRAF3deficient T cells originate with defective TCR signaling, which we described in T-Traf3 −/− mouse T cells and which was corroborated in human patients with one mutated TRAF3 allele (22,26). A major role of TRAF3 in promoting TCR function is to interfere with negative regulators of early TCR signals.…”

GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

“…Future research including studies in mice is required to investigate a potential causal role of GTF3A mutations in the dysfunction of other immune system components and the other clinical presentations observed. In line with this notion, recent work on TRAF3 deficiency, initially described as a genetic etiology of HSE ( 48 ), has now been associated with B cell dysfunction in patients exhibiting an immune dysregulation syndrome ( 49 ).…”

TRAF3: A novel regulator of mitochondrial physiology and metabolic pathways in B lymphocytes

“…This is corroborated by frequent TRAF3 mutations detected in canine non-Hodgkin lymphomas (NHL) (31)(32)(33)(34). Similar to Traf3 -/mouse B cells, human B cells with germline TRAF3 mutations that reduce TRAF3 expression also exhibit constitutive NF-kB2 activation and enhanced responses to BCR, BAFF, TLR9, and IL-6 signaling, including increased proliferation and plasma cell formation associated with elevated activation of NF-kB1, ERK, AKT, and STAT3 (14). Reconstitution of TRAF3 expression in TRAF3-defi c ient human MM cells induces apoptosis, demonstrating a tumor suppressive role of TRAF3 in B cell malignancies (9,35).…”

“…The first germline mutation of TRAF3, an autosomal loss-of-expression mutation (R338W), was initially reported in a patient with a history of herpes simplex virus-1 (HSV-1) encephalitis (12) and also detected in another patient with recurrent Mycobacterium abscessus infection (13). Interestingly, heterozygous germline mutations in TRAF3 (premature stop codon mutations) were recently identified in 9 patients from five unrelated families, causing an immune dysregulation syndrome characterized by recurrent bacterial infection, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia (14). Furthermore, genome-wide association studies (GWAS) and targeted analyses demonstrated that common genetic variants of TRAF3, which reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, hypergammaglobulinemia, and recurrent bacterial infection in a wider population (14).…”

“…Interestingly, heterozygous germline mutations in TRAF3 (premature stop codon mutations) were recently identified in 9 patients from five unrelated families, causing an immune dysregulation syndrome characterized by recurrent bacterial infection, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia (14). Furthermore, genome-wide association studies (GWAS) and targeted analyses demonstrated that common genetic variants of TRAF3, which reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, hypergammaglobulinemia, and recurrent bacterial infection in a wider population (14). Taken together, the above evidence highlights the importance of TRAF3 in the immune system, and particularly in B lymphocytes.…”