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

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. Turning down TRAF3 revs up B cells: TRAF3 is a cytoplasmic adaptor protein involved in multiple intracellular signal transduction pathways. Rae et al. identified nine individuals with a previously undescribed monogenic immune dysregulatory syndrome caused by a loss-of-function mutation in one of their two TRAF3 alleles. Patients with this newly described TRAF3 haploinsufficiency syndrome exhibited B cell hyperactivity leading to hypergammaglobulinemia and autoimmunity but also displayed increased susceptibility to recurrent bacterial infections. Common human genetic variants of TRAF3 associated with lower gene expression were found to carry an increased risk of autoimmune disease and some B cell malignancies. These findings point to functional impairment of TRAF3 as a shared mechanism leading to B cell dysfunction, hyperactivity, and disease in the presence of either rare loss-of-function germline mutations or much more common genetic variants. [ABSTRACT FROM AUTHOR]