Germline pathogenic TRAF3 variants were first reported in 2022 as autoimmune lymphoproliferative immunodeficiency disease (ALPID), characterized by autoimmunity and lymphoproliferation. More recently, TRAF3 variants have also been described in adults with common variable immunodeficiency (CVID). TRAF3 is a key regulator of immune homeostasis that negatively controls the noncanonical NF-κB pathway downstream of CD40 signaling in B cells.
To characterize the clinical and immunological characteristics of TRAF3 variants among patients with inborn errors of immunity presenting diverse phenotypes.
Targeted TRAF3 sequencing using AmpliSeq was performed in 64 patients with inborn errors of immunity, identifying novel TRAF3 variants in five patients from two families. Clinical histories, immunophenotypes, plasma cytokines, and TRAF3 protein function were analyzed.
In family A (A1, A2), an ALPID phenotype was observed, characterized by childhood-onset lymphadenopathy and splenomegaly with recurrent respiratory infections, persisting into adulthood. In family B (B1, B2, B3), hypogammaglobulinemia and recurrent infections developed in adulthood, consistent with a CVID-like phenotype. Lymphocyte profiling revealed increased B cell proportions in family A (A1) and reduced B cell proportions in family B (B1–B3). Both families showed decreased naïve T cell proportions and altered Th1/Th2 balance leading to the diagnosis of late onset combined immunodeficiency (LOCID). Plasma cytokine profiling demonstrated elevated BAFF levels in both families, while IL-5, IL-10, and TNF-α were specifically increased in family A. Functional assays in HeLa cells showed truncated TRAF3 protein expression and activation of the noncanonical NF-κB pathway.
TRAF3 variants manifest a broad clinical spectrum ranging from ALPID to CVID-like disease, influenced by mutation site, type, and age of onset. It is associated with dysregulated B and T cell differentiation and cytokine imbalance due to increased senescence of T cells. These findings demonstrate the important role of TRAF3 in maintaining immune homeostasis and adaptive immune cell differentiation in humans.
