Minne kaikki IgG:t ovat kadonneet? Uusi TRAF3 variantti johtaa varhaiseen CVI-tautiin

Common variable immunodeficiency (CVID) is the most prevalent symptomatic inborn error of immunity (IEI) characterized by impaired antibody production and susceptibility to recurrent infections. Its clinical manifestations vary from mild to severe. While the diverse genetic contributions have been recognized, the origin of pathogenesis often remains unknown. In this study, we aim to characterize heterozygous rare missense and novel truncating variants in TNF receptor associated factor 3 (TRAF3), which were discovered from an early-onset CVID patient with agammaglobulinemia, low levels of IgM and IgA, and recurrent respiratory and gastrointestinal tract infections. Adaptor protein TRAF3 has various cell-type specific, essential signaling and regulatory roles in immune and other cells. TRAF3 positively controls type I interferon production, and negatively regulates several key immune signaling cascades, like alternative NF-B and MAPK pathways. It enhances T cell receptor (TCR) signaling promoting T cell activation, differentiation and effector functions. The phenotypic manifestation and function of the patient’s peripheral blood mononuclear cells (PBMCs) were studied by flow cytometry. Class-switch recombination assay in vitro suggests defect in naïve B cell differentiation into antibody-secreting plasma blasts. Aberrant T cell subpopulations were discovered, like high proportion of regulatory (Treg) and circulating follicular helper (TFH) cells. TCR activation with anti-CD3 and anti-CD28 showed elevated CD25 and early decreasing CD69 activation marker responses. Analysis of PMA and ionomycin induced PBMCs revealed significant elevation of IFN- and reduced IL-2 cytokine expression in CD4+ and CD8+ T cells. Western blot method was used to detect reduced TRAF3 expression in patient’s lymphocytes, and basal expression of ZAP-70 and its phosphorylated form at Tyr319 under TCR activation. Our results suggest that the novel TRAF3 variant’s implication for the protein leads to loss-of-function and haploinsufficiency. Combined unbalanced mechanisms cause T cell dysfunction and exhaustion. Further studies are needed to identify the variant’s contribution for CVID pathogenesis.