Högskolan i Skövde

Common variable immunodeficiency (CVID) encompasses a heterogeneous group of inborn immune system errors characterized by a failure in antibody production. The defective immune response in CVID subjects results in poor clearance of infectious agents and higher susceptibility to severe diseases, mainly caused by encapsulated extracellular bacteria in the respiratory tract. On top of that, autoimmunity, and inflammatory complications are common clinical manifestations, leading to important impairment in the overall health status and lifespan of these patients. This study aimed to understand, at the genetic level, the particularities of the immune pathways from a CVID cohort in contrast to a healthy control group. For that, transcriptomic analyses from bulk RNA-sequencing from in vitro activated B cells were performed. Results from differentially expressed genes and enrichment analyses involving both naïve and memory cells unveiled the peculiarities of the expression network from the pathological B-cell environment. For instance, pathways involving mTOR1, MYC, E2F, and IL-2/STAT5 signaling were downregulated in activated naïve B cells from the CVID group, following the lower expression of genes related to the metabolic processes. Nevertheless, the activated memory B cells revealed an opposite pattern: enrichment in genes related to cell metabolism, as well as the enhancement of mTOR1, p53, STAT3, and MYC targets. Markers of inflammation such as type I interferons and complement, immunosurveillance, and cellular stress response, the latter represented by processes relative to unfolded protein responses, apoptosis, and autophagy, were found over-represented in all activated B cells, naïve and memory, in the CVID group. In summary, these results could indicate major problems in the germinal center reactions from secondary lymphoid organs causing a defective transition from naïve to memory and long-lived plasma cells in patients with CVID, but further studies are needed to validate these assumptions. Finally, since epigenetic mechanisms were also found more expressed in the disease group, the genetic signature solely may not determine an illness’ fate. If future researchers could determine how environmental factors could influence the disease phenotype, a personalized and maybe curative approach for these patients would be a reality.