Autoimmunity and Inflammation in CVID: a Possible Crosstalk between Immune Activation, Gut Microbiota, and Epigenetic Modifications

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency among adults and is characterized by a B cell dysfunction and increased risk of respiratory tract infections with encapsulated bacteria. However, a large proportion of patients also has inflammatory and autoimmune complications. It may seem like a paradox that immunodeficiency and inflammation/autoimmunity coexist within the same individuals. In this commentary, we propose that CVID immunopathogenesis involves an interplay of genes, environmental factors, and dysregulation of immune cells, where gut microbiota and gastrointestinal inflammation can both be important contributors or endpoints to the systemic immune activation seen in CVID, and where epigenetic mechanism may be the undiscovered link between these contributors. In our opinion, these pathways could represent novel targets for therapy in CVID directed against autoimmune and inflammatory manifestations that represent the most severe complications in these patients. Considering the heterogeneous nature of CVID, these mechanisms may not be present in all patients, and different complications may be triggered by different risk factors. CVID is really a variable disease and in the future there is clearly a need for a more personalized medicine based on both genotypic and phenotypic findings.