The Immune Dysregulation of Common Variable Immunodeficiency Disorders

Common variable immunodeficiency (CVID) is established as a heterogeneous collection of disorders of immune dysregulation rather than an infectious complication of antibody deficiency. Approximately 70% of patients have one or more of the non-infectious complications of autoimmunity, enteropathy, polyclonal lymphocytic and malignancy. The CVID-disorders represent a particular challenge as they fall under an umbrella diagnosis governed currently by non-universal diagnostic criteria. The rubric of CVID is shrinking as next generation sequencing is progressively and rapidly identifying the genetic basis for many of its disorders. Although identification of monogenic cause of CVID allows for naming of separate or specific entities, it still provides valuable insight into the immune dysregulation of these disorders along with recognition of a polygenic basis of disease and cellular changes observed in innate and adaptive immune pathways. Cellular abnormalities in the T-cell (reduced regulatory T cells (Tregs) and increased T follicular helper cells), and B-cell compartments (reduced switched memory B-cells and increased peripheral CD21^low cells) along with an increase in innate lymphoid cells type 3 promote a milieu for inflammation. Immune dysregulation also results from increased microbial translocation from impaired gastrointestinal barrier function in CVID-patients with loss of Tregs. An understanding of the manifestations and mechanisms of immune dysregulation allows for improved vigilance in screening for the diagnosis, monitoring for complications of disease and the continued development and introduction of targeted therapies for non-infectious phenotypes.