Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

Abstract

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency and comprises a group of disorders with similar antibody deficiency but a myriad of different etiologies, most of which remain undefined. The variable aspect of CVID refers to the approximately half of patients who develop non-infectious complications in addition to heightened susceptibility to infection. The pathogenesis of these complications is poorly understood and somewhat counterintuitive because these patients that are defined by their immune futility simultaneously have elevated propensity for autoimmune disease. There are numerous aspects of immune dysregulation associated with autoimmunity in CVID that have only begun to be studied. These findings include elevations of T helper type 1 and follicular helper T cells and B cells expressing low levels of CD21 as well as reciprocal decreases in regulatory T cells and isotype-switched memory B cells. Recently, advances in genomics have furthered our understanding of the fundamental biology underlying autoimmunity in CVID and led to precision therapeutic approaches. However, these genetic etiologies are also associated with clinical heterogeneity and incomplete penetrance, highlighting the fact that continued research efforts remain necessary to optimize treatment. Additional factors, such as commensal microbial dysbiosis, remain to be better elucidated. Thus, while recent advances in our understanding of CVID-associated autoimmunity have been exciting and substantial, these current scientific advances must now serve as building blocks for the next stages of discovery.

Keywords: autoimmunity; common variable immunodeficiency; cytopenia; genetics; microbiome; precision therapy; primary immunodeficieny.

Figure 1

B-cell and T-cell dysregulation and immunophenotypic characteristics of autoimmunity in CVID. Some features of B-cell dysregulation in CVID patients with autoimmunity include elevated CD21^low B cells and IgM and increased autoreactive B cells in the periphery. On the other hand, memory B-cells, and B-cell receptor diversity are decreased. Disturbance of T-cell homeostasis, with a decrease in T regulatory cells (T_R) and a skew toward type 1 immunity, has been associated with autoimmunity in CVID. Factors that have been identified in CVID patients which lead to downregulation of T_R cells include LRBA and CTLA-4 deficiency, as well as IgA deficiency. Upregulation of mTOR activity in GOF PIK3CD may also promote this immune dysregulation, while STAT3 GOF leads to expansion of T_H17. BAFF augments T_H1 cytokine production via its effects on the BAFF receptor on T cells, and promotes the survival of autoreactive antibodies via its receptor on B cells.