Pathogenesis of autoimmunity in common variable immunodeficiency

Abstract

Common variable immunodeficiency (CVID) presents in up to 25% of patients with autoimmune (AI) manifestations. Given the frequency and early onset in some patients with CVID, AI dysregulation seems to be an integral part of the immunodeficiency. Antibody-mediated AI cytopenias, most often affecting erythrocytes and platelets make up over 50% of these patients. This seems to be distinct from mainly cell-mediated organ-specific autoimmunity. Some patients present like patients with AI lymphoproliferative syndrome. Interestingly, in the majority of patients with AI cytopenias the immunological examination reveals a dysregulated B and T cell homeostasis. These phenotypic changes are associated with altered signaling through the antigen receptor which may well be a potential risk factor for disturbed immune tolerance as has been seen in STIM1 deficiency. In addition, elevated B cell-activating factor serum levels in CVID patients may contribute to survival of autoreactive B cells. Of all genetic defects associated with CVID certain alterations in TACI, CD19, and CD81 deficiency have most often been associated with AI manifestations. In conclusion, autoimmunity in CVID offers opportunities to gain insights into general mechanisms of human autoimmunity.

Increased serum IgM, immunodeficiency, and autoimmunity: A clinical series

“…30 Autoimmunity coexists with immunodeficiency in 20-30% of HIGM and CVID patients but the pathogenesis remains vague and still not well identified. Several groups have analyzed this apparent paradoxical phenomenon 31 and proposed a role for different molecules/cell subsets 32,33 in promoting Graph represents the fold increased mRNA expression of AID and UNG in the overall patients (mean + SD). Note that intensity of specific PCR products was measured by densitometry and reported to the unit (arbitrary densitometry value obtained from triplicates using a pool of stimulated PBMCs from five healthy controls).…”

Succumbing to the laws of attraction

“…11 Indeed, in separate work our group reported decreased NK cell cytotoxicity in GWI subjects as well as altered expression in genes associated with NK cell function. 12 Similar immune deficiencies have been associated with autoimmune 13 and allergic pathologies, 14 as well as in another poorly understood multi-symptom disorder: chronic fatigue syndrome (CFS). 15,16 The clinical presentation of GWI overlaps in many ways with that of CFS, 17,18 however significant differences Feedback mechanisms throughout the immune and endocrine systems play a significant role in maintaining physiological homeostasis.…”

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen

“…TACI signaling causes sustained expression of BLIMP-1 (2), a transcription factor that orchestrates maturation of B cells into long-lived antibody-secreting cells (3,4) and inhibits apoptosis of plasma cells (5); however, the full spectrum of functions of TACI is not known. Deficiency of TACI in mice and humans causes Ig concentrations in blood to be low (hypogammaglobulinemia), impairs long-lived responses to encapsulated bacteria and influenza (6)(7)(8), and can predispose to various combinations of lymphoproliferation, tumor formation, and autoimmunity (9,10). This constellation of findings is called common variable immunodeficiency (CVID) and is associated with allelic variants of the genes encoding TACI and proteins conveying TACI functions (11,12).…”