Characterization of immunologic defects in patients with common variable immunodeficiency (CVID) with intestinal disease

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. The diagnosis of CVID is established based on reduced levels of two serum immunoglobulins, IgG and IgA and/or IgM, at least two standard deviations below the age-specific mean values, and impaired specific antibody production in response to either vaccination in vivo or recent infection.1 The hypogammaglobulinemia results from the failure of B cells to differentiate into plasma cells; however, T-cell abnormalities and defective cytokine production have also been described.2–5 Most commonly, CVID patients present with recurrent sinopulmonary infections such as bronchitis, sinusitis, and pneumonia, although autoimmunity and gastrointestinal (GI) disease are also quite prevalent and may be the initial presentation of disease.6,7 Several studies have reported the incidence of GI diseases in patients with CVID ranging from 20%–60%.6–10 This is not unexpected, given that the GI tract with its large surface area contains the most immunoglobulin-producing cells in the body; IgA being the major immunoglobulin in the gut. GI diseases observed in CVID patients include chronic diarrhea,10–12 inflammation of the small or large intestine resembling Crohn’s disease (CD) or ulcerative colitis (UC),13–15 villous flattening resembling celiac sprue,6,8,16,17 pernicious anemia,18 nodular lymphoid hyperplasia,11 lymphoma, and gastric adenocarcinoma.8 Immune abnormalities in CVID include impaired antibody production, disruption in T-cell function,19–23 and defects in innate immunity.24–27 However, few studies have examined specifically what immune parameters and mechanisms predispose these patients to GI tract disease. Recent studies have suggested that GI infections are more frequent in patients with undetectable serum IgA (47 [36%] of 131 patients) compared to patients with residual IgA production.28 However, unlike X-linked agammaglobulinemia (XLA) and IgA deficiency, GI disease is far more common in CVID, suggesting that T-cell dysfunction contributes to the pathogenesis of intestinal disease. Furthermore, immunoglobulin replacement, which replaces antibody (predominately IgG) but not T-cell defects, improves the infectious complications of CVID; however, GI symptoms often persist and progress further, supporting the complexity of GI disease pathogenesis in the setting of CVID. As a human model of primary immunodeficiency with disruption of mucosal immunity, CVID patients represent a unique population to investigate immune-mediated GI disease. In this study we examined whether defects in peripheral and intestinal lymphocytes exist that may be involved in the disruption of the mucosal immune response in CVID patients with inflammatory diseases of the gut. In addition, we examined the cellular composition in the gut of these patients with CVID and GI disease to better understand the nature of the intestinal inflammation. We show that CVID patients with inflammatory GI disease have trends toward greater reduction in serum IgG compared to non-GI affected CVID patients, as well as reduced/absent plasma cells in both the small intestine and colon with consequent reductions in intestinal IgM and IgA. CVID patients with and without GI disease exhibited increased CD3+ cells, specifically CD8+ T cells, in the colon compared to normal and inflammatory bowel disease (IBD) controls, supporting the potential for immune dysregulation. The results presented here represent a limited patient population and the variability in data further support that the defects in the immune system that predispose these patients to mucosal inflammation are complex, likely involving both T- and B-cell immunity, rather than a single mechanism.