Excess IL-12 but not IL-23 Accompanies the Inflammatory Bowel Disease Associated With Common Variable Immunodeficiency

Background & Aims: Common variable immunodeficiency (CVID) patients can develop an idiopathic inflammatory bowel disease resulting in chronic diarrhea and life-threatening malabsorption. This study was designed to assess the status of the gastrointestinal tract and to define the mucosal immune abnormalities in patients with and without symptomatic gut inflammatory disease. Methods: CVID patients underwent tests of gut absorption, peripheral blood mononuclear cell phenotyping, and upper and lower endoscopy for histology and lamina propria mononuclear cell (LPMC) cytokine production. Results: CVID patients with gastrointestinal symptoms differed from asymptomatic CVID patients by having significantly longer duration of disease and lower body mass index, D-xylose absorption, serum albumin, CD4/CD45RA cells, CD3/CD25 cells, and natural killer cells. Symptomatic CVID patients showed diffuse histologic inflammatory changes in the duodenal and colonic mucosa including villus blunting, increased lamina propria and intraepithelial lymphocytes, and epithelial apoptosis, less frequently seen in asymptomatic patients. LPMCs from symptomatic CVID patients produced significantly higher T-helper (Th) 1 cytokines, interleukin-12, and interferon-γ. Compared with the Th1 cytokines produced by LPMCs from Crohn's disease, CVID patients did not produce excess amounts of interleukin-23, interleukin-17, or tumor necrosis factor-α. Conclusions: The idiopathic inflammatory bowel disease associated with gastrointestinal symptoms in CVID is a unique combination of diverse histologic findings accompanied by excessive Th1 cytokine production, distinct from that in Crohn's disease. These data show that human gut mucosal inflammatory disease can occur with excess interleukin-12 and interferon-γ production alone and provide a rationale for developing targeted therapies for this complication of CVID.