Selected loss of tolerance evidenced by Crohn's disease-associated immune responses to auto- and microbial antigens

Abstract

Background & Aims: Previous studies in Crohn's disease suggest global loss of tolerance with sonicated bacteria preparations containing hundreds of antigens. Monoassociation studies show that a solitary bacterium can induce colitis in one animal model, whereas another is responsible in other models. Among patients with Crohn's disease, serum responses have been documented to microbial and autoantigens (antibodies to the Escherichia coli outermembrane porin C and the Pseudomonas fluorescens- associated sequence I2, antisaccharomyces cerevisiae antibody (ASCA), and perinuclear antineutrophil cytoplasmic antibodies). Our aim was to determine whether there are heterogeneous responses to these specific antigens. Methods: Sera from 330 Crohn's patients were analyzed. Immunoglobulin A enzyme-linked immunosorbent assays to ASCA, outer-membrane porin C, or I2 and immunoglobulin G enzyme-linked immunosorbent assay to ASCA and ANCA determined the presence and level of antibodies. Perinuclear antineutrophil cytoplasmic antibodies were determined by immunofluorescence. Results: ASCA was detected in 56% of patients; 55% were seroreactive to outermembrane porin C, 50% were seroreactive to I2, and 23% were perinuclear antineutrophil cytoplasmic antibody positive. Eighty-five percent responded to at least 1 antigen; only 4% responded to all 4. Among microbial antigens, 78% responded to at least 1, and 57% were double positive, but only 26% responded to all 3. The level of response was stable over time and with change in disease activity. Among patients with the same qualitative antigen-response profiles, quantitative response differed. Cluster analysis of these antibody responses yielded 4 groups: ASCA, outer-membrane porin C/I2, perinuclear antineutrophil cytoplasmic antibodies, or no/low response. Conclusions: Rather than global loss of tolerance, there seem to be patient subsets with differing responses to selected microbial and autoantigens.