The presence of several types of antibodies in the sera of inflammatory bowel disease (IBD) patients is 1 of several findings suggesting the immune-mediated nature of both Crohn's disease (CD) and ulcerative colitis (UC). The first detection of such a reactivity emerged in the late 1950s with the report of autoantibodies against colonic epithelial cells in UC patients.1 Since then, several types of antibodies have been shown to react with a vast array of antigens, including microbial as well as autoantigens from intestinal or extraintestinal structures. Many studies have been performed that were mainly aimed at evaluating the possible use of these antibodies as a noninvasive diagnostic tool or as a means to detect distinct clinical subsets of patients with particular phenotypic or prognostic profiles. Fewer efforts have been devoted to understanding the possible role of such antibodies in the pathogenesis of IBD.

Among the circulating antibodies detected in IBD, the most studied are those directed toward some specific intestinal epithelial antigens (ECAC and TM-5), a yet undefined nuclear antigen of neutrophils (p-ANCA), and mannose residues from the cell wall mannans of Saccharomyces cerevisiae (ASCA). More recently, circulating antibodies reacting with different glycans and other microbial antigens have also been reported.

ECAC are intestinal goblet cell glycoproteins recognized by both circulating antibodies and mononuclear cells from IBD patients, suggesting autosensitization to these potential autoantigens. Mucosal CD3+ lymphocytes inducing antibody-mediated cytotoxicity against ECAC have also been reported.2 However, further characterization of this reactivity has not been carried out, so its importance in IBD pathogenesis remains undefined.

TM-5 is a colonic isoform of the cytoskeletal protein tropomyosin. Circulating and lamina propria mononuclear cell-secreted antibodies against this protein have been reported in UC but not in CD subjects. An intriguing finding related to this antigen is the observation that similar epitopes are present in skin, eye, joint, and bile ducts, all common sites of extraintestinal complications of IBD.3 This finding suggests that a crossreactive antigenic recognition might play a role in the pathogenesis of the disease and its complications. Although the observation of an activated complement and of IgG1 deposits colocalized with anti-TM-5 monoclonal antibody in intestinal epithelium would suggest a direct pathogenic role of this autoantigen–antibody reaction, its relevance in the pathogenesis of IBD is still undefined.

p-ANCA (perinuclear antineutrophil cytoplasmic antibodies) are directed toward a yet undefined nuclear lamina antigen(s) of human neutrophils, different from the antigens recognized by sera of patients with vasculitis or nephritis.4 Several studies have shown that this antibody is associated with UC, where it is detected in 40%–80% of the patients,5 whereas in CD it is observed in a smaller proportion of patients (5%–15%), particularly those with a UC-like disease pattern. However, very few studies have addressed their possible pathogenic role, and most have produced negative results. In particular, contrary to what is observed with vasculitis associated p-ANCA, IgG from p-ANCA-positive UC patients were not able to activate neutrophil respiratory burst.6 This, together with the observation that 20%–50% of UC patients develop in the absence of the antibody, suggests that p-ANCA does not play a prominent role in the pathogenesis of the disease.

Anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with CD, where they are observed in up to 68% of the patients.5 Since they are directed against the cell wall mannan of S. cerevisiae, they cannot be considered a true autoantigen. Although they may be observed in association with increased intestinal permeability, a putative pathogenetic mechanism of CD, their direct role in the mechanism of disease appears unlikely. The sensitivity of this antibody is quite poor, in fact, 30%–50% of CD patients do not have ASCA. Thus, despite both pANCA and ASCA being specific markers of UC and CD, respectively,5 and seemingly predicting the development of the disease years before the onset, as shown in a Jewish cohort of patients,7 their low prevalence in affected subjects does not support the hypothesis of their primary involvement in IBD pathogenesis.

Interestingly, the seroreactivity against oligosaccharides appears to be a preeminent feature of CD. In fact, recently each component of a wide panel of anti-glycan antibodies has been tested for its association with IBD; among these, antibodies anti-laminaribioside (ALCA), anti-chitobioside (ACCA), anti-mannobioside (AMCA) and against a mannan epitope of S. cerevisiae (gASCA) displayed a high specificity for CD; furthermore, some data suggest that these novel antibodies might be particularly useful in differentiating between the 2 forms of IBD, especially in ASCA-negative patients.8, 9

Both the “classical” markers (p-ANCA and ASCA) and the more recent ones (ALCA, ACCA, AMCA, and gASCA) have been associated with specific disease phenotypes, i.e., treatment-resistant UC and a predisposition to pouchitis after surgery for p-ANCA, and stricturing, ileal CD for ASCA, more severe and complicated disease for ALCA, ACCA, AMCA, and gASCA.9 Again, whether these associations are a result of specific pathogenetic mechanisms is unknown.

Several other antibodies against bacterial antigens have been reported in IBD patients, particularly CD. The reported antibodies are directed toward antigens from different sources: the outer membrane porin C of Escherichia coli (ompC),10 fragments of bacterial DNA associated with Pseudomonas fluorescens (I2), and subtypes of flagellins (CBir1).11 IBD patients also have an increased frequency of immunoglobulin-coated fecal bacteria. The presence of these bacteria-associated antibodies has been associated with particular disease behaviors in CD, such as a good response to antibiotic treatment for anti-OmpC or I210 or complicated disease for anti-CBir1 antibodies.11 Systemic antibodies toward mucosal bacteria have been shown to differentially activate the innate immune response in UC and CD.12 However, it is generally accepted that the presence of these antibodies suggests a general and probably genetically determined defect in immune tolerance toward normal intestinal flora rather than the recognition of specific, possibly pathogenic, bacterial species.

Many antibodies against other nonintestinal antigens have also been reported, including anti-pancreas, anti-phospholipid, anti-tissue plasminogen activator, anti-sperm, and others. Because they are detected in a minority of IBD patients, a role in disease pathogenesis appears remote. However, although direct proof of their participation has not been provided, they could conceivably contribute to the pathogenesis of some extraintestinal manifestations, i.e., CD-associated chronic pancreatitis, thromboembolism, and infertility.

Very recently, as a possible marker of an altered immunological environment in IBD, changes in antibodies glycosilation have been reported in Japanese patients with IBD; in fact, IgG antibodies, in both CD and UC patients, have a higher agalactosyl fraction in the fucosylated oligosaccharides in comparison to healthy controls13; changes in the oligosaccharide structure of IgG might lead to modifications in antibodies functional characteristics, although there are no data regarding the potential effect of different immunoglobulin glycosylation in disease pathogenesis.

In conclusion, although both forms of IBD are characterized by the production of several antibodies with distinct antigenic specificity, these antibodies appear to be markers of an aberrant immune response rather than direct effectors involved in the pathogenesis of the disease.


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