Gastroenterology
Volume 131, Issue 1 , Pages 312-314, July 2006

In Search of Desire: Mimicry, MAP, and Crohn’s Disease

  • Jonathan Braun

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Jonathan Braun, MD, PhD, Department of Pathology and Lab Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1732. fax: (310) 825-5674.

Department of Pathology and Lab Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California

Article Outline

 

See article on page 85.

Something about M avium paratuberculosis (MAP) brings out the full vitality and fighting spirit of the Crohn’s disease community. An intellectual and emotional vacuum opened in the community as it became clear that an untoward response to certain intestinal bacteria is a key feature of Crohn’s disease. What organisms might represent the offenders in susceptible individuals? The successful identification of H pylori in chronic inflammatory disease of the upper gastrointestinal tract raised the urgency and anticipation in the search for microbial etiologic agents in Crohn’s disease. MAP is a recurrent candidate for several reasons: it causes epidemic colitis in cattle and other species; it is reportedly detectable in tissues of many Crohn’s disease patients; antibodies to the organism are often disease-associated; and, in some cases, antimycobacterial drugs ameliorate disease.1, 2, 3, 4, 5, 6, 7, 8 However, several groups find substantial technologic difficulty in the detection of these microorganisms, the prevalence of disease-associated anti-MAP antibodies, and the limited evidence for T cell immunity to MAP in association with Crohn’s disease—an expected correlate of infection in mycobacterial disease. Moreover, the highly effective anti-TNF therapy strongly weighs against mycobacterial drive in Crohn’s disease, since this agent exquisitely impairs host resistance to mycobacterial infection. The benefit of anti-mycobacterial chemotherapy is not uniformly observed in patients and has not been assessed for a concomitant reduction in the load of MAP organisms.9, 10, 11, 12, 13, 14, 15

A variety of arguments have been advanced to explain these limitations in the establishment of MAP as an etiologic agent in Crohn’s disease. However, it is fair to say that MAP still remains a prospect rather than a selectant in Crohn’s disease pathogenesis. During the past few years, several microorganisms have emerged with data similar to MAP with respect to increased prevalence of tissue levels of organism, host antibody levels, and partial effectiveness of pertinent antibiotics.16 Most recently, exotic bacteria bearing distinct flagellin isoforms have gained attention, due to the synergy of adaptive and innate immune recognition of these flagellins, their colitigenicity in mouse models of Crohn’s disease, and their striking prevalence in a subset of human Crohn’s disease.17, 18, 19, 20 One appealing perspective is that a small number of offending microorganisms have microbial traits suitable for eliciting inflammation of Crohn’s disease. Accordingly, the known genetic and heterogeneity of Crohn’s disease may resolve as patient subsets, each with host traits matched for susceptibility to the traits of distinct microbial species. In this view, antimicrobial therapy would be useful, but its efficacy could only be resolved if patients could be stratified to observe the subsets susceptible to the microbial species targeted for treatment.

In this issue, Polymeros et al21 present a provocative line of investigation suggesting a link between MAP and antibody self-reactivity. Taken at face value, this study not only refreshes the issue of MAP in Crohn’s disease, but also reopens the issue of autoimmune-mediated dysfunction in Crohn’s disease. This article addresses the profile of antipeptide antibody levels for MAP and human analogue sequences in Crohn’s disease patients. First, the article further details the antigenic peptides of MAP in Crohn’s disease patients, but also identifies ones similarly reactive for ulcerative colitis and healthy individuals. Some of these peptides coincide with ones previously reported. However, “positive” rates are no more than 30%, which is lower than the seropositive rates reported in some previous studies.

Second, the paper identifies human analogue sequences for these MAP peptides. Most of the analogues (16 of 23) were nonantigenic, and some (4 of 23) were not differentially reactive in Crohn’s disease versus UC or healthy individuals. Among the remaining 3 groups, human tumor overexpressed protein (TOG) was more frequently reactive in Crohn’s disease patients than its MAP peptide analogue and was frequently reactive in healthy individuals as well. This is most simply construed as a polyreactive sequence. Antibodies constitute the B lymphocyte antigenic receptor repertoire and are encoded by an extremely diversified family of antibody genes. However, despite this diversity, there are overrepresented antibody gene products, and recurrent, functionally conserved variable region segments (particularly among antibodies bearing nonmutated germline variable regions). These antibodies bind with detectable avidity to diverse peptides prevalent in many host and microbial proteins. Such polyreactive antibodies are an abundant constituent of the serum and are probably important for providing baseline antimicrobial defense prior to the formation of an antigen-specific adaptive immune response.22

This leaves two interesting sets of MAP and human peptides that were disease-specific. The authors demonstrated the crossreactivity for these peptide pairs, and evidence that the native proteins displayed the epitope. The most novel implication of this finding is that they represent structural mimics, where an anti-MAP immune response to the microbial peptide could elicit a host autoimmune response. The idea of antigenic mimicry and autoimmune pathogenicity has been a topic of recurrent interest.23, 24, 25, 26, 27, 28, 29 However, this scenario remains to be tested for these peptide pairs. First, the frequency and pattern of crossreactivity is well within the random rates predicted for heterologous peptides. This antigenic degeneracy problem makes the pathogenic argument of antigenic mimicry difficult to establish by correlation alone. Accordingly, the present data are not compelling for these correlates to be greater than chance. Second, the present study does not test for the existence of crossreactive autoantibodies or T-cell immunity with pathogenic activity. Thus, the interesting and provocative ideas presented in this study await experimental validation.

Investigation of Crohn’s disease pathogenesis draws on many facets of cell biology, immunology, genetics, and microbiology. Indeed, Crohn’s disease research is driving key advances in host-bacterial interaction, the genetics of common disease, and the modern era of immunotherapy. The present study captures the creative spirit of this enterprise and also the continuing challenge to define simple paradigms for Crohn’s disease pathogenesis and its definitive treatment.30

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PII: S0016-5085(06)01195-4

doi:10.1053/j.gastro.2006.05.042

Refers to article:

  • Does Cross-Reactivity Between Mycobacterium avium paratuberculosis and Human Intestinal Antigens Characterize Crohn’s Disease?

    Dimitrios Polymeros, Dimitrios P. Bogdanos, Richard Day, Dimitryi Arioli, Diego Vergani, Alastair Forbes
    Gastroenterology July 2006 (Vol. 131, Issue 1, Pages 85-96)

Gastroenterology
Volume 131, Issue 1 , Pages 312-314, July 2006

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