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Current consensus holds that the pathogenesis of Crohn's disease involves the interacting elements of multigenic host susceptibility factors and environmental priming from the enteric microflora.1 2 Tissue damage is mediated by the immune system, although the contributory mechanisms are still unclear, and may be multiple or varied in different individuals. In addition, many immunological alterations in patients with Crohn's disease seem to have no direct role in mediating tissue injury and are frequently dismissed as epiphenomena. The history of medical discovery is replete with examples of overlooked clues hitherto dismissed as unimportant. Could some of the antibody markers in Crohn's disease yet provide useful clues to disease aetiology and pathogenesis? Could some of these phenomena be manifestations of the linkage across genetic, immunological and environmental contributions to aetiopathogenesis?
Marker antibodies have attracted considerable attention as putative manifestations of the disease related immune response in inflammatory bowel disease.3 The relative specificity of some of these antibodies for either Crohn's disease or ulcerative colitis indicates that their expression is not a simple epiphenomenon of intestinal injury or mucosal inflammation. At present, the clinical diagnostic utility of antibody detection is of limited value, although combined detection of multiple antibody markers seems promising.4 5 In contrast, detection of disease related antibodies may have particular value as markers of heterogeneity within inflammatory bowel disease, as markers of underlying immune dysregulation or cross reactivity with an environmental agent, and as possible immunological traits related to disease susceptibility.3
The value of autoantibodies as markers of disease susceptibility is well established in the case of islet cell antibodies and insulin dependent diabetes mellitus. In inflammatory bowel disease, some but not all antibody markers exhibit familial aggregation, and might, therefore, represent markers of genetic susceptibility. Epithelial and lymphocytotoxic autoantibodies have been reported in familial association with Crohn's disease and ulcerative colitis, whereas antineutrophil cytoplasmic autoantibodies (ANCA) have been controversial in this regard in ulcerative colitis, and pancreatic antibodies which are associated with Crohn's disease do not seem to be familially expressed.3
In this issue, Sutton et al (see page58) report that antibodies to Saccharomyces cerevisiae mannan (ASCA) are both disease associated and also a familial immunological trait expressed in both affected and unaffected family members of patients with Crohn's disease. An association between serum antibody reactivity to the cell wall mannan polysaccharide of the yeast S cerevisiae and Crohn's disease, but not ulcerative colitis, was noted over a decade ago and has been confirmed by several investigators.4 5The present study confirms and extends the findings of an earlier report on the familial pattern of expression of ASCA in Crohn's disease.6 It is noteworthy that it involved a large study population of family members with appropriate controls and included additional analysis for intraclass correlation of anti-mannan immunoglobulin levels which showed antibody expression to be a trait of family members independent of clinical disease.
Familial aggregation of an immunological observation might reflect environmental or genetic factors, or both. Earlier reports on the increased prevalence of lymphocytotoxic and epithelial antibodies in family members of patients with inflammatory bowel disease varied in their interpretation of potential genetic or environmental contributions.7 8 Suttonet al provide two circumstantial lines of evidence for a genetic contribution to the familial expression of ASCA; the correlation was stronger for first degree relatives versus all relatives, and concordance was significant in sibling pairs (reflecting genetic and environmental contribution) but not in genetically dissimilar marital pairs (reflecting environmental contribution alone). Thus, the findings cannot be accounted for by close environmental contact alone, although the authors concede that an environmental contribution, perhaps a common childhood exposure, cannot be discounted.
Although the findings of Sutton and colleagues raise the possibility that ASCA might have value as a preclinical marker of Crohn's disease, this will require long term prospective study. A more immediate application for ASCA relates to the assessment of heterogeneity within Crohn's disease. As Sutton et al point out, the concordance of seropositivity or seronegativity among probands with Crohn's disease and affected relatives provides evidence for distinct immunological subsets of this disease. What is needed now is careful correlation with other potential markers of heterogeneity in Crohn's disease, incorporating genetic, immunological, clinical, and therapeutic profiles. This will be facilitated by standardisation of serum testing and rigorous clinical categorisation of patients, and can be accelerated by interlaboratory collaboration with exchange and sharing of serum samples and data.
In conclusion, there remains an unacceptable gap in our knowledge of the molecular mechanisms underlying the genetic, environmental, and immunological contributions to the pathogenesis of Crohn's disease. Multidimensional approaches that attempt to link immunogenic and clinical observations with due recognition of the likelihood of distinct disease subsets, are required. Immunological phenomena, including marker antibodies, have provided a bridge between clinical and basic sciences in the investigation of several other diseases,9 and promise to fill a similar role in inflammatory bowel disease.
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