IMMUNOPATHOLOGY & AGGRESSIVE CROHN'S DISEASE IMMUNOPHENOTYPE

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Among patients with CD, immune responses to microbial antigens may be related to different pathophysiologic mechanisms as well as unique clinical phenotypes. We have shown that CD patients can lose tolerance to specific bacterial antigens and can be clustered into groups depending on patterns of serum antibody expression in response to certain antigens. Genotypes have been associated with aggressive clinical phenotypes, however, we have recently shown that serologic responses to microbial antigens are more closely related to the pathophysiologic mechanisms. Patients who respond the most, to a greater number of microbial antigens (CD highR), have a disease course that progresses from mild to severe and is likely to require surgery, as opposed patients who are non-responsive (CDlowR) to these antigens, who have a mild, non-progressive, disease course. We further showed that serum responses to these microbial antigens can be used to select patients whose clinical symptoms ameliorate with therapeutic manipulation of the bacterial flora, either by pro- or antibiotic therapy and/or surgical bypass of the fecal stream. Recently, we collaborated in studies that led to the discovery of serum antibody responses to a unique flagellin, CBirl. We showed that patients with the highest responses to specified microbial antigens have the highest amplitude responses to this novel bacterial antigen, as well. Thus, these studies have now demonstrated that the number and magnitude of adaptive immune responses to microbial antigens, as measured by serum antibody expression, can be used to substratify the CD population into groups of patients with aggressive disease and those with benign disease. Results from parallel studies in mouse models demonstrated that the most severe and progressive disease was elicited in the mice engineered to have the highest Th1 responses and a lack of regulatory function. The hypothesis to be tested in this next grant cycle is that the highest amplitude responses to the greatest number of microbial antigens will reflect pathophysiologic mechanisms leading to an aggressive form of CD characterized by enhanced Th 1 responses at least partially resulting from altered innate immune function or defect(s) in generation and/or function of immunoregulatory cell populations. We will: 1) Determine whether de novo and/or in vitro generated Th1 function and/or associated factors are the highest in CD-highR patients. 2) Determine whether monocyte/monocyte-derived dendritic cell (MDDC)-associated Th1 generating cytokines are enhanced, and/or inflammatory cytokines reduced, following commensal associated molecular pattern (CAMP) activation, specifically in CD-highR patients. 3) Determine whether the frequency and/or the function of CD4+CD25+ or Tr1 regulatory cells are diminished specifically in CDhighR patients. 4) Determine whether altering the level/composition of commensal bacteria with antibiotics will provide the greatest clinical benefit in CD-highR patients.