IMMUNOPATHOLOGY & AGGRESSIVE CROHN'S DISEASE IMMUNOPHENOTYPE

在CD患者中，对微生物抗原的免疫反应可能与不同 病理生理机制以及独特的临床表型。我们已经证明，CD患者可能会对特定的细菌抗原失去耐受性，并可以根据对某些抗原的血清抗体表达模式而分组。基因分型与侵袭性临床表型有关，然而，我们最近发现，对微生物抗原的血清学反应与病理生理机制有更密切的关系。与对这些抗原无反应(CDlowR)的患者相反，对更多的微生物抗原(CD High)反应最强的患者的病程从轻微发展到严重，可能需要手术，后者的病程较轻，无进展。我们进一步证明，血清对这些微生物抗原的反应可以用来选择临床症状通过治疗操作细菌菌群改善的患者，无论是通过支持或抗生素治疗和/或手术绕过粪便流。最近，我们合作的研究导致了对一种独特的鞭毛蛋白CBirl的血清抗体反应的发现。我们表明，患有这种疾病的患者 对特定微生物抗原的最高反应也具有对这种新细菌抗原的最高幅度反应。因此，这些研究现在已经证明，通过血清抗体表达来衡量对微生物抗原的适应性免疫反应的数量和程度，可以将CD人群分为侵袭性疾病组和良性疾病组。在小鼠模型上进行的平行研究结果表明，最严重和进展最快的疾病发生在具有最高Th1反应和缺乏调节功能的转基因小鼠身上。下一个赠款周期将检验的假设是，对最多微生物抗原的最高幅度反应将反映导致侵袭性CD的病理生理机制，其特征是Th1反应增强，至少部分原因是免疫调节细胞群体的天然免疫功能或缺陷(S)改变。我们将：1)确定重生和/或体外产生的Th1功能和/或相关因子是否在CD-High患者中最高。2)确定是否 在共系膜相关分子模式(CAMP)激活后，单核细胞/单核细胞来源的树突状细胞(MDDC)相关的Th1产生细胞因子增加，和/或炎性细胞因子减少，尤其是CD-High患者。3)明确CDHighR患者外周血中CD4+CD25+或TR1调节细胞的频率和/或功能是否降低。4)确定用抗生素改变共生菌的水平/组成是否能为CD-High患者提供最大的临床益处。

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.