Combination of Innate and Adaptive Immune Alterations Increased the Likelihood of Fibrostenosis in Crohn’s Disease
| Autor: | Carol J. Landers, Jerome I. Rotter, Andrew Ippoliti, Ling Mei, Huiying Yang, Kent D. Taylor, Dermot P.B. McGovern, Eric A. Vasiliauskas, Maria T. Abreu, Omid Shaye, Shane M. Devlin, Pedram Enayati, Gary Chen, Gil Y. Melmed, Stephan R. Targan, Konstantinos A. Papadakis, Jennifer M. Choi |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Adolescent Nod2 Signaling Adaptor Protein Porins Constriction Pathologic Adaptive Immunity Polymorphism Single Nucleotide Article Antibodies Cohort Studies Mannans Young Adult Immune system Antigen Crohn Disease Immunity NOD2 medicine Immunology and Allergy Humans Genetic Predisposition to Disease Child Aged Aged 80 and over Crohn's disease biology Gastroenterology Antibody titer Middle Aged Acquired immune system medicine.disease Immunity Innate Child Preschool Immunology Mutation biology.protein Antibody |
| Popis: | Crohn’s disease (CD) is a heterogeneous disorder with variability in disease presentation as well as the response to medical and surgical therapies. The natural history of the disease is influenced by site of involvement (intestinal versus colonic), and disease behavior, uncomplicated (inflammatory), or complicated by stricture (fibrostenosis), or by abscess, mass, or fistula (penetrating). The prevailing pathogenic hypothesis of CD is hyperresponsiveness of the gut mucosal immune system to normal luminal bacteria. This aberrant response results from a combination of defects in innate and acquired immunity. The relationship between markers of altered immunity and the clinical features and phenotypes of CD has been extensively studied. NOD2 (nucleotide oligomerization domain 2) was the first gene to be linked to CD.1,2 From a meta-analysis of 42 studies, the odds ratio (OR) for a single allelic variant was 2.2–4.1 for non-Jewish Caucasians and 1.7–2.5 for Jewish patients.3 Three major NOD2 polymorphisms have been recognized in CD, referred to initially as single nucleotide polymorphisms 8, 12, and 13 (SNP8, SNP12, SNP13), more properly referred to as R702W, G908R, and 1007fs. Carriage of 2 alleles increased the OR to 17.1.3 All 3 mutations of the NOD2 gene, in vitro, are associated with impairment of muramyl dipeptide (MDP)-driven nuclear factor-kappa B activation (NF-κB).4 In mononuclear cells from homozygote CD subjects impaired secretion of MDP-induced interleukin 1-α and interleukin 8 was observed, indicating a defect in innate immunity in some CD patients.5 NOD2 has been primarily linked to 2 clinical features of CD, small bowel involvement and the fibrostenosis phenotype. The association with small bowel disease location has been found by most investigators; the overall OR was 2.5.6 However, there was some variability in the association of NOD2 expression and the fibrostenosis phenotype, overall OR of 1.9.3 In a recent review 10 studies examined the genotype/phenotype interaction; 6 reported a significant association.6 The sample size, allelic frequency, and ethnicity of the reported patients were comparable between the studies that found a significant association and those that did not. In 2 prospective studies, no association was found between the NOD2 genotype and progression from the inflammatory to the fibrostenosing phenotype.7,8 Ahmed et al9 reported that the fibrostenosis and NOD2 association in their study was not independent by logistic regression of the association with ileal disease. Many CD patients have serologic evidence of a loss of tolerance to luminal bacteria. Duchmann et al10 were the first to show that CD patients have reactivity to multiple bacterial antigens. Specific associations between antibody responses to oligomannan (anti-Saccharomyces cerevisiae [ASCA], Escherichia coli outer membrane protein C [anti-OmpC], a CD-related protein from Pseudomonas fluorescens anti-CD-related bacterial sequence [I2], and Cbir1 flagellin [anti-Cbir1]) and CD phenotypes have been described.10–12 The presence of antibody positivity and elevated antibody titer has been directly associated with small bowel disease, the fibrostenosis and internal penetrating phenotypes, and small bowel surgery, and is inversely correlated with colonic disease.11,12 These associations were strongest when the individual antibody responses were combined either as the number of positive antibodies or as the total antibody level. In the prospective study of Scottish patients the presence and the magnitude of antibody responses to ASCA, anti-I2, and anti-OmpC was associated with progression of disease type.7 The in vitro evidence of defective MDP recognition and NF-κB activation found with NOD2 mutations provides a theory for a defect in innate immunity. We have recently shown that the defect in innate immunity is associated with a presumed compensatory hyperresponse in adaptive immunity.14 CD phenotypes are likely associated with specific genetic defects as well as markers of loss of tolerance to luminal bacteria. The purpose of this study was to clarify the relationship between the presence of allelic variants to the NOD2 gene and the presence and titer of antibodies to microbial antigens, Cbir, I2, OmpC, and oligomannan and the fibrostenosis phenotype. Further, in those CD patients with fibrostenosis, we proposed that an association would be found between innate (NOD2 mutations) and adaptive (microbial antigens) immune alterations. Our findings indicate that the presence of NOD2 variants and elevated titers of antibody to microbial antigens both contribute individually and, further, act synergistically to increase the likelihood of fibrostenosis in CD patients. |
| Databáze: | OpenAIRE |
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