title: Combination of innate and adaptive immune alterations increased the likelihood of fibrostenosis in Crohn's disease.
abstract: BACKGROUND
  Mutations in the nucleotide oligomerization domain-2 (NOD2) gene and positive antibodies to microbial antigens have been found to be associated with the Crohn's disease (CD) phenotype, fibrostenosis. The aim of this study was to confirm these relationships in a large cohort of CD patients and to determine the correlation between the presence of NOD2 variants and antibodies to oligomannan, CBir, outer membrane porin-C (OmpC), and I2 in CD patients with fibrostenosis.
  
  
  METHODS
  Sera and DNA from 731 unrelated CD patients were tested for NOD2 variants (SNP 8, 12, and 13) and the antibodies. The results were correlated with CD phenotypes, fibrostenosis, internal penetrating, perianal penetrating, and ulcerative colitis (UC)-like as well as other clinical features.
  
  
  RESULTS
  The presence of NOD2 allelic variants was primarily associated with fibrostenosis, secondarily with small bowel disease and small bowel surgery, and was inversely associated with UC-like disease. This association was present in patients with a fibrostenosis only (Vienna B2) and those with both stricturing and penetrating disease. The presence and level of antibodies to microbial antigens was also associated with the fibrostenosis phenotype. In the 316 patients with fibrostenosis the prevalence of NOD2 variants was significantly correlated with the antibody titer by quartile sum score. Further, when these patients with fibrostenosis were clustered by quartile sum score, the odds ratio for fibrostenosis was significantly higher in the patients with NOD2 variant alleles within each cluster, indicating synergy.
  
  
  CONCLUSIONS
  Defects of innate (NOD2 variants) and adaptive (antibodies to microbial antigens) immunity act synergistically to increase the risk of the fibrostenosis phenotype.
authors.affiliation: Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ippoliti
authors.forename: Shane
authors.initials: S
authors.lastname: Devlin
authors.forename: Ling
authors.initials: L
authors.lastname: Mei
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Papadakis
authors.forename: Eric A
authors.initials: EA
authors.lastname: Vasiliauskas
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
authors.forename: Gil
authors.initials: G
authors.lastname: Melmed
authors.forename: Omid
authors.initials: O
authors.lastname: Shaye
authors.forename: Pedram
authors.initials: P
authors.lastname: Enayati
authors.forename: Gary
authors.initials: G
authors.lastname: Chen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Choi
authors.forename: Kent
authors.initials: K
authors.lastname: Taylor
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Landers
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000097:blood; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003251:Constriction, Pathologic / Q000235:genetics / Q000276:immunology; D003424:Crohn Disease / Q000150:complications* / Q000235:genetics / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D008351:Mannans / Q000276:immunology; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018272:Porins / Q000276:immunology; D055815:Young Adult
chemical_list: D000906:Antibodies; D008351:Mannans; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C113724:OmpC protein; D018272:Porins