NOD2 variants and antibody response to microbial antigens in Crohn's disease patients and their unaffected relatives.
OBJECTIVE
The Cdcs1 locus of the C3Bir mouse confers severe colitis associated with a decrease in innate immune function and an increase in adaptive T-cell responses to commensal bacterial products. The aim of our study was to determine if defects in innate immunity are similarly associated with increased adaptive immune responses to microbial antigens in Crohn's disease patients.


METHODS
Sera from 732 patients, 220 unaffected relatives, and 200 healthy controls were tested for antibodies to oligomannan, the Pseudomonas fluorescens-related protein, Escherichia coli outer membrane porin C, CBir1 flagellin, and DNA from the same subjects was tested for 3 Crohn's disease-associated variants of the NOD2 gene, and 5 toll-like receptor (TLR) 2, 2 TLR4, and 2 TLR9 variants. The magnitude of responses to microbial antigens was examined according to variant status.


RESULTS
NOD2 variant carriage increased in frequency with increasing number of positive antibodies and increasing cumulative quantitative response as measured by quartile sum (P for trend, .0008 and .0003, respectively). Mean antibody and quartile sums were higher for patients carrying any NOD2 variant versus those carrying none (2.24 vs 1.92 and 10.60 vs 9.72; P = .0008 and P = 0.0003, respectively). The mean quartile sum was higher for unaffected relatives carrying any NOD2 variant versus those carrying none (10.67 vs 9.75, respectively; P = .02). No association was found between any TLR variant and the magnitude of response.


CONCLUSIONS
Patients with Crohn's disease and unaffected relatives carrying variants of the NOD2 gene have increased adaptive immune responses to microbial antigens.
Devlin
Shane M
SM
Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Yang
Huiying
H
Ippoliti
Andrew
A
Taylor
Kent D
KD
Landers
Carol J
CJ
Su
Xiaowen
X
Abreu
Maria T
MT
Papadakis
Konstantinos A
KA
Vasiliauskas
Eric A
EA
Melmed
Gil Y
GY
Fleshner
Phillip R
PR
Mei
Ling
L
Rotter
Jerome I
JI
Targan
Stephan R
SR
D000942:Antigens, Bacterial / Q000097:blood*; D001426:Bacterial Proteins / Q000276:immunology; D002140:California; D016022:Case-Control Studies; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology / Q000382:microbiology*; D029968:Escherichia coli Proteins / Q000276:immunology*; D005408:Flagellin / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D011551:Pseudomonas fluorescens / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D005408:Flagellin