Distinct IFNG methylation in a subset of ulcerative colitis patients based on reactivity to microbial antigens.
BACKGROUND
High antibody reactivity toward microbial antigens in Crohn's disease (CD) patients is predictive of a more aggressive disease course. However, few ulcerative colitis (UC) patients exhibit serologic reactivity toward microbial antigens. Mucosal expression of IFN-γ plays a pivotal role in inflammatory bowel disease (IBD) pathogenesis. Recent genome-wide association studies (GWAS) surprisingly link UC, but not CD, risk loci to IFNG. We recently demonstrated that mucosal T cells from IBD patients exhibit distinct patterns of IFNG methylation compared to controls. This study evaluated the relationship between IFNG methylation and serologic and clinical profiles in peripheral T cells from IBD patients.


METHODS
DNA from peripheral T cells of 163 IBD patients (91 CD and 64 UC) and 42 controls was analyzed for methylation of eight IFNG sites. Serum markers ASCA, OmpC, I2, CBir, and pANCA were measured by enzyme-linked immunosorbent assay (ELISA). IFN-γ secretion was measured by ELISA.


RESULTS
IBD patients requiring surgery exhibited reduced IFNG methylation compared to nonsurgical patients (P < 0.02). Enhancement of IFN-γ secretion (P < 0.003), along with high antibody responses toward multiple microbial antigens (P < 0.017) in UC, but not CD, patients was correlated with decreased IFNG methylation. pANCA levels were not correlated with IFNG methylation.


CONCLUSIONS
Levels of IFNG methylation were correlated with immune response to microbial components and expression of IFN-γ in UC patients. Serological and epigenetic markers identify a subset of UC patients with an expression profile of a key TH1 pathogenic cytokine. These data may provide a useful tool to classify a more homogeneous subset of UC patients, allowing for improved diagnostics and targeted therapeutics.
Gonsky
Rivkah
R
Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Deem
Richard L
RL
Landers
Carol J
CJ
Derkowski
Carrie A
CA
Berel
Dror
D
McGovern
Dermot P B
DP
Targan
Stephan R
SR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology*; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D055815:Young Adult
D019268:Antibodies, Antineutrophil Cytoplasmic; D000942:Antigens, Bacterial; D007371:Interferon-gamma