Interleukin-10 Autoantibodies and HLA-DRB1*01:03 in Inflammatory Bowel Disease.
Gharahdaghi N., Yeh P-J., Ceron-Gutierrez L., Griffin H., Gordon H., Jayamanne C., Fracchia A., Chong AY., Walsh A., Brain O., Baker K., Kockelbergh H., Luo Y., Guevara Becerra M., Vadakethala K., Coy M., Kabiri L., Barnardo M., Dunachie S., Kronsteiner B., Adams A., Fowler D., Zhang Q., Fachal L., Anderson CA., Desoki R., Vestergaard MV., Larsen L., Wyatt NJ., Lees RD., Mulligan RJ., Dong C., Sharip MT., Faustini SE., Shields A., Pakpoor J., Naz B., Richter A., Satsangi J., Lamb CA., Parkes M., Powrie F., Mentzer AJ., Sazonovs A., Jess T., Klenerman P., Travis S., Hambleton S., Doffinger R., Uhlig HH.
BackgroundNeutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD). The allele HLA-DRB1*01:03 is the strongest genetic risk factor for ulcerative colitis.MethodsWe used a cellular interleukin-10 reporter assay and a confirmatory competitive enzyme-linked immunosorbent assay to assess neutralizing interleukin-10 autoantibodies in serum samples obtained from patients with IBD in the Oxford and U.K. IBD BioResource cohorts and from persons without IBD (controls). An in vitro cytokine-release bioassay was performed in a subgroup of patients to assess interleukin-10, interleukin-23, interleukin-1β, tumor necrosis factor, and interleukin-6. We performed HLA association analysis using imputation and high-resolution sequencing.ResultsInterleukin-10-neutralizing autoantibodies were detected in 173 of 4909 patients with IBD (3.5%; 95% confidence interval [CI], 3.0 to 4.1) and in none of 1006 controls (P<0.001). High anti-interleukin-10 activity in serum was associated with a reduction in detectable interleukin-10 and with an exaggerated proinflammatory cytokine response, consistent with functional neutralization of interleukin-10 signaling. Anti-interleukin-10 seropositivity was strongly associated with HLA-DRB1*01:03 on the basis of imputed data from the Oxford cohort (odds ratio, 50.0; 95% CI, 16.4 to 152.3; P = 6.14×10-12) and the U.K. IBD BioResource cohort (odds ratio, 24.7; 95% CI, 14.5 to 42.1; P = 6.20×10-32) and in a high-resolution sequencing analysis of data from the Oxford cohort (odds ratio, 29.5; 95% CI, 12.2 to 71.1; P = 4.85×10-14).ConclusionsNeutralizing interleukin-10 autoantibodies were present in a subgroup of patients with IBD and were strongly associated with HLA-DRB1*01:03. (Funded by the National Institute for Health and Care Research and others.).