Patients with inflammatory bowel disease may have a transforming growth factor-β-, interleukin (IL)-2- or IL-10-deficient state induced by intrinsic neutralizing antibodies

Abstract

SummaryUlcerative colitis (UC) and Crohn's disease (CD) are considered to be immunologically mediated disorders that share certain features with murine models of colitis. Whether any of these models are physiologically relevant to the human condition remains controversial. The hypothesis is that increased amounts of antibodies neutralizing transforming growth factor (TGF)-b, interleukin (IL)-2 or IL-10 create a relative immunodeficient state in inflammatory bowel disease (IBD) that predisposes to disease. To evaluate this, serum samples from patients with UC or CD and from normal healthy individuals were studied by enzyme-linked immunosorbent assays. Antibodies recognizing TGF-b were most prevalent in UC (P < 0·01); anti-IL-10 antibodies were elevated in CD (P < 0·05), while anti-IL-2 antibodies were the same for all three groups. Importantly, the percentage of IBD patients with at least one of the antibody levels greater than any control value was 30% for UC and 33% for CD. To verify the presence of these antibodies, immobilized TGF-b was exposed to UC sera and the attached proteins identified by Western blot assay. The proteins proved to be exclusively immunoglobulin (Ig) G. To evaluate the neutralizing activity of these antibodies, cytokine-specific IgG from subjects in each group of patients was incubated with TGF-b, IL-2 or IL-10 before addition to a bioassay with changes in viability determined by a colorimetric analysis. Antibodies from most individuals in all three groups neutralized the action of each cytokine. This study shows that about one-third of IBD patients may have a relative deficiency of TGF-b, IL-2 or IL-10 due to an increase in neutralizing antibodies in their sera.

Evidence for non-neutralizing autoantibodies against IL-10 signalling components in patients with inflammatory bowel disease

“…Furthermore, in contrast to other diseases with neutralizing anti-cytokine autoantibodies [23,24], but similar to the anti-IL-10 antibodies found by Ebert et al [19], the increase in OD values was not striking in our patients.…”

Macrophages from IBD patients exhibit defective tumour necrosis factor-α secretion but otherwise normal or augmented pro-inflammatory responses to infection

“…IL-10 has long been recognized as an anti-inflammatory cytokine. Defects in IL-10 production have been associated with the pediatric onset of IBD (Ebert et al 2009) and IL10-deficient mice are known to develop spontaneous colitis (Kuhn et al 1993). IL-10 was implicated in maintaining Treg cells' Foxp3 expression and suppressive function in mice with colitis (Murai et al 2009).…”

Genome-Wide Association Studies in Primary Biliary Cirrhosis

“…Knockout models of IL-12 subunits and associated downstream signals are particularly interesting in light of the GWAS-based evidence for the important role of this pathway in PBC. The dnTGFBRII mouse model results in transforming growth factor beta deficiency, which causes pleiotropic immunologic abnormalities including cholangitis, colitis, and early death 69,70 . Using this model, Yoshida et al .…”