Abstract #1283 HLA-B27 Misfolding Activates the IL-23/IL-17 Axis via the Unfolded Protein Response in Transgenic Rats: Evidence for a Novel Mechanism of Inflammation
Authors
Robert A. Colbert1, Matthew J. Turner1, Monica L. DeLay1, Judith A. Smith2, Erin I. Klenk1, Dawn P. Sowders1, Shuzhen Bai1. 1Cincinnati Childrens Hospital Medical Center, Cincinnati, OH; 2University of Wisconsin School of Medicine, Madison, WI
Background
One of the oft-noted paradoxes of the B27-associated diseases is the relative lack of CD8+ T cells, and the enrichment and activation of CD4+ T cells in affected tissues and sites. Several lines of evidence suggest that the class 1 molecule B27 possesses several unique properties, including the ability to dimerize and form an extended class 2-like antigen binding pocket, and the propensity to accumulate and misfold generating an unfolded protein response (UPR) in the cell. This unfolded “stress” response is hypothesized to trigger unique processing and presentation events, which might lead to CD4+ T cell activation.
Methods
Differential cytokine expression following the induction of the UPR was analyzed using microarrays and real-time PCR on bone marrow derived macrophages from wild type and B27 transgenic rats. An additional control was an HLA B7 transgenic (a class 1 allele not associated with disease susceptibility in animals or humans). Pathology specimens from the colons of wild type and B27 transgenic animals were examined for the presence of UPR-induced cytokines.
Results
IL23 and IFN-beta are strikingly upregulated in macrophages from the B27 animals following stimulation with LPS; this induction was not seen in the B7 or wild type transgenics, and other cytokines were not appreciably upregulated. IL-23 was found throughout the colon and mesenteric lymph nodes in the B27 transgenics; this correlated with the degree of inflammation in these animals. Most strikingly, IL-17, a product of a unique class of CD4+ T cells, was equally upregulated and anatomically co-localized with IL-23 expression.
Editorial Comment
This abstract, presented at the 3rd plenary session, suggests a possible mechanism that links B27 expression in antigen presenting cells with stimulation of effector CD4+ T cells. In this paradigm, B27 expression induces the UPR in macrophages; this UPR induces the macrophages to synthesize and express IL23, a potent inducer of Th17 (IL-17 producing) effector CD4+ T cells. These effector cells are then responsible for generating the severe tissue inflammation seen in the spondyloarthropathies. This data is all the more significant given increasing evidence that IL-23 plays a major role in these diseases in humans, and suggests a novel therapeutic target in this group of diseases
