Abstract
Objectives HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272–specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders.MethodsThe monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry.ResultsHD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules.ConclusionHD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders.
Highlights
Spondyloarthritides (SpAs) are a group of common inter-related inflammatory rheumatic diseases associated with the human leukocyte antigen B27 (HLA-B27) allele
Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders
Given the role that these receptors play in maintaining immune homeostasis, it is suggested that ligation by aberrant forms of B272 may upset this balance in favor of a pro-inflammatory response
Summary
Spondyloarthritides (SpAs) are a group of common inter-related inflammatory rheumatic diseases associated with the human leukocyte antigen B27 (HLA-B27) allele. Unusual biochemical properties of HLA-B27 include its ability to misfold and form cell-surface β2mfree heavy chain homodimers (B272) [4, 5] that are thought to influence inflammatory responses [6, 7]. It still remains undetermined how the interaction of B272 with immunoregulatory receptors leads to disease. Cell-surface B272 has been shown to interact with killer cell Immunoglobulin-like receptors (KIR) and Leukocyte Immunoglobulin-like receptors (LILR) in a manner different from HLA-B27 heterotrimers [7,8,9]. Cellsurface B272 can be detected in B27-transfected cell lines, AS patients' peripheral blood mononuclear cells (PBMCs) and leukocytes from B27-transgenic rats [7, 10,11,12]
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