The shared epitope (SE) is the single most significant risk factor for severe rheumatoid arthritis (RA), yet its mechanism of action is not completely understood. During budget years 01-05 of this R01 project, we identified the SE as a signal transduction ligand that specifically interacts with a well-defined binding site on cell surface calreticulin (CRT) and activates intracellular signaling events that lead to Th17 polarization and osteoclast activation. When administered to mice with collagen-induced arthritis, a synthetic SE ligand enhanced the severity of erosive joint destruction. Furthermore, based on structure-function characteristics of SE-CRT interaction, we have therapeutically targeted the pathway with CRT-binding small molecules that potently inhibited the arthritogenic pathway with resultant amelioration of experimental arthritis in mice. Based on preliminary results obtained in the current funding cycle of this project, in years 06 ? 10 we will carry out experiments that will advance our understanding of the molecular mechanisms and functional outcomes of the SE-activated pathway. Additionally, we will elucidate the signaling and functional effects of a protective epitope (PE) ligand that we recently discovered. This ligand appears to counteract the SE pathway and may explain a long-established but poorly understood epidemiologic association between particular HLA-DRB1 alleles and protection against RA. The hypothesis of this project states that in RA: A. Disease-facilitating and disease-protective HLA- DRB1alleles code for distinct ligands, which transduce reciprocal cell activation and differentiation signals; B. The SE pathway activates protein citrullination. The research plan in the coming 5 years will address this hypothesis with the following specific aims: 1. To delineate the respective signaling pathways activated by the SE and PE ligands and determine their functional effects on cell differentiation; 2. To analyze signature HLA- DRB1-coded ligand-activated transcriptomes using an RNA-seq approach; 3. To characterize the mechanism of a recently discovered SE-activated protein citrullination pathway, and determine its in vivo effects. Successful completion of the proposed research will illuminate fundamental questions concerning HLA-disease association, provide important new insights into the pathogenesis and etiology of RA, and set the stage for designing novel therapeutic strategies.

Public Health Relevance

Rheumatoid arthritis (RA) is a common disease that afflicts millions of individuals worldwide. Unfortunately, the mechanisms that cause the disease and determine its severity are incompletely understood. Here we will test a novel hypothesis concerning the role of one of the most important genetic factors in RA called ?shared epitope? and another genetic marker that has been previously found to protect against the disease. We will analyze their effects on white blood cells known as monocytes and on bone-destroying cells called osteoclasts. We expect that the new knowledge that this project will generate will shed important new light on the mechanisms that control disease risk or protection against the disease. In turn, this information might teach us about possible ways to treat the disease, or prevent it.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Fu, Jiaqi; Nogueira, Sarah V; Drongelen, Vincent van et al. (2018) Shared epitope-aryl hydrocarbon receptor crosstalk underlies the mechanism of gene-environment interaction in autoimmune arthritis. Proc Natl Acad Sci U S A 115:4755-4760
van Drongelen, Vincent; Holoshitz, Joseph (2017) Human Leukocyte Antigen-Disease Associations in Rheumatoid Arthritis. Rheum Dis Clin North Am 43:363-376
Van Drongelen, Vincent; Holoshitz, Joseph (2017) A reciprocal HLA-Disease Association in Rheumatoid Arthritis and Pemphigus Vulgaris. Front Biosci (Landmark Ed) 22:909-919
Chukkapalli, Sasanka; Rivera-Kweh, Mercedes; Gehlot, Prashasnika et al. (2016) Periodontal bacterial colonization in synovial tissues exacerbates collagen-induced arthritis in B10.RIII mice. Arthritis Res Ther 18:161
Gehlot, Prashasnika; Volk, Sarah L; Rios, Hector F et al. (2016) Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying a human shared epitope-coding HLA-DRB1 allele. RMD Open 2:e000349
Ling, Song; Liu, Ying; Fu, Jiaqi et al. (2015) Shared epitope-antagonistic ligands: a new therapeutic strategy in mice with erosive arthritis. Arthritis Rheumatol 67:2061-70
Ling, Song; Cline, Erika N; Haug, Timothy S et al. (2013) Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. Arthritis Rheum 65:618-26
Blanco, Luz P; Plegue, Melissa; Fung-Leung, Wai-Ping et al. (2013) Gender-biased regulation of human IL-17-producing cells in vitro by peptides corresponding to distinct HLA-DRB1 allele-coded sequences. J Immune Based Ther Vaccines Antimicrob 2:29-38
Holoshitz, Joseph (2013) The quest for better understanding of HLA-disease association: scenes from a road less travelled by. Discov Med 16:93-101
Fu, Jiaqi; Ling, Song; Liu, Ying et al. (2013) A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis. J Immunol 191:2096-103

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