Predisposition to develop Rheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes while others offer resistance from arthritis. HLA-DQ8 and DRB1*0401 molecules render humans and mice susceptible to develop arthritis while DRB1*0402 provides protection. Collagen-induced arthritis (CIA) susceptible HLA transgenic mice produce rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies similar to that in RA patients. Similar to humans, the HLA-DR4 transgenic mice develop CIA more often in females than males.
In aim 1 we will investigate the mechanism of association of DR and DQ alleles with arthritis by studying immunogenicity and presentation of posttranslationally modified synovial proteins. We hypothesize that DR4 has a role in gender-bias of arthritis, where DR4 expression, presentation of antigen by various APCs and ensuing responses are different in males and females. Female sex hormone, estrogen, is involved in pathogenesis by enhancing production of peptidyl arginine deiminase (PAD) enzyme that leads to citrullination of synovial proteins. These citrullinated proteins are presented with greater efficiency by HLA-DR4 molecules leading to an autoreactive T and B cell response and disease. On the other hand, DQ8 can present native and de-amidated peptides derived from synovial proteins generating a robust autoimmune response.
In aim 2 we will test role of shared epitope in protection versus susceptibility. For this aim, we will study modulation of immune response by gene complementation and epistatic interactions between DR and DQ molecules. We will use DRB1*0401 and DRB1*0402 transgenic mice to determine the mechanism of protection to understand how three amino acid difference in these molecules leads to protection by the latter. We hypothesize that antigen presentation by DQ8 molecule leads to production of high levels of pro- inflammatory IL-17 while polymorphism in DR4 gene leads to production of either pro-inflammatory or acute inflammatory cytokines. In this aim we will focus on the role of IL-17 and IFNg in susceptibility Vs protection/modulation of disease. We are generating IL-17 knockout, IFNg knockout and triple transgenic *0401/*0402/DQ8 mice for this aim. Recent literature has shown a protective/ susceptible effect of non- inherited maternal antigen (NIMA) on the development of arthritis.
In aim3, we will use various matings to generate mice that have been exposed in utero to one NIMA. These mice will be evaluated for in vivo arthritis, autoantibodies and function of T and B cells. The proposed experiments will test several new, original and innovative theories on the role of MHC genes in predisposition, onset, progression, severity and modulation in arthritis. The findings would shed light on the role of MHC, immune system in health and disease and may identify new therapeutic approaches for arthritis.

Public Health Relevance

Rheumatoid arthritis is a disabilitating disease, affecting women more often than men. There are some genes that have been shown to be associated with arthritis while some are protective. In this study we will use mice that express human arthritis associated genes and develop pathology with a gender-bias similar to RA to delineate the role of genes. Further, we will define if proteins that are modified to clear viral infections might enhance autoreactive response in genetically susceptible individuals. We will study the mechanism of protection by using mice that carry RA protective genes. The proposed experiments will determine the mechanism of protection versus susceptibility. The information gained may be instructive in developing preventive immuno intervention for ongoing arthritis especially in women.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Vassallo, Robert; Luckey, David; Behrens, Marshall et al. (2014) Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes. Clin Immunol 152:25-35
Luckey, David; Behrens, Marshall; Smart, Michele et al. (2014) DRB1*0402 may influence arthritis by promoting naive CD4+ T-cell differentiation in to regulatory T cells. Eur J Immunol 44:3429-38
Taneja, Veena (2014) Arthritis susceptibility and the gut microbiome. FEBS Lett 588:4244-9
Mangalam, Ashutosh K; Taneja, Veena; David, Chella S (2013) HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile. J Immunol 190:513-8
Behrens, Marshall; Papadopoulos, George K; Moustakas, Antonis et al. (2011) Trans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized mice. Arthritis Rheum 63:1552-61
Jiang, Chao; Deshmukh, Umesh S; Gaskin, Felicia et al. (2010) Differential responses to Smith D autoantigen by mice with HLA-DR and HLA-DQ transgenes: dominant responses by HLA-DR3 transgenic mice with diversification of autoantibodies to small nuclear ribonucleoprotein, double-stranded DNA, and nuclear antigens. J Immunol 184:1085-91
Taneja, Veena; Behrens, Marshall; Basal, Eati et al. (2008) Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis. J Immunol 181:2869-77
Taneja, Veena; Krco, Christopher J; Behrens, Marshall D et al. (2007) B cells are important as antigen presenting cells for induction of MHC-restricted arthritis in transgenic mice. Mol Immunol 44:2988-96
Taneja, Veena; Behrens, Marshall; Mangalam, Ashutosh et al. (2007) New humanized HLA-DR4-transgenic mice that mimic the sex bias of rheumatoid arthritis. Arthritis Rheum 56:69-78
Taneja, Veena; Taneja, Neelam; Behrens, Marshall et al. (2005) Requirement for CD28 may not be absolute for collagen-induced arthritis: study with HLA-DQ8 transgenic mice. J Immunol 174:1118-25

Showing the most recent 10 out of 50 publications