B cell depletion dramatically affects clinical symptoms in RA patients, this observation suggests that B cells are involved in the pathogenesis of the disease. In addition to the """"""""primary"""""""" function (autoantibody production) of B cells these cells express costimulatory molecules and cytokines, which may have profound effects on the initiation and/or chronic progression of disease. However, very little is known about how these other functions of B cells are involved in RA. Our animal model, proteoglycan (PG)-induced arthritis (PGIA), has many similarities to RA and so has the potential to provide important information on the mechanism of human disease. PGIA is critically dependent on PG-specific T cell activation and autoantibody production, consequently, if either of these components are missing arthritis does not develop. The overall goal of this proposal is to understand the mechanisms by which B cells contribute to PGIA. Our strategy in aim 1 is to more closely link PGIA to RA by showing that depletion of B cells in acutely arthritic mice suppresses arthritis. The immunological parameters that correlate B cell depletion with reduction in arthritis will be assessed. Our hypothesis is that T cell activation will be reduced in B cell depleted mice. Furthermore, we hypothesize that costimulatory molecules and cytokines expressed by B cells play a key role in maintaining T cell activation. Hence, in aim 2 and aim 3 we will begin to dissect the mechanisms by which B cells contribute to arthritis. Because cells other than B cells express costimulatory molecules and cytokines we need a strategy to separately examine the role of B cells from other antigen-presenting populations. Our approach is to generate mice with either selective deletion, or reciprocally, selective expression of costimulatory molecules (CD80/86, B7RP-1, and PD-L1) or cytokines (IFN-gamma and IL-10) in B cells and not other cell populations. Our overall hypothesis is that B cells are able to control the development of arthritis through stimulatory and inhibitory interactions that principally affect T cell activation. This is an important area of investigation, which is expected to shed new light on the mechanisms of B cell function in RA, and more generally in autoimmune disease, and thereby provide novel potential targets for the development of therapeutic strategies to selectively block or enhance immune responses.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rush University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Olalekan, Susan A; Cao, Yanxia; Hamel, Keith M et al. (2015) B cells expressing IFN-? suppress Treg-cell differentiation and promote autoimmune experimental arthritis. Eur J Immunol 45:988-98
Hamel, Keith M; Cao, Yanxia; Olalekan, Susan A et al. (2014) B cell-specific expression of inducible costimulator ligand is necessary for the induction of arthritis in mice. Arthritis Rheumatol 66:60-7
Finnegan, Alison; Ashaye, Susan; Hamel, Keith M (2012) B effector cells in rheumatoid arthritis and experimental arthritis. Autoimmunity 45:353-63
Hamel, Keith M; Cao, Yanxia; Ashaye, Susan et al. (2011) B cell depletion enhances T regulatory cell activity essential in the suppression of arthritis. J Immunol 187:4900-6
Glant, Tibor T; Radacs, Marianna; Nagyeri, Gyorgy et al. (2011) Proteoglycan-induced arthritis and recombinant human proteoglycan aggrecan G1 domain-induced arthritis in BALB/c mice resembling two subtypes of rheumatoid arthritis. Arthritis Rheum 63:1312-21
Hamel, Keith M; Cao, Yanxia; Wang, Yumei et al. (2010) B7-H1 expression on non-B and non-T cells promotes distinct effects on T- and B-cell responses in autoimmune arthritis. Eur J Immunol 40:3117-27
O'Neill, Shannon K; Veselits, Margaret L; Zhang, Miao et al. (2009) Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells. Proc Natl Acad Sci U S A 106:6262-7
Farkas, Balint; Boldizsar, Ferenc; Tarjanyi, Oktavia et al. (2009) BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance. Arthritis Res Ther 11:R21
Hamel, Keith; Doodes, Paul; Cao, Yanxia et al. (2008) Suppression of proteoglycan-induced arthritis by anti-CD20 B Cell depletion therapy is mediated by reduction in autoantibodies and CD4+ T cell reactivity. J Immunol 180:4994-5003
O'Neill, Shannon K; Cao, Yanxia; Hamel, Keith M et al. (2007) Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the development of arthritis. J Immunol 179:5109-16

Showing the most recent 10 out of 18 publications