The Lee laboratory is focused on understanding autoimmune and inflammatory mechanisms that contribute to inflammatory arthritis (such as Rheumatoid Arthritis). The laboratory studies these mechanisms of joint inflammation in both mouse models of disease and in human specimens obtained from patients with rheumatoid arthritis. Studies in the K/BxN T-cell receptor transgenic mouse model of arthritis have demonstrated that T- and B-cell autoimmunity results in development of pathogenic anti-glucose-6-phosphate isomerase (anti-GPI) autoantibodies. The arthritogenic activity of anti-GPI autoantibodies proceeds from immune complex formation and deposition in joint tissues via activation of complement and IgG Fc-receptors. Interestingly, this autoimmune arthritis integrates cellular members of the innate immune system (neutrophils and mast cells) for arthritis induction and perpetuation. Specific areas of investigation include mechanisms governing leukocyte recruitment (such as integrins and other adhesion molecules) and pro-inflammatory mediators that participate in joint inflammation (such as leukotrienes and prostaglandins). The laboratory also has a major interest in understanding the regulation of mast cells in arthritic joint tissues.
Furthermore, to gain insight into the mechanisms by which autoantibodies contribute to autoimmune arthritis, the laboratory has recently begun investigating a potential regulatory role for glycosylation in IgG function. IgG in humans with rheumatoid arthritis and in the K/BxN mouse model have markedly aberrant glycosylation of their circulating IgG. Studies focused in modulation of IgG function and the regulation of IgG glycosylation are underway.
Guided by observations in the murine K/BxN model, the laboratory also analyzes human specimens from patients with rheumatoid arthritis. Contributions from mast cell, neutrophils and macrophages as well as leukotrienes and prostaglandins are under active investigation.
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Papers & Publications:
1. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 2002;297(5587):1689-92.
2. Chen M, Lam BK, Kanaoka Y, Nigrovic PA, Audoly LP, Austen KF, Lee DM. Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. J Exp Med 2006;203:4:837-842.
3. Shin K, Gurish MF, Friend DS, Pemberton AD, Thornton EM, Miller HR, Lee DM. Murine synovium is populated with lymphocyte-independent connective tissue mast cells. Arthritis Rheum 2006;Aug 31;54(9):2863-2871.
4. Nigrovic PA, Binstadt BA, Monach PA, Johnsen A, Gurish MF, Iwakura Y, Benoist C, Mathis D, Lee DM. Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1. PNAS 2007. 104:2324.
5. Lee DM, Kiener HP, Agarwal SA, Noss EH, Watts GFM, Chisaka O, Takeichi M, Brenner MB. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 2007. 315:1006 |
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