Mary K. Crow, MD
The immune system has evolved to maintain the integrity of the organism in an environment rich in infectious microbes. When the immune system becomes misdirected toward components of one’s own tissue, autoimmune disease and chronic inflammation can result. In systemic lupus erythematosus (SLE), the prototype systemic autoimmune disease, proteins present in intracellular particles, along with the DNA or RNA bound by those proteins, are targeted by lymphocytes and antibodies of the immune system, resulting in inflammation and widespread tissue damage. This autoreactive immune response is mediated by CD4+ helper T lymphocytes that orchestrate a coordinated program of immune and inflammatory functions through interactions with B lymphocytes, macrophages, dendritic cells, as well as cells outside the immune system, such as the endothelial cells that line blood vessels. The goals of the laboratory are to define the triggers of immune activation in autoimmune disease and to characterize the mechanisms used by the immune system to regulate the effector cells that contribute to inflammation and tissue damage.
A current paradigm proposes that apoptotic cells may serve as a source of the self-antigens that initiate autoimmunity. However, all individuals are exposed to apoptotic cells. Our challenge is to understand why some individuals develop autoimmune disease and others do not. We propose that while apoptotic cells may serve as one source of self-antigen, adjuvant-like factors in the immune microenvironment of some individuals promote the effective presentation of available antigens to CD4+ T cells, resulting in T cell activation and generation of effector mechanisms targeted at self-antigens. Active projects include identification of the stimuli and molecular pathways involved in induction of type I interferon in SLE, with genome-derived immunostimulatory DNA and double stranded or single stranded RNA potential mediators of this effect; characterization of proinflammatory gene products produced in SLE and associated with active disease; and investigation of the relationship between interferon pathway activation and production of specific autoantibodies, particularly those targeting RNA-binding proteins.
As clinical investigators, we search for applications of our laboratory studies that may have impact on patients with disease. Efforts underway are aimed at identifying novel approaches to inhibition of the type I interferon pathway that may inform development of new therapeutic interventions in SLE. We are identifying the gene products that are differentially expressed between SLE patients with and without accelerated atherosclerosis, with the aim of characterizing novel targets that could modulate development of this clinically important outcome. Finally, we are studying the contribution of immune system activation and inflammation to disease in patients with osteoarthritis.
Senior Scientist, Hospital for Special Surgery
Professor of Medicine, Weill Medical College of Cornell University
Professor, Immunology Program, Weill Graduate School of Medical Sciences
Attending Physician, New York-Presbyterian Hospital
Benjamin M. Rosen Professor of Immunology and Inflammation Research and Senior Member, Hospital for Special Surgery
Attending Physician, Hospital for Special Surgery
Cron RQ, Bandyopadhyay R, Genin A, Brunner M, Kersh GJ, Yin J, Finkel TH, Crow MK. Egr-1 is required for CD154 transcription. J Immunol, 176:811-818, 2006.
Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, Sammaritano L, Devereux RB, Schwartz JE, Levine DM, Salmon JE. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med. 144(4):249-56, 2006.
Hua J, Kirou K, Lee C, Crow MK. Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Arthritis Rheum. 2006 Jun;54(6):1906-16.
Asokan R, Hua J, Young KA, Gould HJ, Hannan JP, Kraus DM, Szakonyi G, Grundy GJ, Chen XS, Crow MK, Holers VM.Characterization of Human Complement Receptor Type 2 (CR2/CD21) as a Receptor for IFN-a: A Potential Role in Systemic Lupus Erythematosus. J Immunol. 2006 Jul 1;177(1):383-94.
Kirou KA, Lee C, George S, Louca K, Peterson MGE, Crow MK. Interferon-alpha pathway activation identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum, 52:1491-503, 2005.
Roman MJ, Devereux RB, Schwartz JE, Lockshin MD, Paget SA, Davis A, Crow MK, Sammaritano L, Levine DM, Shankar B-A, Moeller E, Salmon JE. Arterial Stiffness in Chronic Inflammatory Diseases. Hypertension, 46:194-9, 2005.
Crow MK, Kirou KA. Interferon-alpha in systemic lupus erythematosus. Curr Opin Rheum, 16:541-547, 2004.
Liu S, Cerutti A, Casali P, Crow MK. Ongoing immunoglobulin class switch DNA recombination in lupus B cells: analysis of switch regulatory sequences. Autoimmunity, 37:431-443, 2004.
Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MGE, Ly N, Woodward RN, Fry KE, Lau A Y-H, Prentice JG, Wohlgemuth JG, Crow MK. Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus. Arthritis Rheum, 50:3958-67, 2004.
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