Prof. Cornelia Weyand
December 01, 2009, 5–7 p.m.
Professor Cornelia Weyand (Stanford University) will talk about “The Immune System in Rheumatoid Arthritis – In Need for Rejuvenation”.
Weyand has just joined the faculty of Stanford University as a professor of medicine. She received her training in medicine and immunology in Germany and completed a fellowship in rheumatology at Stanford University. She was the Barbara Woodward Lips Professor of Medicine and Immunology at the Mayo Medical and Graduate School in Rochester and in 2004 became the David Lowance Professor of Medicine and the Director of the Lowance Center for Human Immunology and Rheumatology at Emory University School of Medicine.
Weyand has received numerous awards and honors including the Henry Christian Award for Excellence in Research (1991), the Henry Kunkel Young Investigator Award (1992), the Carol Nachmann Award for Rheumatology (1995), the Mayo Foundation Outstanding Investigator Award (1999), the Emory University Outstanding Research Citation Award (2006), and the Paul Klemperer Award (2006). She has been elected a member of the American Society of Clinical Investigation and the American Association of Physicians.
Professor Weyand’s principal area of research investigates mechanisms of disease in patients with chronic inflammatory syndromes, with a specific focus on rheumatoid arthritis and inflammatory blood vessel disease. Her primary objective has been to define molecular mechanisms of immune-mediated tissue damage, with the ultimate goal to reduce the burden of autoimmune disease and to develop diagnostic and therapeutic tools to improve immune function in patients and in healthy individuals.
Delivering the Albrecht Hasinger Lecture 2009, Cornelia Weyand will talk about “The Immune System in Rheumatoid Arthritis – In Need for Rejuvenation”:
“Rheumatoid arthritis (RA) is a prototypic autoimmune syndrome in which chronic joint inflammation causes pain, deformity and disability. Besides the joint destruction, RA is complicated by accelerated cardiovascular disease; significantly shortening life expectancy. RA patients have increased risk to develop lymphoma and are susceptible to infection, disease complications resistant to current anti-inflammatory therapy. The traditional dogma proposes that innate and adaptive immunity is hyperactive, promoting autoantibodies and formation of complex lymphoid structures in the inflamed joint. Persistence of arthritogenic antigen is assumed to sustain chronicity. Cytokines have been identified as critical amplifiers of inflammation and as valid targets for anti-inflammatory therapy.
Recent evidence suggests that beside antigen-induced T cell activation other pathways are critically involved in promoting tissue-destructive immunity. Specifically, by determining the survival and longevity of T cells, mechanisms of maintaining DNA integrity and repairing broken DNA strands have emerged as key regulators of the immune system. T cells with shortened and uncapped telomeres and fragmented DNA occupy the immune system in RA, suggesting mechanistic similarities between this autoimmune syndrome and the progeroid syndromes.
T cells are long-lived cells and the carrier of immune memory believed to mediate chronic inflammation. Unlike most other somatic cells, T cells can upregulate telomerase and elongate their telomeres to prolong survival. In RA telomeres are age-inappropriately eroded by 1500 kb. Telomeric loss affects not only memory T cells, but also unprimed naïve T cells and, as we have recently shown, CD34 bone marrow hematopoietic precursor cells. The underlying mechanism involves a defect in upregulating the telomere-elongating enzyme telomerase. Knock-down of telomerase activity in healthy T cells renders them susceptible to apoptosis. Repair of telomerase activity in RA T cells protects them from apoptotic death implicating this enzyme in cell fate decisions. Insufficiency to maintain intactness and stability of DNA is not limited to the telomeric ends of chromosomes but equally involves non-telomeric DNA strands. RA T cells are loaded with damaged DNA, mostly double strand breaks. Unless tackled by vigorous repair activity double stand breaks are lethal. Molecular analysis of the DNA repair machinery demonstrate that RA T cells are deficient for the DNA repair enzyme ataxia-telangiectasia-mutated (ATM) and essentially mimic abnormalities in patients with the inherited syndrome ataxia telangiectasia. Forced overexpresion of ATM in RA T cells restores DNA repair, improves radiosensitivity and protects cells from apoptotic death.
In essence, RA emerges as a syndrome of subtle chronic T cell loss, forcing the system to respond with excessive autoproliferation. This response pattern imposes chronic proliferative stress and premature immunosenecence. With nuclear instability emerging as an RA-associated mechanism, therapeutic approaches should be reconsidered and should include measures of immune rejuvenation.”
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