Characterization and Immunomodulation of B Lymphocyte Responses in Human Spondyloarthritis

Dominique Baeten, M.D., Ph.D.

University of Amsterdam

Funded in December, 2006: $355000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

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Identifying Immune B Cell Defects in Spondyloarthritis May Lead to Improved Therapy

This consortium will identify the role that immune B cells, and their interactions with immune T cells, play in the autoimmune arthritic disease, called “spondyloarthritis.” Better understanding may lead to improved treatment for this and other autoimmune diseases, and for preventing rejection of transplanted organs.

Spondyloarthritis is an autoimmune disease affecting mainly young men. It is a severe form of chronic inflammatory arthritis, in which patients' “adaptive” immune cells errantly attack the body's joints, producing inflammation and structural changes. Research has focused on errant immune T cell attacks that produce inflammation in the membrane that lines joints. Pain relief is aided by recently developed anti-inflammatory drugs—called TNF-alpha blockers” (infliximab and etanercept)—as long as patients remain on the medications. The consortium researchers, however, hypothesize that immune B cells that are dependent on interactions with immune T cells are the major culprit. Their preliminary evidence suggests that these immune B cells, interacting with T cells, mistake certain parts of cartilage in the joints as bacteria (a process called molecular mimicry) and release antibodies to attack the cartilage. The anti-inflammatory drugs, therefore, may actually confer benefit by blocking these immune T and B cell interactions.

If this is the case, drugs that block T and B cell interactions would provide greater therapeutic benefit in a number of autoimmune diseases compared to current therapies that simply deplete immune B cell levels. To determine if their hypotheses are correct, consortium researchers will characterize patients' immune B cells found in joint membrane tissues, identify the B-cell antibody targets in joint cartilage, and study patients before and after treatment with infliximab and etanercept to determine whether the drugs block B and T cell interactions.

The consortium will contribute the three essential areas of expertise. These include the Amsterdam University researcher's understanding of drug interactions, the Irvine University researcher's understanding of the molecular basis of autoimmunity, and the French Centre investigator's understanding of the effects of antibodies.

Significance: Study findings could produce profound new insights into immune cell interactions in spondyloarthritis and other autoimmune diseases, and in immune-related tissue rejection that occurs following transplantation. This understanding, in turn, could lead to fundamentally improved therapeutic approaches to treating autoimmunity and tissue rejection.

ABSTRACT

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Characterization and Immunomodulation of B Lymphocyte Responses in Human Spondyloarthritis

Spondyloarthritis (SpA) is a frequent and severe form of chronic inflammatory arthritis affecting 0.5-1% of young adults. It leads to severe symptoms and, in the longer term, functional handicap. Recently, TNFalpha blockade has been introduced as a very effective form of immunomodulation in SpA. However, the potential side effects of this treatment (including the induction of autoantibodies) and the rapid relapse upon interruption of the treatment warrant further investigation into the pathogenesis of this disease and new targets for immunomodulation.

B lymphocytes and autoantibodies, which play a prominent role in many other forms of autoimmunity and immune-mediated inflammatory diseases, have never been thoroughly investigated in this disease. We now have preliminary evidence that this crucial part of the immune system is also affected in SpA. Therefore, the aim of the present project is to characterize the alterations of the humoral immunity in human SpA, to identify antigen-driven B cell responses which may contribute to the pathology, and to explore new ways of immunomodulation of the B cell responses in vivo. We anticipate that this will ultimately lead to new diagnostic, prognostic, and therapeutic applications in SpA.

Our international consortium brings together a large expertise in SpA immunopathology, B cell biology, and cellular and molecular techniques to analyze a unique collection of clinically relevant biological samples obtained from SpA patients. Moreover, our interest in clinical science emphasizes our commitment to translate the biological findings back to the clinics. Of particular importance, the multi-disciplinary background of our consortium may allow the application of these findings not only to SpA but also to other important immune-mediated disorders such as rheumatoid arthritis, multiple sclerosis, and solid organ graft rejection.

INVESTIGATOR BIOGRAPHIES

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Dominique Baeten, M.D., Ph.D.

Dominique Baeten, M.D., Ph.D., is Associate Professor at the Department of Clinical Immunology and Rheumatology of the Academic Medical Center/University of Amsterdam, The Netherlands. He was trained as physician, specialist in internal medicine, and rheumatologist at the University of Ghent, Belgium. He obtained his Ph.D. in Biomedical Sciences at the same university in 2001. After spending two years as a visiting scientist at the transplantation immunology laboratory of INSERM U643, Nantes, France, and at the Center for Neurological Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, he started his own research group in Amsterdam. His main interest is the immunopathology of inflammatory arthritis, with focus on rheumatoid arthritis and spondyloarthritis. This encompassess histopathology and immunomonitoring of human samples obtained during targeted therapies as well as more basic immunological work in vitro and in animal models. Yiping Zhang, M.D., Ph.D., is Associate Professor at the Department of Neurology of the University of California at Irvine. He obtained his M.D. from The Medical College, Shanghai First Medical University (now Fudan University) Shanghai, China. After finishing his post graduate trainings in Max-Planck Society, Clinical Research Institute for Multiple Sclerosis, Würzburg, Germany, and Service de Neurobiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, he joined the Department of Neruroimmunology, Max-Planck Institute for Psychiatry, Martinsried/Munich, Germany, as Research Scientist. Then he worked in Joint Disease Laboratory, Shriner's Hospital for Children, Montreal, Quebec, Canada as Associate Professor, Department of Surgery, McGill University. Dr. Zhang's Research interests are regulatory T and B lymphocyte interaction and immunotherapy in autoimmune diseases. His research is focused on multiple sclerosis, rheumatoid arthritis, and spondyloarthropathy, in particular. He has large expertise in biomolecular and antibody work in the area of B cell biology. Sophie Brouard, Ph.D., is First Rank Researcher of the CNRS (Centre National pour la Recherche Scientifique) working at the INSERM U643 laboratory in Nantes, France. She has been trained at the National Veterinary School of Nantes and subsequently as a transplantation immunologist at the largest kidney transplantation centre in Europe, in Nantes, France. After obtaining her Ph.D. degree in immunology, she spend two years in the Immunobiology Center of the Harvard Medical School Hospital, Boston, where she studied molecular biology. Over the last 4 years, she co-directed with Professor Soulillou a team of 10 researchers (1 post-doc, 6 Ph.D. students, 3 technicians) that studies the role of lymphocytes in transplantation tolerance in humans, as well as in animal models. She developed an innovative technique to analyse T cell clonality in blood and tissue samples, including human synovial tissue biopsies, and has a large expertise in antibody-mediated pathology in graft rejection.

SELECTED PUBLICATIONS

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Cantaert T., De Rycke L., Mavragani C., Wijbrandts CA., Niers T., Vandooren B., Veys EM., Richel D., Tak P.P., Crow M., and Baeten D. Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during TNF alpha blockade. Ann Rheum Dis. 2008 Jul 14.

Cantaert T., Kolln J., Timmer T. Van der Pouw-Kraan T., Vandooren B., Thurlings R., Canete J., Catrina A.I., Out T., Verweij C., Zhang Y., Tak P.P., and Baeten D.   B lymphocyte autoimmunity in rheumatoid synovitis is independent of ectopic lymphoid neogenesis.  J Immunol. 2008 Jul 1;181(1):785-94.

Baeten D., Kruithof E., Breban M., and Tak P.P.  Spondyloarthritis in the absence of B lymphocytes.  Arthritis Rheum. 2008 Mar;58(3):730-3.