Background and Objective: These studies are targeted towards understanding the pathogenesis of psoriatic arthritis and the development of specific immunotherapies for psoriatic arthritis, a relatively common chronic inflammatory disease affecting skin and joints. Patients with known or suspected psoriatic arthritis are evaluated at the Clinical Center. Studies include characterization of the clinical and laboratory features of the disease, research studies of the natural history and pathogenesis and determination of the patients' eligibility to enter experimental therapeutic protocols. Patients are asked to contribute blood, skin or synovial membrane samples for immunologic research studies. Immunologic studies include investigations of 1) T cell antigen receptor (TCR) repertoire in the peripheral blood and at sites of inflammation (i.e., skin and joints); 2) relative importance of monocyte and T cell-derived cytokines in the disease process; and 3) biology and role of metalloproteinases and angiogenesis in this disease. Results 1) T cell receptor repertoire analysis. TCR BV gene analysis in peripheral blood mphocytes (PBL), skin and synovium of 9 patients with psoriatic arthritis revealed significant TCR BV biases in all three sites. CDR 3 sequencing demonstrated that these expansions frequently consisted of oligo-or monoclonal populations. Although, no ubiquitous CDR3 nucleotide sequences were identified, several highly homologous amino acid motifs were present in skin and synovium among and between individual patients. These findings suggest that T cell expansions are driven by engagement with a limited set of conventional antigens and that the inciting antigen(s) is identical or homologous between involved skin and synovium. 2) Monocyte derived cytokines in psoriatic arthritis. Multiple synovial fragments obtained at closed-needle joint biopsy and skin tissue obtained by punch biopsy from 26 patients with psoriatic arthritis were analyzed by immunohistochemical methods. Significant amounts of the proinflammatory cytokines TNFa, IL-1a and IL-1beta were found in both tissues. Patients also exhibited significant amounts of the T cell stimulatory monokines IL-12 and IL-15. CD40 and CD 40L expressions was widespread on lymphocytes and macrophage/fibroblasts/keratinocytes respectively. These data provide the first comprehensive localization of key proinflammatory cytokines in psoriatic arthritis synovial membrane and skin. Analysis of T cell derived cytokines and studies of Th1 vs Th2 immune response are in progress. 3) Angiogenesis and endothelial cell activation. Angiogenesis is a prominent feature of psoriatic arthritis. Using monoclonal antibodies against von Willebrand factor, anb3 integrin, P-selectin and E-selectin we demonstrated widespread new vessel formation and endothelial cell activation. Efforts to identify growth factors promoting angiogenesis are in progress. Activated endothelial cells express high levels of the T stimulatory monokine IL-15. Since metalloproteinases (and their tissue inhibitors) are involved in tissue destruction and angiogenesis, our future plans include a comprehensive examination of the types of metalloproteinases involved by both immunohistochemistry and zymography. The availability of selective inhibitors of metalloproteinases and other angiogenic molecules provides for the first time the opportunity to examine their role in the pathogenesis of disease in humans. Lay Summary Psoriasis is a common inflammatory disease of the skin that affects approximately 2% of the population of the USA. Psoriasis is accompanied by a destructive arthritis in 5-15% of patients. Our studies examine the relative contribution of certain types of blood cells and their products in causing this disease. Thus far we have established an important role of certain blood cells called T lymphocytes and monocytes in causing inflammation. In addition, we have identified several molecules produced by these cells that cause inflammation which could be targets for future therapy.
|Takada, K; Danning, C L; Kuroiwa, T et al. (2003) Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects. Ann Rheum Dis 62:1112-5|