Leptin is produced almost exclusively by adipocytes and regulates body weight at the hypothalamic level. In addition, recent studies showed that leptin plays an important role in T lymphocyte responses. To examine the role of leptin in Ag-induced arthritis, the development of joint inflammation was assessed in immunized leptin-deficient mice (ob/ob), +/?, and wild-type mice (+/+) following the administration of methylated BSA into the knees. The results showed that ob/ob mice developed less severe arthritis compared with control mice. The levels of IL-1β and TNF-α mRNA in the synovium of arthritic knees were lower in ob/ob than in +/? mice. In vitro Ag-specific T cell proliferative responses were significantly decreased in ob/ob mice with lower IFN-γ and higher IL-10 production, suggesting a shift toward a Th2-type response in ob/ob mice. The serum levels of anti-methylated BSA Abs of any isotype were significantly decreased in arthritic ob/ob mice compared with controls. Essentially identical results were obtained in db/db mice, which lack the expression of the long isoform of leptin receptor. By RT-PCR, we observed that B lymphocytes express leptin receptor mRNA, indicating that in addition to its effect on the cellular response, leptin may exert a direct effect on B cell function. In conclusion, leptin contributes to the mechanisms of joint inflammation in Ag-induced arthritis by regulating both humoral and cell-mediated immune responses.

Dipeptidyl peptidase IV (DPPIV, CD26), a proteasecleaving N-terminal X-Pro dipeptide from selected proteins including some chemokines, is expressed both as a soluble form in plasma and on the cell surface of various immune and nonimmune cell types. To gain insights into the pathophysiological role of CD26 in arthritis, we explored DPPIV/CD26 expression during murine antigen-induced arthritis (AIA), an experimental model of arthritis. AIA induction led to reduced plasma DPPIV activity. In CD26-deficient mice, the severity of AIA was increased as assessed by enhanced technetium uptake and by increased histological parameters of inflammation (synovial thickness and exudate). We demonstrated that CD26 controls the in vivo half-life of the intact active form of the proinflammatory chemokine stromal cellderived factor-1 (SDF-1). CD26-deficient mice exhibited increased levels of circulating active SDF-1, associated with increased numbers of SDF-1 receptor (CXCR4)-positive cells infiltrating arthritic joints. In a clinical study, plasma levels of DPPIV/CD26 from rheumatoid arthritis patients were significantly decreased when compared to those from osteoarthritis patients and inversely correlate with C-reactive protein levels. In conclusion, decreased circulating CD26 levels in arthritis may influence CD26-mediated regulation of the chemotactic SDF-1/CXCR4 axis.

Summary. Background: Activation of coagulation and ®brino-lysis play a role in the pathophysiology of experimental arthritis. Objective: To determine the extent of activation of the coagulation and ®brinolytic pathways in different joint diseases in humans and to ascertain the factors that may in¯uence ®brin deposition within the joint. Methods: Plasma from normal subjects (controls, n 21) and plasma and synovial¯uid samples from patients with rheumatoid arthritis (RA; n 64), osteoarthritis (OA; n 29), spondyloarthropathy (SpA; n 22) and crystal arthritis (CA; n 25) were analyzed for the levels of TF (tissue factor) and tissue factor pathway inhibitor (TFPI) activities, thrombin±antithrombin III (TAT) complexes, and F1 2 (thrombin fragment), ®brin D-dimer and thrombin-activated ®brinolysis inhibitor (TAFI) antigenic levels. The measurements were analyzed by pairwise correlation with each other as well as with standard parameters of in¯ammation [C-reactive protein (CRP), joint leukocyte count]. Inter-group comparisons were performed to look for diseasespeci®c differences. Results: Compared with healthy controls, patients with joint diseases had higher levels of TAT, F1 2 and D-dimers in their plasma. In the synovial¯uid, TF activity, TAT, D-dimers, and TAFI were signi®cantly higher in in¯ammatory arthritides than in OA. The levels were highest in RA patients. In the plasma, TF activity was correlated with TAT and D-dimer levels with CRP, TFPI, and TAT. In the synovial¯uid, TF activity correlated with plasma CRP levels, synovial¯uid leukocyte count, and synovial TAT and TAFI levels. In addition, synovial D-dimers correlated with CRP, and synovial TAFI levels were correlated with synovial F1 2 and TAT. Conclusions: Activation of the coagulation and ®brinolytic cascades in the joint and in the circulation is evident in both in¯ammatory and degenerative joint diseases. Within the joint, in¯ammatory mechanisms leading to TF-mediated activation of the coagulation pathway and subsequent ®brin deposition is the most likely explanation for the observed ®ndings. In the plasma, the link between in¯ammation (CRP increase) and TF activation is weak, and a non-TF-mediated mechanism of coagulation activation could explain these ®ndings. RA is characterized by signi®cantly higher levels of TAT in the synovial¯uid and plasma than other arthritides. Although ®brinolytic activity is linked to in¯ammation, the increased amounts of TAFI in the joint, particularly in RA, may explain why ®brin formation is so prominent in this condition compared with other joint diseases.