Angelo A. Manfredi Patrizia Rovere, Guacomo Galati Silvia Heltai, Ennca Bozzolo, Laura Soldini, Jean Davoust, Genesio Balestrieri, Angela Tincani, and Maria Grazia Sabbadini 205

Accelerated apoptosis and unregulated clearance and presentation of antigens from dying cells are implicated in the pathogenesis of systemic autoimmune diseases. This study shows that the plasma membrane of human cells undergoing apoptosis is recognized by aPL. Furthermore, aPL facilitate the clearance of apoptotic cells by FcR-positive scavenger cells and bias the cytokines secreted by macrophages as a consequence of apoptotic cell recognition and engulfment. Opsonization of autoantigen-containing apoptotic cells by aPL may contribute danger signals, thus eliciting and facilitating the maintenance of an adaptive immune response toward nuclear self antigens.

Angelo A. Manfredi Patrizia Rovere, Silvia Heltai Giacomo Galati Gaia Nebbia, Angela Tincani, Genesio Balestrieri, and Maria Grazia Sabbadini 215

β₂-GPI is required for recognition of anionic phospholipids by aPL in vitro. This study demonstrates that β₂-GPI binds to phosphatidylserine-positive human apoptotic cells and is required for their recognition by opsonizing human aPL. However, human macrophages recognize and clear apoptotic cells in a β₂-GPI independent manner. Recognition of apoptotic cells via the β₂-GPI/aPL/FcR pathway, which is different from the thrombospondin/CD36/vitroectin receptor pathway, may trigger phlogistic responses from scavenger phagocytes.

Miri Blank Jacob George, Pnina Fishman, Yair Lely, Vladimir Toder, Shoshana Savion, Vivian Barak Takoo Kolke, and Yehuda Shoenfeld 224

APS is characterized by thromboembolic phenomena, recurrent fetal loss, and thrombocytopenia. Treatment with IL-3 has been shown to abrogate all manifestations of experimental APS due to its beneficial effect in pregnancy and on platelet precursors. The antibiotic ciprofloxacin has been found to stimulate the production of IL-3. This study shows the favorable effects of ciprofloxacin on the clinical and serologic markers of experimental APS. These beneficial effects of ciprofloxacin, if reproduced in additional experimental models, may allow for this medication to be considered as a possible alternative after careful clinical evaluation in patients with APS.

Hans P. Kiener, Mehrdad Baghestanian, Martin Dominkus, Sabine Walchshofer, Minoo Ghannadan, Martin Willheim, Christian Sillaber, Winfried B. Graninger, Josef S. Smolen, and Peter Valent 233

The accumulation of MC in the synovium of patients with RA indicates a contribution of these cells in the pathogenesis of RA. To gain new insights into the role of MC in RA, the immunophenotype and functional properties of synovial MC (SyMC) in patients with RA and OA were analyzed. The results of this study show that SyMC in RA, but not OA, patients express receptors for the anaphylatoxin C5a (C5aR/CD88) and release histamine in response to the respective ligand' recombinant C5a. It is hypothesized that SyMC, C5a, and C5aR/CD88 play a role in the pathogenesis of RA.

Grace A. Loredo and Hilary P. Benton 246

Extracellular ATP has been widely implicated as an inflammatory mediator in a number of cell systems. This study demonstrates the presence of calcium/mobilizing P2u-like receptors on the surface of adherent rheumatoid Synovial cells. Activation of these receptors by either ATP or UTP significantly enhances interleukin-1-induced prostaglandin release, thus suggesting that extracellular purines may be important in the pathologic processes within the damaged joint.

Identification of the genes that predispose to autoimmune diseases is a major issue that is relevant to both basic and clinical science. This study provides genetic and molecular evidence supporting the important role of complement C5 in the pathogenesis of collagen-induced arthritis in mice. These findings may promote further investigations to determine whether this complement component has the same important role in RA in humans.

This study provides evidence that CDMPs, members of the TGF,13 superfamily, enhance matrix replenishment in bovine articular cartilage explant cultures. Immunohistochemical staining and Western blotting analysis indicated their presence in adult bovine and human articular cartilage. The data from this study therefore suggest a possible role of CDMPs in the maintenance of the integrity of joint surfaces.

The studies described here examined the effects of 2 relevant cytokines, interferon-y and tumor necrosis factor a, on the expression of the genes encoding the core proteins of various proteoglycans (aggrecan, biglycan, and decorin) in human articular chondrocytes. The results demonstrate that these cytokines, known to be present in inflamed joints, can cause a synergistic and potent inhibition of the production of these critical cartilage components. The inhibition of the genes encoding these important proteoglycans may be one significant mechanism by which these cytokines affect the overall integrity of articular cartilage in arthritis.

The final phase of OA seems to reflect a failure of the reparative process, resulting in degradation of the matrix, cell death, and total loss of cartilage integrity. Whether apoptotic cell death of chondrocytes can explain the hypocellularity of cartilage from OA patients is unknown. The present report documents the characteristic features of apoptosis in chondrocytes and cartilage from OA patients. Understanding this mechanism could lead to new treatment options in OA.

Oral tolerization is currently under active investigation as a possible treatment approach for a variety of human autoimmune diseases. The present report describes the results of a multicenter trial of oral type II collagen in the treatment of rheumatoid arthritis. At the lowest dosage tested, this novel therapeutic agent appeared to be both safe and effective.

Gail E. Wright, Jerry C. Parker, Karen L. Smarr,Jane C. Johnson, John E. Hewett, and Sara E. Walker 298

In this study of 2 independent RA cohorts, depressive symptoms were found to be more common in middleaged or younger persons with RA than in elderly patients. Interestingly, younger persons with RA were also shown to exhibit more life stress and higher pain scores, which may contribute to the more frequent depressive symptoms. The results indicate that practitioners providing care for persons with RA should be vigilant for depressive symptoms, especially in middle-aged or younger cohorts, particularly given that depression is known to be a major contributor to disability. In most cases depression can be successfully treated with medications and/or supportive psychological care.

Recent evidence has suggested that interferony (IFNy)-producing Thl cells may be associated with the chronic inflammation of RA. This study demonstrates that low but significantly detectable levels of IL-12 are present in Synovial tissues obtained from patients with chronic RA, and that infiltrating T cells are capable of producing large amounts of IFNy in response to IL-12. These results indicate that Ikl2 is a contributory factor in maintaining the IFNy-dominant T cell cytokine response in RA joints.

This study is of interest because it identifies specific immunodominant Yersinia proteins against which the local T cell response is directed in Synovial fluid mononuclear cells from patients with Yersinia-induced reactive arthritis. These results have implications for distinguishing the diagnosis of reactive arthritis and understanding the pathogenesis of the disease.

This study shows that Vδ1+ T cells express both adhesion molecules and activation markers. The findings strongly support the notion of γ/δ T cell homing to sites of inflammation. The increase in the Vδ1 subset suggests a selective V gene subset expansion. Taken together, these data suggest a pathogenetic role of γ/δ T cells. Thus, monoclonal antibodies against this subset could be considered for future therapeutic strategies in early SSc.

Current therapies for the treatment of end-organ damage in systemic lupus erythematosus do not sepcifically target pathogenic mechanisms associated with autoantibody production and immune complex formation. Furthermore, most therapies are associated with significant toxicity, including sterility, avascular necrosis, hemorrhagic cystitis, and malignancy. The nucleoside analogs are promising agents for the treatment of autoimmune diseases because of their ability to specifically target memory and naive T cells, and low incidence of side effects. In this open-label study, 12 patients with lupus nephritis were treated with the nucleoside analog 2-CdA, with good clinical response including prolonged reductions in lymphocyte populations.

The present study reveals the presence of anti-Fast autoantibodies that inhibit Fas/FasL-mediated apoptosis in at least some patients with SLE. Although it remains controversial, soluble Fas has been reported to inhibit Fas/FasL-mediated apoptosis. Anti-FasL autoantibodies may perturb self tolerance by inhibiting Fas/ FasL-mediated elimination of autoreactive lymphocytes in the peripheral Iymphoid tissue of patients with SLE.