[Peloid therapy in various temperature modes in rehabilitation of patients with seronegative spondylarthritis].

Fifty patients with ankylosing spondylarthritis (AS) and 21 patients with reactive arthritis, Reiter's disease received peloid therapy. AS patients with a prevalent spinal lesion received mud applications (38-40 degrees), those with a prevalent joint lesion - applications of colder mud (22-24 degrees C), those free of inflammation in the joints and periarticular tissues - mud of 38-40 degrees C temperature. In reactive arthritis and Reiter's disease mud applications with temperature 22-24 degrees are indicated.

Correlation between Yersinia enterocolitica and type I collagen reactivity in patients with arthropathies.

We investigated the association with Yersinia infection in patients with arthropathies in our region. To assess the reactivity to articular antigens, the correlation of anti-Yersinia with anti-type I and type II collagen antibodies was studied. Sera from 124 patients with musculoskeletal symptoms, and 47 synovial fluids (SF) from patients with rheumatoid arthritis (RA), spondyloarthopathies (SpA) or osteoarthritis (OA) were examined. Immunoglobulins against Yersinia enterocolitica, type I and type II collagens were determined by enzyme-linked immunosorbent assay. Immunoglobulin (Ig) A to Yersinia lipopolysaccharide (LPS) was present in 13/124 sera (10%) and 3/47 SF (6%). By Western blot, IgA to Yersinia outer proteins (Yops) was found in 14/124 sera (11%) and 2/47 SF (4%). Yersinia DNA from SF was not amplified by polymerase chain reaction. We found a significant correlation with anti-collagen type I but not type II antibodies. These results suggest different reactivity to articular collagen in patients with Yersinia antibodies.

Association of citrullinated proteins with synovial exosomes.

OBJECTIVE: In addition to releasing proteins and mediators, cells also release membrane vesicles (exosomes and apoptotic blebs) into the extracellular environment. Apoptotic blebs contain multiple autoantigens, but few data are available concerning the protein content of exosomes. Exosomes are formed during an immune response and can directly stimulate T cells or bind to dendritic cells. The aim of this study was to identify the nature of synovial exosomes from patients with different rheumatic diseases and to examine their potential autoantigenic content, which may be involved in the induction of an autoimmune response. METHODS: Synovial exosomes from patients with rheumatoid arthritis (RA), patients with reactive arthritis, and patients with osteoarthritis were purified, analyzed by electron microscopy, and labeled with immunogold to detect IgG and IgM molecules. Autoantigen content was identified by 2-dimensional electrophoresis-immunoblotting and subsequent mass spectrometry. In order to investigate the presence of citrullinated proteins, immunoblotting with anticitrulline antibodies was performed. RESULTS: Citrullinated proteins were observed in all exosome preparations, in contrast to other autoantigenic proteins (e.g., BiP and heterogeneous nuclear RNP A2) that were previously observed in RA and other autoimmune diseases. These citrullinated proteins included the fibrin alpha-chain fragment, fibrin beta-chain, fibrinogen beta-chain precursor, fibrinogen D fragment, and the Sp alpha (CD5 antigen-like protein) receptor. Purification of synovial exosomes led to the detection of citrullinated fibrinogen and citrullinated Sp alpha associated with IgM and IgG. CONCLUSION: Synovial exosomes contain citrullinated proteins, which are known to be autoantigens in RA. Although immune mechanisms in which exosomes carry citrullinated peptides could play an important role in the induction and distribution of citrullinated proteins, there must be a specific recognition of these proteins that is unique to the RA immune system.

FOXP3 identifies regulatory CD25bright CD4+ T cells in rheumatic joints.

Regulatory T cells have recently been implicated in a number of human diseases, including rheumatoid arthritis. To investigate whether the presence of CD25+CD4+ regulatory T cells is a general finding in arthritic joints, synovial fluid of patients with different rheumatic diseases such as undifferentiated arthritides, systemic rheumatic diseases and reactive arthritis were investigated for the presence of such cells. In 95% of the patients, a higher frequency of CD25(bright)CD4+ T cells was found in synovial fluid as compared with peripheral blood. Both in vitro suppression experiments and FOXP3 mRNA analysis confirmed these cells to be natural regulatory T cells. Together with our previous data, we conclude that arthritic joints, irrespective of precise diagnosis and disease duration, are enriched with natural regulatory T cells. These results suggest that suppressor cells migrate to and/or multiply at the sites of inflammation as part of the immune responses' effort to combat injurious inflammation.

Blockade of parathyroid hormone-related protein prevents joint destruction and granuloma formation in streptococcal cell wall-induced arthritis.

OBJECTIVE: To determine whether parathyroid hormone-related protein (PTHrP), an interleukin-1beta-inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA. METHODS: PTHrP expression and the effect of PTHrP 1-34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW)-induced arthritis, an animal model of RA. RESULTS: As has been reported in RA, while serum levels of PTHrP did not change during SCW-induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW-treated animals. However, PTHrP antibody significantly inhibited SCW-induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor-positive neutrophils and in SCW-induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1-34. CONCLUSION: These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders.

Complement depletion aggravates Staphylococcus aureus septicaemia and septic arthritis.

The aim of the study was to assess the role of the complement system in Staphylococcus aureus arthritis and septicaemia. The murine model of haematogenously acquired septic arthritis was used, injecting intravenously toxic shock syndrome toxin-1 (TSST-1), producing S. aureus LS-1. Complement was depleted using cobra venom factor (CVF). Evaluation of arthritis was performed clinically and histopathologically. In addition, the effect of complement depletion on the phagocytic activity of leucocytes was assessed in vivo and in vitro. Six days after inoculation of S. aureus the prevalence of arthritis in decomplemented mice was three-fold higher than that in controls (91% versus 25%). The clinical severity of arthritis at the end of the experiment, expressed as arthritic index, was 7.3 and 1.9, respectively. These findings were confirmed by histological index of synovitis as well as of cartilage and/or bone destruction being significantly higher in decomplemented mice than in controls (9.8 +/- 1.7 versus 4.9 +/- 1.2, P < 0.05; and 7.9 +/- 1.7 versus 3.0 +/- 0.9, P < 0.05, respectively). Also, the septicaemia-induced mortality was clearly higher in decomplemented mice compared with the controls. CVF treatment significantly reduced in vivo polymorphonuclear cell-dependent inflammation induced by subcutaneous injection of olive oil and mirroring the capacity of polymorphonuclear cells (PMNC) to migrate and/or extravasate. Besides, the decomplementation procedure significantly impaired phagocytic activity of peripheral blood leucocytes in vitro, since the number of phagocytes being able to ingest bacteria decreased by 50% when the cells were maintained in decomplemented serum compared with those in intact serum. The conclusion is that complement depletion aggravates the clinical course of S. aureus arthritis and septicaemia, possibly by a combination of decreased migration/extravasation of PMNC and an impairment of phagocytosis.

Cellular immune mechanisms in rheumatoid arthritis and other inflammatory arthritides.

Advances in molecular genetics, cellular immunology and microbiology have offered promise in unravelling the aetiopathogenesis of inflammatory arthritides such as rheumatoid arthritis and reactive arthritis. Such insights are challenging the orthodox view that these diseases are primarily autoimmune in nature, and should lead to exciting and novel therapeutic approaches.

Pathogenetic role of Chlamydia, Yersinia and Borrelia in undifferentiated oligoarthritis.

We studied the cellular and humoral immune response to Chlamydia trachomatis, Yersinia enterocolitica and Borrelia burgdorferi in paired samples of peripheral blood and synovial fluid (SF) in undifferentiated oligoarthritis, reactive arthritis (ReA) and rheumatoid arthritis. Antigen specific lymphocyte proliferation was found in SF of 43% of patients with ReA and 34% of patients with undifferentiated oligoarthritis. C. trachomatis was the most frequent single agent. HLA-B27 was positive in 83% of patients with ReA and in 62% of patients with undifferentiated oligoarthritis with antigen specific lymphocyte proliferation. Antigen specific lymphocyte proliferation correlated poorly with the specific antibody response. Only chlamydial antigen was detected in SF cells using monoclonal antibodies. We conclude that some patients with undifferentiated oligoarthritis may have a forme fruste of ReA. This finding is important in view of recent evidence supporting the efficacy of antibiotic therapy in ReA.

Influence of antibiotics on IgA and IgG response and persistence of Yersinia enterocolitica in patients with Yersinia-associated spondylarthropathy.

The IgA and IgG antibody response to plasmid-encoded outer membrane proteins was studied in 59 patients with yersinia-associated spondylarthropathy during 15 months of follow-up. Initially, all patients had specific IgA and IgG antibodies to the 36 and 46 kDa and 30% also to the 26 and 58 kDa released proteins, which correlated with the finding of virulent Yersinia bacilli in intestinal biopsies. IgA disappeared in 69% of untreated patients after nine months and persisted in 31% after one year. IgA disappeared within three to six months in 81% of the patients treated with antibiotics for four to six weeks and persisted in 6% after one year (p less than 0.002). IgG antibodies to the 36 and 46 kDa outer membrane proteins persisted in 80% of all patients. Disappearance of IgA was coupled with disappearance of yersinia from intestinal biopsies.