Depletion of B cells in rheumatoid arthritis is therapeutically efficacious. Yet, the mechanism by which B cells participate in the inflammatory process is unclear. We previously demonstrated that Ag-specific B cells have two important functions in the development of arthritis in a murine model of rheumatoid arthritis, proteoglycan (PG)-induced arthritis (PGIA). PG-specific B cells function as autoantibody-producing cells and as APCs that activate PG-specific T cells. Moreover, the costimulatory molecule CD86 is up-regulated on PG-specific B cells in response to stimulation with PG. To address the requirement for CD80/CD86 expression on B cells in the development of PGIA, we generated mixed bone marrow chimeras in which CD80/CD86 is specifically deleted on B cells and not on other APC populations. Chimeras with a specific deficiency in CD80/CD86 expression on B cells are resistant to the induction of PGIA. The concentration of PG-specific autoantibody is similar in mice sufficient or deficient for CD80/86-expressing B cells, which indicates that resistance to PGIA is not due to the suppression of PG-specific autoantibody production. CD80/86-deficient B cells failed to effectively activate PG-specific autoreactive T cells as indicated by the failure of T cells from PG-immunized CD80/86-deficient B cell chimeras to transfer arthritis into SCID mice. In vitro secondary recall responses to PG are also dependent on CD80/86-expressing B cells. These results demonstrate that a CD80/86:CD28 costimulatory interaction between B cells and T cells is required for autoreactive T cell activation and the induction of arthritis but not for B cell autoantibody production.
CD44, the leukocyte adhesion receptor for hyaluronan, has been considered a therapeutic target on the basis of the robust anti-inflammatory effect of CD44-specific antibodies in animal models of immune-mediated diseases. However, CD44 deficiency does not provide substantial protection against inflammation. Using intravital video microscopy in a murine model of rheumatoid arthritis, we show that CD44 deficiency and anti-CD44 antibody treatment exert disparate effects on leukocyte recruitment in inflamed joints. Leukocyte rolling, which is increased in CD44-deficient mice, is promptly abrogated in anti-CD44-treated wild-type mice. CD44-specific antibodies also trigger platelet deposition on granulocytes and subsequent depletion of this leukocyte subset in the circulation. These in vivo effects require CD44 cross-linking and are reproducible with an antibody against Gr-1, a molecule that, like CD44, is highly expressed on granulocytes. Anticoagulant pretreatment, which prevents platelet deposition, mitigates both granulocyte depletion and the suppressive effect of CD44-specific antibody on joint swelling. Our observations suggest that cross-linking of prominent cell surface molecules, such as CD44 or Gr-1, can initiate a rapid self-elimination program in granulocytes through engagement of the coagulation system. We conclude that the robust anti-inflammatory effect of CD44-specific antibodies in arthritis is primarily the result of their ability to trigger granulocyte depletion. (Blood. 2008; 112:4999-5006)
TSG-6 (TNF-α-stimulated gene/protein 6), a hyaluronan (HA)-binding protein, has been implicated in the negative regulation of inflammatory tissue destruction. However, little is known about the tissue/cell-specific expression of TSG-6 in inflammatory processes, due to the lack of appropriate reagents for the detection of this protein in vivo. Here, we report on the development of a highly sensitive detection system and its use in cartilage proteoglycan (aggrecan)-induced arthritis, an autoimmune murine model of rheumatoid arthritis. We found significant correlation between serum concentrations of TSG-6 and arthritis severity throughout the disease process, making TSG-6 a better biomarker of inflammation than any of the other arthritis-related cytokines measured in this study. TSG-6 was present in arthritic joint tissue extracts together with the heavy chains of inter-α-inhibitor (IαI). Whereas TSG-6 was broadly detectable in arthritic synovial tissue, the highest level of TSG-6 was co-localized with tryptases in the heparin-containing secretory granules of mast cells. In vitro, TSG-6 formed complexes with the tryptases murine mast cell protease-6 and -7 via either heparin or HA. In vivo TSG-6-tryptase association could also be detected in arthritic joint extracts by co-immunoprecipitation. TSG-6 has been reported to suppress inflammatory tissue destruction by enhancing the serine protease-inhibitory activity of IαI against plasmin. TSG-6 achieves this by transferring heavy chains from IαI to HA, thus liberating the active bikunin subunit of IαI. Because bikunin is also present in mast cell granules, we propose that TSG-6 can promote inhibition of tryptase activity via a mechanism similar to inhibition of plasmin.
Age is the greatest risk factor for cardiovascular disease. In addition, inflammation and age (senescence) have been linked at both the clinical and molecular levels. In general, senescent cells have been described as pro-inflammatory based on their senescence associated secretory phenotype (SASP). However, we have previously shown that senescence induced by overexpression of SENEX (or ARHGAP18), in endothelial cells results in an anti-inflammatory phenotype. We have investigated, at the individual cellular level, the senescent phenotype of endothelial cells following three of the chief signals associated with ageing; oxidative stress, disturbed flow and hypoxia. All three stimuli induce senescence and, based on neutrophil adhesion and expression of the adhesion molecules E-selectin and VCAM-1, a population of senescent cells is seen that is resistant to inflammatory stimuli and thus we define as anti-inflammatory. The proportion of anti-inflammatory cells increases with time but remains stable at approximately 50% by eight days after induction of senescence, suggesting that these are stable phenotypes of endothelial cell senescence. Similar to other senescent cell types, p38MAPK blockade inhibits the development of the pro-inflammatory phenotype but unique to EC, there is a corresponding increase in the number of anti-inflammatory senescent cells. Thus stress-induced senescent endothelial cells display a mosaic of inflammatory phenotypes. The anti-inflammatory population suggests that senescent endothelial cells may have an unique protective role, to inhibit uncontrolled proliferation and to limit the local inflammatory response.
IntroductionThe major histocompatibility complex (H-2d) and non-major histocompatibility complex genetic backgrounds make the BALB/c strain highly susceptible to inflammatory arthritis and spondylitis. Although different BALB/c colonies develop proteoglycan-induced arthritis and proteoglycan-induced spondylitis in response to immunization with human cartilage proteoglycan, they show significant differences in disease penetrance despite being maintained by the same vendor at either the same or a different location.MethodsBALB/c female mice (24 to 26 weeks old after 4 weeks of acclimatization) were immunized with a suboptimal dose of cartilage proteoglycan to explore even minute differences among 11 subcolonies purchased from five different vendors. In vitro-measured T-cell responses, and serum cytokines and (auto)antibodies were correlated with arthritis (and spondylitis) phenotypic scores. cDNA microarrays were also performed using spleen cells of naïve and immunized BALB/cJ and BALB/cByJ mice (both colonies from The Jackson Laboratory, Bar Harbor, ME, USA), which represent the two major BALB/c sublines.ResultsThe 11 BALB/c colonies could be separated into high (n = 3), average (n = 6), and low (n = 2) responder groups based upon their arthritis scores. While the clinical phenotypes showed significant differences, only a few immune parameters correlated with clinical or histopathological abnormalities, and seemingly none of them affected differences found in altered clinical phenotypes (onset time, severity or incidence of arthritis, or severity and progression of spondylitis). Affymetrix assay (Affymetrix, Santa Clara, CA, USA) explored 77 differentially expressed genes (at a significant level, P < 0.05) between The Jackson Laboratory's BALB/cJ (original) and BALB/cByJ (transferred from the National Institutes of Health, Bethesda, MD, USA). Fourteen of the 77 differentially expressed genes had unknown function; 24 of 77 genes showed over twofold differences, and only 8 genes were induced by immunization, some in both colonies.ConclusionsUsing different subcolonies of the BALB/c strain, we can detect significant differences in arthritis phenotypes, single-nucleotide polymorphisms (SNPs), and a large number of differentially expressed genes, even in non-immunized animals. A number of the known genes (and SNPs) are associated with immune responses and/or arthritis in this genetically arthritis-prone murine strain, and a number of genes of as-yet-unknown function may affect or modify clinical phenotypes of arthritis and/or spondylitis.
Background and objectives The purpose of this study was to develop an understanding of treatment preferences in patients with inflammatory arthritis (IA) [rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA)] focussing on treatment attributes that patients' value, their relative importance, and the risk-benefit trade-offs that characterise patients' choices around treatment. Methods A discrete choice experiment (DCE) approach was used. Attributes of interest were clinical efficacy; slowing of disease progression; risk of mild-moderate side effects; risk of severe side effects; frequency of administration; real-world product evidence; management of related conditions; and availability of a patient support programme. Using data from the DCE component, a restricted latent class model (LCM) was estimated to determine discrete 'classes' of treatment preferences. Results In this analysis, 206 participants were included (AS n = 59; PsA n = 62; RA n = 85). Two classes were identified. For 'class 1' (59.9%), the most important attributes (across all treatment modalities) were preventing disease progression, clinical efficacy and risk of mild-to-moderate side effects. For 'class 2' (40.1%), clinical and non-clinical attributes were important, and attribute importance depended on treatment modality. Patient demographic and treatment characteristics did not predict class membership. Conclusion For most patients with IA, clinical efficacy, stopping disease progression and risks of mild-to-moderate side effects are important treatment attributes. Patients with prior biologic DMARD experience had greater preference for injection treatments. For a subset of patients, patient support programmes and the frequency of administration were important. Clinicians should be mindful of preferences when prescribing treatment to patients with IA. Key Points • Most patients consider clinical efficacy, stopping disease progression and the risk of mild-to-moderate side effects as important treatment attributes • Patients with prior biologic DMARD experience have greater preference for injection treatments. • For a subset of patients, patient support programmes, and the frequency of administration were important. • Clinicians should be mindful of preferences when prescribing treatment to patients with IA.
Golimumab (Simponi, Centocor Ortho Biotech Inc., PA, USA) is the first transgenic human monoclonal antibody against TNF-alpha that has been approved in the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Golimumab is synthesized using conventional hybridoma technique after immunizing transgenic mice containing human immunoglobulin genes. The constant region of golimumab is identical to that of infliximab, but the variable regions of golimumab have fully human sequences. In this article, we present the pharmacodynamic and pharmacokinetic properties as well as the clinical efficacy and tolerability of golimumab.
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