Arthritis Research & Therapy

Crow, Mary K;Wohlgemuth, Jay

doi: 10.1186/ar1015pmid: 14680503

Abstract Recent advances in the study of global patterns of gene expression with the use of microarray technology, coupled with data analysis using sophisticated statistical algorithms, have provided new insights into pathogenic mechanisms of disease. Complementary and reproducible data from multiple laboratories have documented the feasibility of analysis of heterogeneous populations of peripheral blood mononuclear cells from patients with rheumatic diseases through use of this powerful technology. Although some patterns of gene expression, including increased expression of immune system cell surface activation molecules, confirm previous data obtained with other techniques, some novel genes that are differentially expressed have been identified. Most interesting is the dominant pattern of interferon-induced gene expression detected among blood mononuclear cells from patients with systemic lupus erythematosus and juvenile dermatomyositis. These data are consistent with longstanding observations indicating increased circulating interferon-α in the blood of patients with active lupus, but draw attention to the dominance of the interferon pathway in the hierarchy of gene expression pathways implicated in systemic autoimmunity.

Wester, Lena; Koczan, Dirk; Holmberg, Jens; Olofsson, Peter; Thiesen, Hans-Jürgen; Holmdahl, Rikard; Ibrahim, Saleh

doi: 10.1186/ar993pmid: 14680511

Arthritis susceptibility genes were sought by analysis of differential gene expression between pristane-induced arthritis (PIA)-susceptible DA rats and PIA-resistant E3 rats. Inguinal lymph nodes of naïve animals and animals 8 days after pristane injection were analyzed for differential gene expression. mRNA expression was investigated by microarray and real-time PCR, and protein expression was analyzed by flow cytometry or ELISA. Twelve genes were significantly differentially expressed when analyzed by at least two independent methods, and an additional five genes showed a strong a tendency toward differential expression. In naïve DA rats IgE, the bone marrow stromal cell antigen 1 (Bst1) and the MHC class II β-chain (MhcII) were expressed at a higher level, and the immunoglobulin kappa chain (Igκ) was expressed at a lower level. In pristane-treated DA rats the MHC class II β-chain, gelatinase B (Mmp9) and the protein tyrosine phosphatase CL100 (Ptpn16) were expressed at a higher level, whereas immunoglobulins, the CD28 molecule (Cd28), the mast cell specific protease 1 (Mcpt1), the carboxylesterase precursor (Ces2), K-cadherin (Cdh6), cyclin G1 (Ccng1), DNA polymerase IV (Primase) and the tumour associated glycoprotein E4 (Tage) were expressed at a lower level. Finally, the differentially expressed mRNA was confirmed with protein expression for some of the genes. In conclusion, the results show that animal models are well suited for reproducible microarray analysis of candidate genes for arthritis. All genes have functions that are potentially important for arthritis, and nine of the genes are located within genomic regions previously associated with autoimmune disease.

Buyon, Jill P;Clancy, Robert M

doi: 10.1186/ar763pmid: 14680501

Abstract Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often referred to as a model of passively acquired autoimmunity. In essence, this disease encompasses two patients, both the mother and her child. The signature histologic lesion of autoimmune-associated congenital heart block is fibrosis of the conducting tissue, and in some cases the surrounding myocardium. It is astounding how rapid and, in most cases, irreversible is the fibrotic response to injury. The mechanism by which maternal anti-SSA/Ro–SSB/La antibodies initiate and perpetuate inflammation, and eventuate in scarring of the atrioventricular node, is not yet defined. In vitro and in vivo studies suggest that one pathologic cascade leading to scarring may be initiated via apoptosis, resulting in translocation of SSA/Ro–SSB/La antigens and subsequent surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors that transdifferentiate fibroblasts into myofibroblasts, a scarring phenotype. Dissecting the individual components in this fibrotic pathway should provide insights into the rarity of irreversible injury and should form the basis of rational approaches to prevention and treatment.

van Vollenhoven, Ronald F; Ernestam, Sofia; Harju, Anders; Bratt, Johan; Klareskog, Lars

doi: 10.1186/ar1005pmid: 14680509

Etanercept can be used both as monotherapy and in combination with methotrexate (MTX), but direct comparisons of these two options have not yet been reported. In order to compare the results seen in actual practice between these two options, clinical data on 97 patients followed in the Stockholm TNFα Follow-Up Registry were analysed. In 57 of these patients etanercept was added to previously started MTX while the others were treated with etanercept alone. The two groups had similar levels of disease activity at baseline. After 3 months, a significantly lower mean disease activity score (28-joint count-based disease activity score) was attained by the patients on etanercept plus MTX. In this group, the number of patients achieving European League Against Rheumatism-defined remission was also significantly greater. Other disease outcomes showed non-significant trends in the same direction. These data suggest that the combination of etanercept plus MTX is clinically more efficacious than etanercept alone.

McInnes, Iain B

doi: 10.1186/ar1017pmid: 14680504

Bresnihan, Barry

doi: 10.1186/ar1003pmid: 14680502

Abstract Synovial tissue is readily accessible by closed needle or arthroscopic biopsy. These techniques provide adequate tissue for most diagnostic requirements. Examination of synovial tissue can assist in the diagnosis of some joint infections, and in several atypical or rare synovial disorders. Histological confirmation is not normally required for diagnosis of the common forms of inflammatory arthritis, including rheumatoid arthritis (RA). In patients with either established or early RA, immunohistological measures of inflammation in synovial tissue are associated with clinical measures of disease activity, may predict the clinical outcome, and change in response to treatment. Surrogate markers of disease activity and outcome that have been identified in synovial tissue include components of the cellular infiltrate, and several mediators of inflammation and matrix degradation. There is evidence that the very early introduction of disease-modifying therapy inhibits progressive structural damage maximally. Clinicians exploiting this 'window of opportunity' therefore require very early indicators of the diagnosis and outcome in patients who present with an undifferentiated inflammatory arthritis. Some immunohistological features have been described that distinguish patients who are likely to develop progressive RA and who might benefit most from early aggressive therapeutic intervention. In this regard, the inclusion of pharmacogenomic and proteomic techniques in the analysis of synovial tissue presents some exciting possibilities for future research.

Peters, John H; Carsons, Steven; Yoshida, Mika; Ko, Fred; McDougall, Skye; Loredo, Grace A; Hahn, Theodore J

doi: 10.1186/ar1001pmid: 14680507

Fragments of fibronectin (FN) corresponding to the N-terminal heparin-binding domain have been observed to promote catabolic chondrocytic gene expression and chondrolysis. We therefore characterized FN species that include sequences from this domain in samples of arthritic synovial fluid using one-and two-dimensional (1D and 2D) Western blot analysis. We detected similar assortments of species, ranging from ~47 to greater than 200 kDa, in samples obtained from patients with osteoarthritis (n = 9) versus rheumatoid arthritis (n = 10). One of the predominant forms, with an apparent molecular weight of ~170 kDa, typically resolved in 2D electrophoresis into a cluster of subspecies. These exhibited reduced binding to gelatin in comparison with a more prevalent species of ~200+ kDa and were also recognized by a monoclonal antibody to the central cell-binding domain (CBD). When considered together with our previous analyses of synovial fluid FN species containing the alternatively spliced EIIIA segment, these observations indicate that the ~170-kDa species includes sequences from four FN domains that have previously, in isolation, been observed to promote catabolic responses by chondrocytes in vitro: the N-terminal heparin-binding domain, the gelatin-binding domain, the central CBD, and the EIIIA segment. The ~170-kDa N-terminal species of FN may therefore be both a participant in joint destructive processes and a biomarker with which to gauge activity of the arthritic process.

Stanevicha, Valda; Eglite, Jelena; Sochnevs, Arturs; Gardovska, Dace; Zavadska, Dace; Shantere, Ruta

doi: 10.1186/ar1000pmid: 14680508

Genetic control of immune reactions has a major role in the development of rheumatic heart disease (RHD) and differs between patients with rheumatic fever (RF). Some authors think the risk of acquiring RHD is associated with the HLA class II DR and DQ loci, but other views exist, due to the various HLA-typing methods and ways of grouping cases. Our goal was to determine the relations between HLA class II alleles and risk of or protection from RF in patients with relatively homogeneous clinical manifestations. A total of 70 RF patients under the age of 18 years were surveyed in Latvia. HLA genotyping of DRB1*01 to DRB1*18 and DQB1*0201-202, *0301-305, *0401-402, *0501-504, and *0601-608 was performed using polymerase chain reaction sequence-specific primers. Data for a control group of 100 healthy individuals typed for HLA by the same method were available from the databank of the Immunology Institute of Latvia. Of the RF patients, 47 had RHD and 8 had Sydenham's chorea. We concluded that HLA class II DRB1*07-DQB1*0401-2 and DRB1*07-DQB1*0302 could be the risk alleles and HLA class II DRB1*06 and DQB1*0602-8, the protective ones. Patients with mitral valve regurgitation more often had DRB1*07 and DQB1*0401-2, and patients with multivalvular lesions more often had DRB1*07 and DQB1*0302. In Sydenham's chorea patients, the DQB1*0401-2 allele was more frequent. Genotyping control showed a high risk of RF and RHD in patients with DRB1*01-DQB1*0301-DRB1*07-DQB1*0302 and DRB1*15-DQB1*0302-DRB1*07-DQB1*0303.

Eskandari, Farideh;Webster, Jeanette I;Sternberg, Esther M

doi: 10.1186/ar1002pmid: 14680500

Abstract Inflammation and inflammatory responses are modulated by a bidirectional communication between the neuroendocrine and immune system. Many lines of research have established the numerous routes by which the immune system and the central nervous system (CNS) communicate. The CNS signals the immune system through hormonal pathways, including the hypothalamic–pituitary–adrenal axis and the hormones of the neuroendocrine stress response, and through neuronal pathways, including the autonomic nervous system. The hypothalamic–pituitary–gonadal axis and sex hormones also have an important immunoregulatory role. The immune system signals the CNS through immune mediators and cytokines that can cross the blood–brain barrier, or signal indirectly through the vagus nerve or second messengers. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. This review discusses neuroimmune interactions and evidence for the role of such neural immune regulation of inflammation, rather than a discussion of the individual inflammatory mediators, in rheumatoid arthritis.

Foey, Andrew D; Field, Sarah; Ahmed, Salman; Jain, Abhilash; Feldmann, Marc; Brennan, Fionula M; Williams, Richard

doi: 10.1186/ar999pmid: 14680506

Vasoactive intestinal peptide (VIP) is an anti-inflammatory immunomodulatory neuropeptide with therapeutic potential demonstrated for collagen-induced arthritis. The aim of this study was to characterise its potential anti-arthritic effect on human monocytes, macrophages, T cells, and rheumatoid arthritis synovial membrane cells. Monocytes, macrophages, and T cells derived from human peripheral blood were treated with VIP and compared with other cAMP-elevating drugs for a range of activating stimuli. Cytokine production was assessed for cell cultures and, in addition, the ability of VIPs to activate cAMP response element binding protein. VIP partially suppressed monocyte- and macrophage-derived tumour necrosis factor α (TNF-α) with no effect on IL-10, whereas VIP fails to regulate IL-10 and TNF-α production by T lymphocytes. No such modulation of cytokine profile was observed for rheumatoid arthritis synovial membrane cells. Elevation of intracellular cAMP, on the other hand, potently suppressed macrophage TNF-α production and modulated T-cell response by inhibiting TNF-α and IFN-γ. VIP's lack of effect on IL-10 and its slight effect on TNF-α results from cAMP being rapidly degraded as the phosphodiesterase IV inhibitor, rolipram, rescues cAMP-dependent activation of cAMP response element binding protein. Interestingly, macrophages stimulated with phorbol 12-myristate 13-acetate/ionomycin displayed an augmented IL-10 response upon addition of dibutyryl cAMP, with corresponding downregulation in TNF-α, suggesting a complex interaction between protein kinase C and protein kinase A in cytokine regulation. In conclusion, VIP may represent an efficaceous anti-arthritic treatment modulating macrophage and T-cell cytokine profiles when used alongside a phosphodiesterase inhibitor.