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ID PMID Title PublicationDate abstract
17934735 Differential expression of toll-like receptor 6 on granulocytes and monocytes implicates t 2008 Mar The objective of this study was to investigate the expressions of toll-like receptors on neutrophils and monocytes in Behcet's disease (BD). Forty-two patients with BD were included in the study. Baseline and stimulated cells with heat shock protein-60 (HSP-60), lipopolysaccharide (LPS) and crude extract of Streptococcus sanguis (SS) were analyzed for toll-like receptor-1, -2, -4 and -6 expressions using flow cytometer. Results were confirmed using semi-quantitative PCR technique. The mean frequency of TLR-6 expressing granulocytes in BD patients was significantly lower than in controls (4.2 +/- 0.6 vs. 9.2 +/- 0.6 and 8.0 +/- 1.4, BD vs. rheumatoid arthritis (RA) and healthy control (HC); P < 0.05). TLR-6 expressing granulocyte population was enhanced after stimulation with HSP-60 and SS (20 +/- 0.5 and 12.8 +/- 0.6, respectively). Decreased TLR-2 expression was noted in monocytes of BD patients after stimulation with HSP-60 and LPS (71.0 +/- 0.5 and 73.0 +/- 0.5; P < 0.02, for both antigens). Functional abnormalities of these receptors or different activation cascades by different microorganisms are associated with disease pathogenesis in Behcet's disease.
17704067 The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible 2008 Apr OBJECTIVE: In countries where parasitic infections are endemic, autoimmune disease is relatively rare, leading to the hypothesis that parasite-derived immunomodulators may protect against its development. Consistent with this, we have previously demonstrated that ES-62, a 62 kDa phosphorylcholine (PC)-containing glycoprotein that is secreted by filarial nematodes, can exert anti-inflammatory action in the murine collagen-induced arthritis (CIA) model and human rheumatoid arthritis-derived synovial tissue cultures. As a first step to developing ES-62-based drugs, the aim of this study was to determine whether the PC-moiety of ES-62 was responsible for its anti-inflammatory actions. METHODS: We compared the anti-inflammatory activity of a PC-free form of recombinant ES-62 (rES-62) and a synthetic PC-ovalbumin conjugate (OVA-PC) with that of native ES-62 in the CIA model and synovial tissues from patients with rheumatoid arthritis. RESULTS: The anti-inflammatory actions of ES-62 in CIA appear to be dependent on the PC moiety as indicated by the reduction in severity of disease and also suppression of collagen-specific T helper 1 cytokine production observed when testing OVA-PC, but not rES-62. Interestingly, the anti-inflammatory activity of PC did not correlate with a reduction in anti-collagen IgG2a levels. Also, the ES-62-mediated suppression of interferon-gamma from human patient tissues could be mimicked by OVA-PC but not rES-62 or ovalbumin. CONCLUSIONS: In countries where filariasis is endemic the reduced detection of inflammatory diseases, such as rheumatoid arthritis may be because of the anti-inflammatory action of the PC moieties of ES-62. PC may thus provide the starting point for the development of novel, safe immunomodulatory therapies.
18635598 A role for the integrin alpha6beta1 in the differential distribution of CD4 and CD8 T-cell 2008 Sep OBJECTIVE: CD4 and CD8 T-cell subsets accumulate in distinct microdomains within the inflamed rheumatoid synovium. The molecular basis for their differential distribution remains unclear. Since chemokines and adhesion molecules play an important role in the positioning of leucocytes at sites of inflammation, we tested the hypothesis that the differential expression and function of chemokine and/or adhesion molecules explains why CD4(+) T cells accumulate within perivascular cuffs, whereas CD8(+) T cells distribute diffusely within the tissue. METHODS: Expression of an extensive panel of chemokine receptors and adhesion molecules on matched CD4(+) and CD8(+) T cells from peripheral blood (PB) and synovial fluid (SF) was analysed by multicolour flow cytometry. Migration assays and flow-based adhesion assays were used to assess the functional consequences of any differences in the expression of chemokine and adhesion receptors. RESULTS: CD4(+) and CD8(+) T cells from PB and SF expressed unique yet consistent patterns of chemokine and adhesion receptors. SF CD8(+) T cells were much less promiscuous in their expression of chemokine receptors than SF CD4(+) T cells. The alpha(6)beta(1) integrin was highly expressed on PB CD4(+) T cells, but not on PB CD8(+) T cells. Laminin, the ligand for alpha(6)beta(1), retained CD4(+) T cells, but less so CD8(+) T cells, within inflamed synovial tissue. CONCLUSION: Infiltrating PB CD4(+) T cells, but not CD8(+) T cells, express functional levels of the alpha(6)beta(1) integrin. We propose that this leads to their retention within the rheumatoid synovium in perivascular cuffs, which are defined and delineated by the expression of laminin.
18794178 Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine 2009 Jul OBJECTIVE: To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis (RA) despite sulfasalazine therapy. METHODS: Patients were randomly assigned to etanercept (25 mg twice weekly; sulfasalazine was discontinued at baseline), etanercept plus sulfasalazine (unchanged regimen of 2-3 g/day) or sulfasalazine in a double-blind, randomised, 2-year study in adult patients with active RA despite sulfasalazine therapy. Efficacy was assessed using the American College of Rheumatology criteria, disease activity scores (DAS) and patient-reported outcomes (PRO). RESULTS: Demographic variables and baseline disease characteristics were comparable among treatment groups; mean DAS 5.1, 5.2 and 5.1 for etanercept (n = 103), etanercept plus sulfasalazine (n = 101) and sulfasalazine (n = 50), respectively. Withdrawal due to lack of efficacy was highest with sulfasalazine (26 (52%) vs 6 (6%) for either etanercept group, p<0.001). Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response, which was sustained at 2 years, than those receiving sulfasalazine: mean DAS 2.8, 2.5 versus 4.5, respectively (p<0.05); ACR 20 response was achieved by 67%, 77% versus 34% of patients, respectively (p<0.01) Overall, PRO followed a similar pattern; a clinically significant improvement in health assessment questionnaire was achieved by 76%, 78% versus 40% of patients, respectively (p<0.01). Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis (p<0.01). CONCLUSION: Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA. The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine.
17953638 Recall injection-site reactions associated with etanercept therapy: report of two new case 2007 Nov Injection site reactions (ISRs) are the most common adverse effect reported with etanercept therapy. It has been observed that some patients treated with etanercept develop ''recall ISRs'', that are reactions at sites where etanercept was previously injected after the last injection. Etanercept-associated recall ISRs have been scarcely published. We report two patients with rheumatoid arthritis who developed recall ISRs during etanercept therapy. Biopsy specimens from ISRs demonstrated a superficial perivascular lymphocytic infiltrated with a few eosinophils. Immunohistochemical study in both cases revealed that T cells bearing a CD4+ phenotype mostly composed the inflammatory infiltrate. Our observations suggest that ISRs may be mediated by classic cellular-hypersensitivity reactions directed by CD4+ T lymphocytes.
17660934 A 57-year-old man who developed arthritis during R-CHOP chemotherapy for non-Hodgkin lymph 2008 Feb Rituximab is a chimeric human-mouse anti-CD20 monoclonal antibody, which is used in the treatment of both B-cell lymphomas and rheumatic diseases. We describe a case of a previously healthy 57-year-old man developing arthritis while being treated with rituximab-CHOP chemotherapy (R-CHOP) for a non-Hodgkin lymphoma. The remittant arthritis developed at successively shorter time-intervals after R-CHOP administration and only improved after rituximab was removed from the chemotherapy schedule, suggesting a rituximab-related phenomenon, as extensive diagnostic testing ruled out any other diagnosis.
18645332 Rituximab is useful in the treatment of Felty's syndrome. 2008 Jul Felty's syndrome is regarded as a severe variant of rheumatoid arthritis (RA) that develops in less than 1% of patients with RA. It consists of a triad of RA, splenomegaly, and leukopenia, which tends to develop after a long course of RA. Treatment of neutropenia is mainly comprised of disease-modifying antirheumatic drugs including methotrexate, hydroxychloroquine, auronofin, penicillamine, glucocorticoids, and granulocyte monocyte colony stimulating factor. Recently, there has been a growing interest in the biologic agent rituximab in the treatment of Felty's syndrome. To our knowledge, only one previous case of rituximab being beneficial in the treatment of Felty's syndrome has been reported. We report the case of a 60-year-old man with Felty's syndrome in whom treatment with rituximab led to a sustained neutrophil response and marked symptomatic improvement in the form of decrease in the size of rheumatoid nodules and better pain control.
16550302 Hemophagocytic syndrome in one patient with adult-onset Still's disease. Presentation with 2007 May Macrophage activation syndrome (MAS) is an important complication seen in systemic for juvenile rheumatoid arthritis; until now, it has been reported in only a few cases of adult-onset Still's disease (AOSD). Here, we shall present a 50-year-old female patient who was using steroids and antimalarial drugs for AOSD, and who developed MAS during follow-up. The patient presented with febrile neutropenia, and the neutropenic period lasted for 15 days. The examination of bone marrow aspiration smears demonstrated increased macrophages and findings of hemophagocytosis. Flow cytometric analysis of peripheral blood showed decreased natural killer cells. The patient developed neurologic findings during this period, and during the recovery of neutropenia, she had icterus and liver function test abnormalities. The patient was given granulocyte colony-stimulating factor during neutropenic period, and her neutropenia improved after the administration of high-dose steroids. Our patient was the first AOSD patient who presented with febrile neutropenia during the course of her disease and who was diagnosed to have MAS.
17500400 Vocal fold deposits in macrophagic myofasciitis. 2007 Apr Macrophagic myofasciitis was first reported in 1998. This disease manifests as diffuse myalgia and chronic fatigue. Its pathophysiology has been traced to the presence of an aluminum adjuvant used in vaccines against hepatitis A and B virus and tetanus toxoid; the adjuvant aggregates at the site of injection. One-third of patients with macrophagic myofasciitis develop autoimmune disease. Vocal fold deposits have been described in autoimmune diseases such as sarcoidosis, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, and Hashimoto's thyroiditis. We report what to the best of our knowledge is the first published case of vocal fold deposits in macrophagic myofasciitis.
17100759 Reduced expression of C1q-mRNA in monocytes from patients with systemic lupus erythematosu 2006 Dec Inherited C1q deficiency is associated strongly with the development of systemic lupus erythematosus (SLE). The aim of our study was to evaluate the ability of monocytes from SLE patients without inherited C1q deficiency to up-regulate C1q-mRNA upon stimulation. Furthermore, we wanted to elucidate the physiological stimulus for up-regulation of C1q-mRNA. Peripheral blood mononuclear cell (PBMC)-derived monocytes from 10 SLE patients, 10 patients with rheumatoid arthritis (RA) and 10 healthy controls (HC) were stimulated with dexamethasone (DXM), interferon-gamma or both. Additionally, purified monocytes from HC were stimulated with interleukin (IL)-10. C1q-mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). C1q protein was detected using the standard alkaline phosphatase/anti-alkaline phosphatase (APAAP) technique. SLE monocytes were significantly less able to up-regulate C1q-mRNA when compared to RA or HC. IL-10 was identified as an important stimulus for C1q synthesis. In SLE patients there is a significant functional impairment of monocytes to synthesize C1q upon stimulation. As C1q is linked to the process of recognition and removal of apoptotic cells, this relative C1q deficiency is likely to contribute to the reduced phagocytosis of apoptotic material observed in SLE and thereby might be a central pathogenetic factor.
19226096 Comparison of complications in transtrochanteric and anterolateral approaches in primary t 2008 Nov Three surgical approaches to primary total hip arthroplasty (THA) have been in use since Charnley popularized the transtrochanteric approach. This study was designed to examine the difference in morbidity between the transtrochanteric approach and the anterolateral approach in primary THA. Information on 891 patients who underwent primary THA performed by a single surgeon was collected prospectively between 1998 and 2003 using a modified SF-36 form, preoperatively, intraoperatively, and at 3 months postoperatively. The transtrochanteric group had higher morbidity and more patients who were dissatisfied with their THA. There was a greater range of motion in the anterolateral group.
16490850 Eosinophilic cellulitislike reaction to subcutaneous etanercept injection. 2006 Feb BACKGROUND: Injection site reactions are well recognized in patients treated with etanercept. Previous reports describe histologic findings of a cell-mediated T(H)1 reaction, with CD8+ T cells composing the majority of the dermal infiltrate. OBSERVATIONS: A pruritic, erythematous, edematous patch occurred on the right thigh of a 57-year-old white woman treated for rheumatoid arthritis within 12 to 24 hours after her second dose of subcutaneous etanercept. The patient had a similar reaction to adalimumab injection 2 weeks prior to presentation. While benzyl alcohol is present in the etanercept preparation, and mannitol in both drugs, dermal injection revealed no reaction to these additives. Biopsy specimens from the etanercept injection site demonstrated papillary dermal edema accompanied by a brisk polymorphous infiltrate with a predominance of eosinophils and scattered flame figures. CONCLUSIONS: Histologic features of eosinophilic cellulitis as a response to etanercept have not been reported to date. Although most injection site reactions contain T cells and represent a T(H)1 immune response, the findings we report suggest a T(H)2-mediated phenomenon.
18084696 Thymic stromal lymphopoietin secretion of synovial fibroblasts is positively and negativel 2007 Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine produced by epithelial cells and triggers dendritic cell-mediated Th2 type allergic inflammatory responses. This study investigated whether Toll-like receptor (TLR) ligands, lipopolysaccharide (LPS) and poly-IC affect TSLP production in synovial fibroblasts. Enzyme-linked immunosorbent assay showed that LPS and poly-IC upregulated TSLP production in synovial fibroblasts obtained from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). In addition, we found that nuclear factor (NF)-kappaB inhibitor IMD-0354, dexamethasone, and interferon (IFN)-gamma inhibited the LPS- and poly-IC-induced TSLP production in RA and OA synovial fibroblasts. Thus, LPS and poly-IC can upregulate TSLP via a NF-kappaB pathway in synovial fibroblasts, which is downregulated by dexamethasone and interferon (IFN)-gamma. The current findings suggest that TSLP may be involved in the pathophysiology of inflammatory arthritis as well as allergic disease.
18603660 Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or 2008 Sep OBJECTIVE: To assess the efficacy and safety of anakinra (ANK) as an add-on therapy in RA patients with inadequate response to monotherapy with non-biological DMARDs. METHODS: A 48-week comparative, prospective study of patients with active RA [mean 28-joint disease activity score (DAS28): 6.81], despite MTX (n = 48), or LEF (n = 42), or CSA (n = 38) treatment, in whom ANK (100 mg/daily SC) was given with corticosteroid cream topical application. RESULTS: At 24 and 48 weeks the patient percentages meeting the ACR20 response criteria were 57 and 73%, respectively, 33 and 41% met ACR50, while 15 and 23% met ACR70. Significant improvements in number of swollen and tender joints, HAQ, pain, global disease assessment, CRP and haemoglobin from baseline to 24 and 48 weeks were evident. DAS28 decreased at 24 weeks (- 1.68; 95% CI - 1.46, - 1.90; P < 0.0001), as well as at study end (- 2.24; 95% CI - 2.01, - 2.47; P < 0.0001). Subgroup analysis revealed a significantly weaker response in terms of pain and DAS28 in patients treated with concomitant CSA. The most common ANK-related adverse event was injection-site reaction (29%), being less frequent in male patients, as well as in patients treated with CSA. There were 17 withdrawals, 6 of them due to inefficacy. No opportunistic infections or new safety signals were observed. CONCLUSION: Considering the limitations of an open-label study, addition of ANK appears to be an effective and well-tolerated treatment option for many RA patients with inadequate responses to non-biologic DMARDs in clinical practice.
18495175 Guggulsterone blocks IL-1beta-mediated inflammatory responses by suppressing NF-kappaB act 2008 Jun 6 Guggulsterone is a plant sterol that is used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on fibroblast-like synoviocytes (FLS) has not yet been reported. Therefore, in this study, the effect of guggulsterone on interleukin (IL)-1beta-induced inflammatory responses in the FLS of rheumatic patients was investigated. Treatment of FLS with IL-1beta induced production of chemokines such as RANTES and ENA-78. In addition, Western blot analysis and gelatin zymography revealed that IL-1beta activated matrix metalloproteinase (MMP)-1 and -3 in FLS. However, pre-incubation with guggulsterone completely inhibited the ability of IL-1beta to induce the production of chemokines and to activate MMPs. Although the NF-kappaB binding activity and nuclear p50 and p65 subunit levels, as well as IkappaBalpha degradation in the cytoplasm was greater in cells stimulated with IL-1beta than in unstimulated cells, treatment with guggulsterone abolished all of these increases. Collectively, these results suggest that guggulsterone would be useful as an inhibitor of joint destruction in patients with rheumatoid arthritis.
18240226 AUF1, the regulator of tumor necrosis factor alpha messenger RNA decay, is targeted by aut 2008 Feb OBJECTIVE: To investigate which members of the heterogeneous nuclear RNP (hnRNP) family are targeted by autoantibodies from patients with systemic rheumatic diseases. METHODS: Using a semipurified preparation of natural hnRNP proteins, 365 sera from patients with rheumatic diseases and control subjects were screened by immunoblotting for the presence of autoantibodies. Bacterially expressed recombinant hnRNP D (AUF1) proteins were used for confirming the data obtained. Binding of RNA and autoantibody to AUF1 was investigated by gel retardation assays. Expression of AUF1 in cultivated cells and synovial tissue was analyzed by indirect immunofluorescence and immunohistochemistry. RESULTS: Autoantibodies to AUF1 proteins were detected in 33% of patients with systemic lupus erythematosus, 20% of patients with rheumatoid arthritis, 17% of patients with mixed connective tissue disease, and <10% of patients with other rheumatic disorders. Epitope mapping studies showed the autoantibodies to be directed to conformational epitopes in the N-terminal RNA-binding part of AUF1. However, autoantibody binding did not interfere with RNA binding as assessed by gel-shift assays. Immunohistochemical studies revealed AUF1 to be expressed in the cytoplasm of RA synovial tissue as compared with nuclear staining in osteoarthritis and normal synovium, particularly in macrophages of the lining layer and in fibroblasts of the sublining areas. CONCLUSION: These data identify AUF1 proteins as novel autoantigens in SLE and related autoimmune disorders. Because AUF1 proteins are major components of messenger RNA stability complexes, our findings suggest that these complexes form a novel macromolecular target structure for autoantibodies in rheumatic autoimmune diseases.
18821693 Interactions of T helper cells with fibroblast-like synoviocytes: up-regulation of matrix 2008 Oct OBJECTIVE: Interactions of immune cells, such as activated T helper cells, with fibroblast-like synoviocytes (FLS) play a crucial role in the joint destruction during human rheumatoid arthritis (RA). This study was undertaken to investigate the expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) by T helper cells, and to assess the role of MIF in overexpression of matrix metalloproteinases (MMPs) in cocultures of FLS from arthritic mice with either Th1 or Th2 cells. METHODS: MIF expression by in vitro-polarized murine Th1 and Th2 cells was determined using 2 different generation protocols. FLS were isolated from the inflamed joints of mice with antigen-induced arthritis. MMP expression was analyzed in cocultures of the FLS with T helper cell subsets. Effects of MIF were blocked by a neutralizing anti-MIF antibody. In addition, analyses were performed on cocultures of either Th1 or Th2 cells with FLS from MIF-deficient mice. RESULTS: Both Th1 and Th2 cells expressed high quantities of MIF. MMPs were overexpressed by FLS after coculture with both Th1 and Th2 cells. Activated T helper cells were more effective than resting cells. Neutralization of MIF by an anti-MIF antibody led to a marked reduction in MMP expression in Th1- and Th2-stimulated FLS. T helper cells generated from MIF-deficient mice exhibited a T helper cell-specific cytokine profile comparable with that in wild-type cells, except in the expression of MIF, but showed an impaired ability to stimulate MMP expression in FLS. CONCLUSION: MIF is an important Th1 and Th2 cell-derived proinflammatory cytokine that stimulates MMP expression in FLS from arthritic mice, and therefore inhibition of MIF might be a promising target for novel therapeutic strategies in human RA.
17558834 Systemic immunomodulatory therapy in severe dry eye secondary to inflammation. 2007 Mar PURPOSE: To report four patients with unusually severe acute keratitis sicca secondary to lacrimal tissue and ocular surface inflammation who eventually required systemic immunosuppressive therapy. METHODS: Observational case series of four patients with extremely severe acute dry eye syndrome who were profoundly disabled by pain and photophobia (to the extent of staying in dark rooms) despite aggressive conventional therapy. Clinical data including visual acuities, other treatments administered for dry eye, systemic medical conditions, Schirmer and rose bengal staining results, degree of conjunctival injection, and medications were recorded. All four patients were treated with systemic immunomodulatory therapy. RESULTS: All four patients were female with a mean age at presentation of 40 years (range 22-58 years), and all had systemic autoimmune diseases: systemic lupus erythematosus (SLE) and Sjogren's syndrome (n = 2), Sjogren's syndrome (n = 1), rheumatoid arthritis (RA) and psoriasis (n = 1). Schirmer test values at onset ranged from 0 to 2 mm. All patients had failed aggressive lubrication, topical cyclosporine, lid care, and punctual plugs. In two patients, serum tears and hyphrecation punctal occlusion were tried without success. Various systemic immunosuppressive agents were used to control inflammation of the lacrimal glands: methotrexate and cyclosporine A (patient 1), cyclosporine A (patient 2), prednisone (patient 3), and methotrexate and infliximab (patient 4). Treatment with systemic immunomodulatory agents resulted in resolution of the acute inflammatory assault on the lacrimal glands and control of signs and symptoms of keratoconjunctivitis sicca in all four patients, and visual acuities improved in all of them. Post-treatment Schirmer values ranged from 7 to 10 mm. CONCLUSION: Systemic immunosuppressive agents may be required in the treatment of recalcitrant primary and secondary Sjogren's syndrome caused by systemic autoimmune conditions. We show that systemic immunomodulatory therapy leads to significantly improved tear production and resolution of the keratoconjunctivitis in these rare but severe cases.
17599744 Endogenous HLA-DR-restricted presentation of the cartilage antigens human cartilage gp-39 2007 Jul OBJECTIVE: The cartilage proteins melanoma inhibitory activity (MIA) and human cartilage gp-39 (HC gp-39) are candidate autoantigens in rheumatoid arthritis (RA). The present study was undertaken to investigate the endogenous HLA-DR4-restricted presentation of these self proteins, in order to seek in vivo evidence in support of their potential immunologic role. METHODS: MIA and HC gp-39 were assessed in synovial fluid (SF) by enzyme-linked immunosorbent assay and in synovial tissue (ST) by immunohistochemistry. Presentation by SF cells was investigated using specific, HLA-DR-restricted T cell hybridomas. RESULTS: MIA and HC gp-39 were detected in RA SF and ST, as well as in specimens from patients with other forms of arthritis. When HC gp-39-specific and MIA-specific HLA-DR4-restricted T cell hybridomas raised in HLA-DR4-transgenic mice were incubated with RA SF cells as antigen-presenting cells in the presence of HC gp-39 or MIA peptides, the corresponding T cell hybridomas showed strong responses, which were blocked by anti-HLA-DR antibodies. Weaker but qualitatively similar responses were observed with exogenous protein, indicating uptake and processing of these antigens by SF cells. More importantly, without addition of peptide or protein, endogenous presentation of MIA and HC gp-39 was detected in SF cells from 53% and 80% of HLA-DRB1*0401-positive RA patients, respectively. In addition, SF cells from 3 of 10 patients with spondylarthritis exhibited endogenous HC gp-39 presentation. CONCLUSION: These data indicate that immunodominant epitopes of MIA and HC gp-39 are actively presented in an HLA-DR-restricted manner in the inflamed RA joint. The question remains as to whether this leads to activation of autoreactive T cells, which could play a role in either the immunopathology or the immunomodulation of arthritis.
17907168 BAFF synthesis by rheumatoid synoviocytes is positively controlled by alpha5beta1 integrin 2007 Oct OBJECTIVE: It was recently demonstrated that synoviocytes (FLS) from rheumatoid arthritis (RA) patients express BAFF transcripts that are up-regulated by tumor necrosis factor alpha (TNFalpha) and interferon-gamma (IFNgamma). Thus, BAFF increases in RA target cells might be related to activation of the receptors of innate immunity. The purpose of this study was to determine whether ligands of Toll-like receptor 2 (TLR-2), TLR-4, TLR-9, and alpha5beta1 integrin are able to induce BAFF synthesis by RA FLS. METHODS: Quantitative reverse transcription-polymerase chain reaction analyses and enzyme-linked immunosorbent assays were performed to evaluate BAFF messenger RNA induction and BAFF release from FLS after stimulation by ligands for TLR-2, TLR-4, TLR-9, alpha5beta1 integrin (bacterial lipopeptide [BLP] palmitoyl-3-cysteine-serine-lysine-4, lipopolysaccharide [LPS], CpG, and protein I/II, respectively), TNFalpha, and IFNgamma. RESULTS: In contrast to IFNgamma, neither TNFalpha, LPS, BLP, nor CpG induced the de novo synthesis and release of BAFF by FLS. Priming of cells with IFNgamma did not have a synergistic effect on BAFF synthesis by FLS stimulated with bacterial products known as pathogen-associated molecular patterns. Moreover, we found that IFNgamma-induced BAFF synthesis is inhibited by simultaneous stimulation with either TLR ligands or TNFalpha. We also showed that interplay between TLRs, TNF receptors, and IFNgamma signaling induces the expression of suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 and reduces IFNgamma-dependent STAT-1 phosphorylation, which might explain this inhibition. In contrast, we demonstrated that stimulation of alpha5beta1 integrin can induce BAFF synthesis and release per se and that stimulation of this pathway has no inhibitory effect on IFNgamma-induced BAFF synthesis. CONCLUSION: Our findings indicate that BAFF secretion by resident cells in target organs of autoimmunity is tightly regulated by innate immunity, with positive and negative controls, depending on the receptors and the pathways triggered.