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ID PMID Title PublicationDate abstract
23146570 Rare diagnosis of IgG4-related systemic disease by lip biopsy in an international Sjögren 2013 Mar IgG4-related disease has been recently defined as a distinct clinic-pathologic entity, characterized by dense IgG-4 plasmacytic infiltration of diverse organs, fibrosis, and tumefactive lesions. Salivary and lacrimal glands are a target of this disease and, when affected, may clinically resemble Küttner tumor, Mikulicz disease, or orbital inflammatory pseudotumor. In some patients, the disease is systemic, with metachronous involvement of multiple organs, including the pancreas, aorta, kidneys, and biliary tract. We report a 66-year-old man who presented with salivary gland enlargement and severe salivary hypofunction and was diagnosed with IgG4-related disease on the basis of a labial salivary gland biopsy. Additional features of his illness included a marked peripheral eosinophilia, obstructive pulmonary disease, and lymphoplasmacytic aortitis. He was evaluated in the context of a research registry for Sjögren syndrome and was the only 1 of 2594 registrants with minor salivary gland histopathologic findings supportive of this diagnosis.
22718459 [Hypocomplementemic tubulointerstitial nephritis in IgG4-related disease]. 2012 May A novel lymphoproliferative disorder producing plasma cell expansion in the affected organ with fibrotic or sclerosing changes, known as ''IgG4-related disease'', was defined in Japan by Umehara's group in 2010. We present the first case reported in Italy. In 2007, a 63-year-old man presented with epigastric pain and elevated serum lipase levels. Computed tomography of the abdomen revealed a Kuttner's tumor of the pancreas. The patient underwent a biliary-enteric anastomosis, and biopsy of the pancreas revealed massive infiltration of lymphocytes and plasma cells. The patient was diagnosed with chronic sclerosing pancreatitis. After one year, he began to show signs of sicca syndrome and at the same time developed progressive renal failure. Immunological tests revealed hypocomplementemia, and the renal biopsy specimen showed diffuse interstitial inflammation. The infiltrate was composed of lymphocytes, while infiltrating plasma cells showed immunoreactivity to IgG-4. Sialography using a radioisotope revealed severe involvement of the salivary glands, and Schirmer's test gave a positive result. This led us to diagnose hypocomplementemic tubulointerstitial nephritis in IgG4-related disease. Corticosteroid treatment resulted in rapid improvement including disappearance of the sicca syndrome and progressive amelioration of renal function. After six months, we discontinued steroid administration and started mycophenolate mofetil to maintain a low degree of immunosuppression. Follow-up after two years showed that this therapy continued to be quite effective in our patient.
22488408 Brief report: first identification of H₄ histamine receptor in healthy salivary glands a 2012 Aug OBJECTIVE: The conventional H(1) and H(2) histamine receptors have >10,000-fold lower avidity for histamine than H(4) histamine receptor, which has been implicated in autoimmune diseases. This study was undertaken to compare H(4) histamine receptor levels in the salivary glands (SGs) of healthy controls with those in the SGs of patients with primary Sjögren's syndrome (SS). METHODS: H(4) histamine receptor messenger RNA (mRNA) was analyzed using real-time quantitative polymerase chain reaction, and the receptor protein was examined using immunostaining. Effects of the H(4) histamine receptor agonist ST-1006 on cytokine synthesis by human SG (HSG) cells were analyzed using xMAP technology and enzyme-linked immunosorbent assay. RESULTS: Healthy SGs contained H(4) histamine receptor mRNA. The receptor protein was localized to the acinar and ductal epithelial cells. H(4) histamine receptor agonist stimulated HSG cells to produce the cytokines interleukin-8 and vascular endothelial growth factor. SS patients had low H(4) histamine receptor levels. CONCLUSION: H(1) and H(2) histamine receptor antagonists are not effective in the treatment of autoimmune diseases. However, such antagonists do not affect the newly discovered H(4) histamine receptor. Dendritic cells and lymphocytes are nonprofessional histamine-producing cells, which produce histamine at 100-1,000-fold lower rates than mast cells do. Saliva contains only 0.31-12.4 ng/ml histamine, which is too low to stimulate H(1) or H(2) histamine receptor, but stimulates H(4) histamine receptor half maximally. Our findings show that H(4) histamine receptor is strongly expressed in tubuloacinar SG cells, which emphasizes the role of these cells in the pathogenesis of SS.
21890001 Dendrobium officinale polysaccharides ameliorate the abnormality of aquaporin 5, pro-infla 2011 Dec Sjögren's syndrome (SS) is a chronic autoimmune disease with exocrine glands disorder. Our previous work demonstrated the protective effect of Dendrobium officinale polysaccharides (DP) both on the phenotypes of patients and animal model with SS. In this study, we expand these observations to explore the possible mechanisms. The experimental SS mice model was established with or without the administration of DP (20mg/ml). The time frame of lymphocytes infiltration, apoptotic indicators such as Bax, Bcl-2 and caspase-3 were determined in submandibular gland (SG), as well as the subsequent mRNA expression of cytokines such as TNF-α, IL-1 beta and IL-6. The expression and localization of aquaporin-5 (AQP-5) was examined by Western blot and immunofluorescent staining. As the result, DP could suppress the progressive lymphocytes infiltration and apoptosis, and balance the chaos of pro-inflammatory cytokines in the SG. Further, DP ameliorated the abnormalities of AQP-5 and maintained its functional importance of saliva secretion. In addition, the protection of AQP-5 by DP from human TNF-α was supported by an in vitro study on A-253 cell line. Our study further supported the efficacy of DP as the promising candidate for the therapy of SS.
21249593 Rhombencephalitis as an initial manifestation of primary Sjögren's syndrome: a case repor 2011 Mar PURPOSE: We present a case report and a comprehensive review of the literature concerning aseptic meningoencephalitis and Sjögren's syndrome (SS). CASE REPORT: We report a 44-year-old woman of primary SS with initial presentation of aseptic meningoencephalitis and a reversible magnetic resonance image (MRI) lesion in the medulla. The diagnosis of primary SS based on ocular dryness, lacrimal hyposecretion, secretory and excretory dysfunction from sialocintigraphy, and positive anti-SS-A antibodies. Corticosteroid and cyclophosphamide therapies reversed the neurological deficits and the MRI lesion. CONCLUSION: Primary SS may have variable manifestations in the central nervous system which may precede the classic sicca symptoms. SS should be investigated in cases of aseptic meningoencephalitis even without clinical signs of xerostomia or xerophthalmia. MRI is useful in demonstrating brain lesions and in evaluating treatment efficacy of the SS.
22548381 Close association between oral Candida species and oral mucosal disorders in patients with 2012 Oct OBJECTIVE: Heightened interest in oral health has lead to an increase in patients complaining of xerostomia, which is associated with various oral mucosal disorders. In this study, we investigated the relationship between Candida species and oral mucosal disorders in patients with xerostomia. SUBJECTS AND METHODS: We evaluated whole salivary flow rate and presence of oral mucosal disorders in 48 patients with xerostomia and 15 healthy controls. The number of Candida species was measured as colony-forming units after propagation on selective medium. Identification of Candida at the species level was carried out by polymerase chain reaction and restriction fragment length polymorphism analysis. We then examined the relationship between Candida species and oral mucosal symptoms. RESULTS: Compared with controls, patients with xerostomia exhibited significantly decreased whole salivary flow rate, increased rate of oral mucosal symptoms, and higher numbers of Candida. Salivary flow rate negatively correlated with the number Candida. Among patients with oral candidiasis, Candida albicans was isolated from the tongue mucosa and Candida glabrata was isolated from the angle of the mouth. CONCLUSION: These results suggest that particular Candida species are involved in the pathogenesis of oral mucosal disorders in patients with xerostomia.
22904194 STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine 2012 Sep 4 Primary Sjögren's Syndrome (pSS) is an autoimmune disease involving salivary and other exocrine glands that leads to progressive lymphocytic infiltration into the gland, tissue damage, and secretory defects. The mechanism underlying this disease remains poorly understood. Here we report that mice with T-cell-targeted deletion of Stromal Interaction Molecule (STIM) 1 and STIM2 [double-knockout (DKO)] mice develop spontaneous and severe pSS-like autoimmune disease, displaying major hallmarks of the disease. In DKO mice, diffuse lymphocytic infiltration was seen in submandibular glands, a major target of pSS, by age 6 wk, progressing to severe inflammation by age 12 wk. Sjögren's syndrome-specific autoantibodies (SSA/Ro and SSB/La) were detected in the serum, and progressive salivary gland destruction and loss of fluid secretion were also seen. Importantly, we report that peripheral blood mononuclear cells as well as lymphocytic infiltrates in submandibular glands from patients with pSS demonstrated significant reductions in STIM1 and STIM2 proteins. Store-operated calcium entry was also reduced in peripheral blood mononuclear cells from pSS patients compared with those from healthy controls. Thus, deficiency of STIM1 and STIM2 proteins in T cells, and consequent defects in Ca(2+) signaling, are associated with salivary gland autoimmunopathy in DKO mice and pSS patients. These data reveal a previously unreported link between STIM1 and STIM2 proteins and pSS.
21209282 Invariant NKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner. 2011 Feb 1 Autoantibody production is a hallmark of autoimmune diseases, such as lupus and rheumatoid arthritis. Accumulating evidence suggests a role of invariant NKT (iNKT) cells in their pathogenesis. Mechanisms underlying the role of iNKT cells in these diseases, however, remain unclear. In this study, we show that iNKT cells suppress IgG anti-DNA Ab and rheumatoid factor production and reduce IL-10-secreting B cells in a contact-dependent manner, but increase total IgG production and enhance activation markers on B cells via soluble factors. In vivo reconstitution with iNKT cells also reduces autoantibody production in iNKT-deficient mice and in SCID mice implanted with B cells. Using an anti-DNA transgenic model, we found that autoreactive B cells spontaneously produce IL-10 and are activated in vivo. In the presence of activated iNKT cells, these autoreactive B cells are selectively reduced, whereas nonautoreactive B cells are markedly activated. Because iNKTs recognize CD1d, we reasoned that CD1d might play a role in the differential regulation of autoreactive versus nonautoreactive B cells by iNKT cells. Indeed, autoreactive B cells express more CD1d than nonautoreactive B cells, and CD1d deficiency in lupus mice exacerbates autoantibody production and enhances Ab response to a self-peptide but not to a foreign peptide. Importantly, iNKT cells fail to inhibit autoantibody production by CD1d-deficient B cells. Thus, iNKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner but activate nonautoreactive B cells via cytokines. Such ability of iNKTs to suppress autoantibody production, without causing global suppression of B cells, has important implications for the development of iNKT-based therapy for autoimmune diseases.
23009273 The changing pattern of renal amyloidosis in Indian subcontinent: two decades of experienc 2012 BACKGROUND: Renal amyloidosis is a major cause of morbidity and mortality among the patients of systemic amyloidosis. The causes of amyloidosis vary from country to country and from time to time at individual center. AIM: This study investigates the changes in epidemiological and clinical profile of renal amyloidosis in recent years. METHOD: Cases of biopsy-proven renal amyloidosis from January 1992 to December 2010 were studied retrospectively. They were divided into two groups: 1990s (between 1992 and 2002) and 2000s (between 2003 and 2010). The clinical characteristics of patients were studied and compared between the groups. RESULT: A total of 2498 (974 in 1990s and 1524 in 2000s) renal biopsies was done during the 19-year period. The incidence of amyloidosis in 1990s and 2000s was 1.74% (n = 17) and 1.9% (n = 29), respectively (p > 0.05). We noted that the incidence of renal amyloidosis increased significantly (p < 0.05) among the females in 2000s. The mean age of patients in 2000s and 1990s was 38 ± 17.9 and 39.2 ± 19 years, respectively (p = 0.83). Renal insufficiency in patients with renal amyloidosis significantly increased (p < 0.05) in 2000s (n = 14; 48.2%) in comparison to 1990s (n = 2; 12.8%). Subnephrotic proteinuria was observed in 12.8% (n = 2) and 48.82% (n = 14) of patients in 1990s and 2000s, respectively (p < 0.05). Infection (n = 10; 58.8%) was the most common cause of secondary amyloidosis during the 1990s, whereas chronic inflammation (n = 14; 48.2%) was the most common cause in 2000s. In 1990s, the incidence of ankylosing spondylitis (AS) and rheumatoid arthritis (RA) was 11.7% (n = 2) and 5.8% (n = 1), respectively, but in 2000s, their respective incidence was 17.2% (n = 5) each. Multiple myeloma (MM) was the most common cause of amyloid light chain protein (AL) amyloidosis in both the groups. We observed systemic lupus erythromatosus (SLE)-related renal amyloidosis in two cases and Hodgkin lymphoma-associated amyloidosis in one case in 2000s. CONCLUSION: The overall incidence of renal amyloidosis showed little change from 1990s to 2000s. Chronic inflammatory diseases were the most common cause of renal amyloidosis in 2000s in contrast to infections in 1990s. Female gender was more affected in 2000s than in 1990s. Renal insufficiency and subnephrotic-range proteinuria were more frequent clinical manifestations of renal amyloidosis in recent years (2000s) in comparison to the earlier decade (1990s).
22622845 The influence of time and adaptation on health state valuations in patients with spinal co 2012 Nov OBJECTIVES: One of the explanations for the difference between health state utilities elicited from patients and the public--often provided but seldom studied--is adaptation. The influence of adaptation on utilities was investigated in patients with spinal cord injury. METHODS: Interviews were held at 3 time points (T1, after admission to the rehabilitation center; T2, during active rehabilitation; T3, at least half a year after discharge). At T1, 60 patients were interviewed; 10 patients withdrew at T2 and T3. At all time points, patients were asked to value their own health and a health state description of rheumatoid arthritis on a time trade-off and a visual analogue scale. The Barthel Index, a measure of independence from help in activities of daily living, and the adjustment ladder were filled out. Main analyses were performed using mixed linear models taking the time-dependent covariates (Barthel Index and adjustment ladder) into account. RESULTS: Time trade-off valuations for patients' own health changed over time, even after correction for gain in independence from help in activities of daily living, F(2, 59) = 8.86, P < 0.001. This change was related to overall adaptation. Both a main effect for adaptation, F(87, 1) = 10.05; P = 0.002, and an interaction effect between adaptation and time, F(41, 1)= 4.10, P = 0.024, were seen for time trade-off valuations. Valuations given for one's own health on the visual analogue scale did not significantly change over time, nor did the valuations for the hypothetical health state. CONCLUSION: Patients' health state valuations change over time, over and above the change expected by the rehabilitation process, and this change is partly explained by adaptation. Experience with a chronic illness did not lead to change in valuations of hypothetical health states.
22399512 Serum BAFF concentrations in patients with Graves' disease and orbitopathy before and afte 2012 May INTRODUCTION: B cells are known to play a key role in the pathogenesis of autoimmune disease. B lymphocyte activating factor (BAFF), a member of TNF family, promotes autoantibody production by increasing B cell survival and proliferation. Serum BAFF concentrations have been found to be increased in systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome. OBJECTIVE: We have measured serum BAFF concentrations in patients with Graves' disease (GD) with or without Graves' orbitopathy (GO) and in active GO in relation to immunosuppressive treatment. METHODS: Forty-two patients and nine normal controls were studied. Thirty-four patients had GO, which was active in 23. Of these, nine were treated with rituximab (RTX) and 14 with i.v. methylprednisolone (MP). Serum BAFF concentrations were measured at baseline in all patients, at peripheral B cell depletion and repopulation after RTX, and after therapy with MP. RESULTS: Serum basal BAFF concentrations in GD patients were significantly higher when compared with normal controls (P = 0.0001), and no difference was observed in those with active or inactive GO. Serum BAFF concentrations were also significantly correlated with serum antithyroglobulin antibodies (P = 0.04) but not with sex, age, smoking habits, therapy for thyroid disease, and serum antithyroperoxidase antibodies and TSH receptor antibodies. After RTX, there was an increase of serum BAFF concentrations at the time of B cell depletion (P = 0.02) but also at B cell repopulation (P = 0.04). In patients treated with MP, serum BAFF concentrations decreased significantly after therapy (P < 0.01). CONCLUSIONS: We report that serum BAFF concentrations are elevated in patients with GD, in whom hyperthyroidism is known to be based on a B-cell-driven pathophysiological mechanism. In active GO, BAFF further increases after therapy with RTX as a consequence of the B cell depletion per se. The decrease of serum BAFF after iv steroids suggests that MP may exert an immunosuppressive effect by modifying B-cell-derived immune reactions.
22373734 Novel acid-type cyclooxygenase-2 inhibitors: Design, synthesis, and structure-activity rel 2012 Apr Cyclooxygenase (COX) is a key rate-limiting enzyme for prostaglandin (PG) production cascades in the human body. The mechanisms of both the anti-inflammation effects and the side-effects of traditional COX inhibitors are associated with the existence of two COX isoforms. Thus while COX-1 is predominantly expressed ubiquitously and constitutively, and it serves a housekeeping role in processes such as gastrointestinal (GI) mucosa protection, COX-2 is absent or exhibits a low level of expression in most tissues, and is highly upregulated in response to endotoxin, virus, inflammatory or tissue-injury stimuli/signals, and tumour promoter in the various types of organs, tissues, and cells. Furthermore, COX-2 contribution to PGE(2) and PGI(2) production evokes and sustains systemic or peripheral inflammatory disease, but it is not involved in the COX-1-mediated GI tract events. Also, hypersensitivity of aspirin owing to its inhibitory action against COX-1 is a significant concern clinically. Consequently, highly selective COX-2 inhibitors have been needed for the treatment of inflammatory- and inflammation related-diseases that include pyrexia, inflammation, pain, rheumatoid arthritis, osteoarthritis, and cancers. In this study, a series of novel [2-{[(4-substituted or 4,5-disubstituted)-pyridin-2-yl]carbonyl}-(5- or 6-substituted or 5,6-disubstituted)-1H-indol-3-yl]acetic acid analogues was designed, synthesized, and evaluated to identify potent and selective COX-2 inhibitors as potential agents against inflammatory diseases. As significant findings, the present study clarified unique structure-activity relationship of the analogues toward potent and selective COX-2 inhibition in vitro, and identified 2-{6-fluoro-2-[4-methyl-2-pridinyl)carbonyl]-1H-indol-3-yl}acetic acid as a potent and selective COX-2 inhibitor in vitro that demonstrated orally potent anti-inflammation efficacy against carrageenan-induced oedema formation in the foot of SPF/VAF male SD rats as a peripheral inflammation model in vivo.
22353382 Autoimmune skin and connective tissue diseases and risk of venous thromboembolism: a popul 2012 May BACKGROUND: Systemic inflammation is associated with vessel wall damage, upregulation of procoagulants, downregulation of anticoagulants, and suppression of fibrinolysis. Autoimmune diseases may therefore increase the risk of venous thromboembolism (VTE). OBJECTIVES: To examine whether autoimmune skin and connective tissue diseases are associated with increased VTE risk. METHODS: We conducted this population-based case-control study in northern Denmark, using administrative databases. From 1999 to 2009, we identified 14,721 VTE cases and 147,210 birth year-matched, sex-matched and county-matched population controls. The date of diagnosis/matching was considered to be the index date for cases and controls. For all study subjects, we identified hospital diagnoses of autoimmune skin or connective tissue diseases between 1977 and the index date. We used conditional logistic regression with adjustment for VTE risk factors to calculate odds ratios and 95% confidence intervals (CIs) for patients with vs. without autoimmune disease. Given the risk-set sampling design, odds ratios estimate incidence rate ratios (IRRs). RESULTS:   Autoimmune skin disease was not associated with VTE (IRR 1.0; 95% CI 0.9-1.2). Patients with connective tissue disease had an increased VTE risk within 90 days (IRR 2.3; 95% CI 1.5-3.7) and 91-365 days (IRR 2.0; 95% CI 1.5-2.8) after diagnosis, but not thereafter (IRR 1.1; 95% CI 1.0-1.2). Among connective tissue diseases, the greatest overall risk increases were found for juvenile rheumatoid arthritis (IRR 3.0; 95% CI 1.4-6.4) and systemic lupus erythematosus (IRR 2.8; 95% CI 1.7-4.7). CONCLUSIONS: Autoimmune connective tissue disease was associated with an increased risk of VTE within 1 year after diagnosis, whereas skin diseases were not.
22292506 A novel naturally occurring salicylic acid analogue acts as an anti-inflammatory agent by 2012 Mar 5 Methyl salicylate 2-O-β-D-lactoside (DL0309), is a molecule chemically related to salicylic acid that is isolated from Gaultheria yunnanensis (FRANCH.) REHDER (G. yunnanensis). G. yunnanensis, a traditional Chinese herbal medicine, is widely used for treating rheumatoid arthritis, swelling, pain, trauma, and chronic tracheitis. In the present study, we explored the mechanism whereby DL0309 exerts anti-inflammatory effects, using the model of lipopolysaccharide (LPS)-treated RAW264.7 cells. We examined the effects of DL0309 on LPS-induced nuclear factor-kappaB (NF-κB) activity by Western blot analysis, cell imaging analysis and an electrophoretic mobility shift assay (EMSA). Production of pro-inflammatory cytokines was also measured. Our observations indicate that DL0309 suppressed production of nitric oxide (NO), reactive oxygen species (ROS) and the pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), in a concentration-dependent manner. The phosphorylation of IKK-β and degradation of IκB-α by LPS were both inhibited by DL0309 in the cytoplasm. The increased protein level of NF-κB by LPS in the nucleus was also reduced by DL0309. Consistent with these results, we found that DL0309 prevents the nuclear translocation and DNA binding activity of NF-κB. Finally, our results demonstrate that DL0309 exerts anti-inflammatory effects, by inhibiting the production of pro-inflammatory cytokines and suppressing of the activation of the NF-κB signaling pathway in LPS-treated macrophage cells. Therefore, DL0309 may have therapeutic potential for treating inflammatory diseases by regulating the NF-κB pathway and pro-inflammatory cytokine production.
22051322 Rose hip and its constituent galactolipids confer cartilage protection by modulating cytok 2011 Nov 3 BACKGROUND: Clinical studies have shown that rose hip powder (RHP) alleviates osteoarthritis (OA). This might be due to anti-inflammatory and cartilage-protective properties of the complete RHP or specific constituents of RHP. Cellular systems (macrophages, peripheral blood leukocytes and chondrocytes), which respond to inflammatory and OA-inducing stimuli, are used as in vitro surrogates to evaluate the possible pain-relief and disease-modifying effects of RHP. METHODS: (1) Inflammatory processes were induced in RAW264.7 cells or human peripheral blood leukocytes (PBL) with LPS. Inflammatory mediators (nitric oxide (NO), prostaglandin E(2) (PGE(2)) and cytokines/chemokines) were determined by the Griess reaction, EIA and multiplex ELISA, respectively. Gene expression was quantified by RT-PCR. RHP or its constituent galactolipid, GLGPG (galactolipid (2S)-1, 2-di-O-[(9Z, 12Z, 15Z)-octadeca-9, 12, 15-trienoyl]-3-O-β-D-galactopyranosyl glycerol), were added at various concentrations and the effects on biochemical and molecular parameters were evaluated. (2) SW1353 chondrosarcoma cells and primary human knee articular chondrocytes (NHAC-kn) were treated with interleukin (IL)-1β to induce in vitro processes similar to those occurring during in vivo degradation of cartilage. Biomarkers related to OA (NO, PGE(2), cytokines, chemokines, metalloproteinases) were measured by multiplex ELISA and gene expression analysis in chondrocytes. We investigated the modulation of these events by RHP and GLGPG. RESULTS: In macrophages and PBL, RHP and GLGPG inhibited NO and PGE(2) production and reduced the secretion of cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-12) and chemokines (CCL5/RANTES, CXCL10/IP-10). In SW1353 cells and primary chondrocytes, RHP and GLGPG diminished catabolic gene expression and inflammatory protein secretion as shown by lower mRNA levels of matrix metalloproteinases (MMP-1, MMP-3, MMP-13), aggrecanase (ADAMTS-4), macrophage inflammatory protein (MIP-2, MIP-3α), CCL5/RANTES, CXCL10/IP-10, IL-8, IL-1α and IL-6. The effects of GLGPG were weaker than those of RHP, which presumably contains other chondro-protective substances besides GLGPG. CONCLUSIONS: RHP and GLGPG attenuate inflammatory responses in different cellular systems (macrophages, PBLs and chondrocytes). The effects on cytokine production and MMP expression indicate that RHP and its constituent GLGPG down-regulate catabolic processes associated with osteoarthritis (OA) or rheumatoid arthritis (RA). These data provide a molecular and biochemical basis for cartilage protection provided by RHP.
21857038 Cementless total hip arthroplasty using titanium, plasma-sprayed implants: a study with 10 2011 Aug PURPOSE: To evaluate long-term outcomes of total hip arthroplasty (THA) using the Perfecta cementless system. METHODS: 73 men and 76 women aged 65 to 88 (mean, 71) years underwent 168 THAs using the Perfecta cementless system and were followed up for a mean of 13 (10 to 15) years. 19 patients had bilateral THA. The diagnoses were idiopathic osteoarthritis (n=121), osteonecrosis of the femoral head (n=25), rheumatoid arthritis (n=14), and post-traumatic osteoarthritis (n=8). Patients were evaluated clinically and radiographically before and after THA. RESULTS: The mean Harris hip score improved from 40 to 84 (p<0.001); the score was excellent or good in 130 hips, fair in 17, and poor in 21. The mean Merle D'Aubigne score improved from 4 to 10 (p<0.001); the score was excellent or good in 138 hips, fair in 9, and poor in 21. Poor results were due to aseptic revision of the cup (n=16) or stem (n=3) or deep infection (n=2). Thigh pain that limited activities of daily living was noted in 3 hips. 142 patients could walk without a limp, 5 had a slight limp, and 3 had a moderate limp and used a cane. The mean Short Form-12 score for the physical function was 49 and for the mental health was 56; the mean Western Ontario and McMaster Universities Osteoarthritis Index was 39; the mean visual analogue scale score for satisfaction was 8. Two patients developed deep infection at postoperative months 8 and 50 and were treated with 2-staged revision. Five patients had hip dislocation within 2 months; 3 of whom endured recurrent dislocation and underwent revision surgery; they had acetabular malposition with excessive anteversion despite a correct acetabular angle. 13 other cups were revised because of loosening or extensive osteolysis (n=10) and polyethylene wear (n=3) after a mean interval of 6 (range, 4-10) years. Three stems were revised because of aseptic loosening after a mean interval of 7 (range, 6-9) years. The survivorship at 14 years was 99% for stems and 91% for cups. CONCLUSION: The long-term outcome of the Perfecta cementless stem was good; most major complications occurred in the cup.
21334982 Treatment with TNFα blockers induces phenotypical and functional aberrations in periphera 2011 Jul To dissect the mechanisms of anti-TNFα-induced autoimmunity we examined the phenotype and function of B cells from anti-TNFα-treated patients. Levels of Lyn, Syk, SHP-1, tyrosine 348 phospho-Syk (Y348-Syk) and tyrosine phosphorylated (P-Y) proteins were evaluated and B-cell-surface CD20, CD21 and CD5 were also assessed in 29 patients treated with TNF-α blockers. Following treatment, Lyn, but not Syk or SHP-1, significantly increased particularly in patients with spondyloarthropathies. Increased Lyn levels following treatment correlated with increased Lyn activity as evidenced by a 2.9-fold increase of Y348-Syk (a Lyn target). Peripheral B-cells from 56.3% of the patients displayed a tendency towards increased P-Y levels without any BCR-initiated activation during treatment. CD20, but not CD21, significantly increased in patients with rheumatoid arthritis. Circulating CD5+ B-cells were also significantly expanded during treatment. Our findings suggest that B cells in anti-TNFα-treated patients display functional and phenotypical aberrations that may enhance our understanding of TNF-α blocker-induced autoimmunity.
21300057 A humanized anti-osteopontin antibody protects from Concanavalin A induced-liver injury in 2011 Apr 25 Osteopontin has been implicated in various inflammatory diseases including rheumatoid arthritis, multiple sclerosis, Crohn's disease, and fulminant hepatitis. Increased expression of osteopontin has been detected in pathological foci of these diseases. RA and fulminant hepatitis have been successfully treated by administration of neutralizing anti-osteopontin antibody in mice. However, rodent antibodies are highly immunogenic in humans and therefore limited in their clinical application. Here, a murine monoclonal antibody 23C3 against human osteopontin, was humanized by complementarity-determining region grafting method based on computer-assisted molecular modeling. The humanized version of 23C3, denoted as Hu23C3, was shown to possess affinity comparable to that of its parental antibody. Hu23C3 could also inhibit monocyte migration in response to osteopontin in vitro. Furthermore, in vivo data showed that Hu23C3 significantly protects mice from Concanavalin A (Con A) induced-liver injury in association with the reduction of transaminase activities and improvement of liver injury. Mechanistic studies demonstrated that Hu23C3 inhibited T and NKT cell infiltration, and activation of nuclear factor κB (NF-κB) in the liver, resulting in reduction of TNF-α and IFN-γ production. Thus, our data strongly support that the humanized anti-osteopontin antibody, Hu23C3, may have a potential for the treatment of T cell mediated-hepatitis in human.
20980463 Interleukin-1β produced in response to islet autoantigen presentation differentiates T-he 2011 Jan OBJECTIVE: The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelB(lo) DCs in the prediabetic period. RESEARCH DESIGN AND METHODS: We injected RelB(lo) DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro. RESULTS: Tolerizing RelB(lo) DCs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelB(lo) DCs exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion. CONCLUSIONS: IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1β/IL-17 checkpoint signals the need for other strategies.
23220116 Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug a 2013 Feb 15 Gold compounds, which were widely used to treat rheumatoid arthritis, have been recently used as experimental agents for tumor treatment. Transient receptor potential (TRP) ankyrin repeat 1 (TRPA1) is a Ca(2+)-permeable ion channel that senses acute and inflammatory pain signals. Electrophilic compounds such as mustard oil and cinnamaldehyde activate TRPA1 by interacting with TRPA1 cysteine residues. Here we investigate the effects of the gold compound auranofin (AUR) on TRPA1 channels. Intracellular Ca(2+) and whole cell patch-clamp recordings were performed on human embryonic kidney cells transiently expressed with TRPA1, TRP melastatin 8 (TRPM8), and vanilloid type TRP (TRPV1-4) channels. AUR stimulated TRPA1 in a concentration-dependent manner with a half-maximum potency of around 1.0 μM. The AUR-induced response was effectively blocked by HC030031, a TRPA1 antagonist. On the other hand, AUR failed to activate TRPM8 and TRPV1-4 channels, which are highly expressed in sensory neurons as nociceptors. The stimulatory effect on TRPA1 channels depended on the C414, C421, C621, and C633 cysteine residues and not on the inhibition of thioredoxin reductase by AUR. Moreover, AUR effectively activated TRPA1 channels expressed in human differentiated neuroblastoma cell lines. The study shows that AUR is a potent stimulator of TRPA1 channels.