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ID PMID Title PublicationDate abstract
16547758 TNFalpha blockers do not improve the hearing recovery obtained with glucocorticoid therapy 2006 Jul The effectiveness of etanercept [tumour necrosis factor-alpha (TNFalpha) blocker] and corticoids in treating immuno-mediated inner ear disease (IMIED) was compared in an animal model of autoimmune labyrinthitis. IMIED is one of the few forms of sensorineural hearing loss that is reversible with proper medical treatment. While the effectiveness and usefulness of immunomodulating agents (corticosteroids) in treating IMIED have been demonstrated, TNFalpha antagonists, which inhibit granuloma formation in rheumatoid arthritis and other autoimmune diseases, have been considered as an alternative therapy. The efficacy of etanercept (anti-TNFalpha) was evaluated in a guinea pig model of experimental autoimmune labyrinthitis in which 25 guinea pigs were divided in a control group, which was used to document the rise in hearing thresholds following immunisation, and two experimental groups, which were treated with steroids (6-methylprednisolone) and anti-TNFalpha (etanercept), respectively, after the immunisation. Comparison of the auditory thresholds obtained by means of auditory brainstem response (ABR) revealed that the auditory thresholds of the two experimental groups were not statistically different (6-methylprednisolone: 41.5 dB, SD: 8.51; etanercept: 37.5 dB, SD: 7.91) and that both compared favourably with that of the control group (60 dB, SD: 7.91) at p=0.001. We therefore conclude that etanercept is as effective as glucocorticoids in an animal model of autoimmune labyrinthitis; however, the potential adverse effects and high price of the former advise against its use as an initial therapy for IMIED.
16503786 Low-level laser therapy induces dose-dependent reduction of TNFalpha levels in acute infla 2006 Feb OBJECTIVE: The aim of this study was to investigate if low-level laser therapy (LLLT) can modulate acute inflammation and tumor necrosis factor (TNFalpha) levels. BACKGROUND DATA: Drug therapy with TNFalpha-inhibitors has become standard treatment for rheumatoid arthritis, but it is unknown if LLLT can reduce or modulate TNFalpha levels in inflammatory disorders. METHODS: Two controlled animal studies were undertaken, with 35 male Wistar rats randomly divided into five groups each. Rabbit antiserum to ovalbumin was instilled intrabronchially in one of the lobes, followed by the intravenous injection of 10 mg of ovalbumin in 0.5 mL to induce acute lung injury. The first study served to define the time profile of TNFalpha activity for the first 4 h, while the second study compared three different LLLT doses to a control group and a chlorpromazine group at a timepoint where TNFalpha activity was increased. The rats in LLLT groups were irradiated within 5 min at the site of injury by a 650-nm Ga-Al-As laser. RESULTS: There was a time-lag before TNFalpha activity increased after BSA injection. TNFalpha levels increased from < or =6.9 (95% confidence interval [CI], 5.6-8.2) units/mL in the first 3 h to 62.1 (95% CI, 60.8-63.4) units/mL (p < 0.001) at 4 h. An LLLT dose of 0.11 Joules administered with a power density of 31.3 mW/cm(2) in 42 sec significantly reduced TNFalpha level to 50.2 (95% CI, 49.4-51.0), p < 0.01 units/mL versus control. Chlorpromazine reduced TNFalpha level to 45.3 (95% CI, 44.0-46.6) units/mL, p < 0.001 versus control. CONCLUSION: LLLT can reduce TNFalpha expression after acute immunocomplex lung injury in rats, but LLLT dose appears to be critical for reducing TNFalpha release.
16391840 Interleukin-10 does not affect IL-1-induced interleukin-6 and metalloproteinase production 2006 Feb Cartilage repair by transplantation of autologous chondrocytes is an option when restoring functional joints. Control of chondrocyte function is thus required. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine affecting the expression of a wide range of immune mediators in hematopoietic and non-hematopoietic cells. Previous studies indicated that IL-10 has therapeutic potential in the treatment of chronic inflammatory joint disorders such as rheumatoid arthritis and osteoarthritis. IL-10 has been found to be chondroprotective by down-regulating metalloproteinase expression and by inhibiting the synthesis of pro-inflammatory cytokines, such as IL-6, in immune cells. In contrast, the effects of IL-10 on chondrocytes are poorly understood and have to be identified with regard to their future clinical use. In this study, we investigated the effects of IL-10 on the expression of cartilage-degrading mediators in the human chondrosarcoma cell line, SW1353, after exposure to IL-1, a key mediator in cartilage and bone destruction. We found a strong induction of the pro-inflammatory cytokine, IL-6, in IL-1-exposed SW1353 cells. Surprisingly, IL-10 had no effect on IL-1-induced IL-6, pro-MMP1, and pro-MMP13 secretion. Although RT-PCR analyses demonstrated the expression of both receptor chains of the IL-10 receptor complex (IL-10R1 and IL-10R2), exposure of SW1353 to IL-10 did not lead to phosphorylation of STAT3, the major transcription factor induced by IL-10. This was not due to a defect in STAT3, because stimulation with IL-6 resulted in its phosphorylation. Failure of SW1353 cells to respond to IL-10 was consistent with a deficient surface expression of IL-10R1. From these results we conclude that IL-10 does not exert its chondroprotective character on chondrocytes directly. Furthermore, the unresponsiveness of chondrocytes towards IL-10 might explain the vulnerability of joint cartilage to inflammation.
15765185 Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, 2005 Apr (-)-DHMEQ, a newly designed NF-kappaB inhibitor, inhibited RANKL-induced osteoclast differentiation in mouse BMMs through downregulation of the induction of NFATc1, an essential transcription factor of osteoclastogenesis. INTRODUCTION: Bone destruction is often observed in advanced case of rheumatoid arthritis and neoplastic diseases, including multiple myeloma. Effective and nontoxic chemotherapeutic agents are expected for the suppression of these bone destructions. RANKL induces activation of NF-kappaB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-kappaB result in impaired osteoclastogenesis, but how NF-kappaB is involved in the regulation of osteoclastogenesis is not known. MATERIALS AND METHODS: The effect of (-)-dehydroxymethylepoxyquinomicin [(-)-DHMEQ] on osteoclast differentiation was studied using a culture system of mouse BMMs stimulated with RANKL and macrophage colony-stimulating factor. The mechanism of the inhibition was studied by biochemical analysis such as immunoblotting and retroviral transfer experiments. RESULTS: (-)-DHMEQ strongly inhibited RANKL-induced NF-kappaB activation in BMMs and inhibited RANKL-induced formation of TRACP(+) multinucleated cells. Interestingly, (-)-DHMEQ specifically inhibited the RANKL-induced expression of NFATc1 but not the expressions of TRAF6 or c-fos. Inhibition of osteoclast differentiation by (-)-DHMEQ was rescued by overexpression of NFATc1, suggesting that the inhibition is not caused by a toxic effect. Moreover, pit formation assays showed that (-)-DHMEQ also inhibited the bone-resorbing activity of mature osteoclasts. CONCLUSION: The inhibition of NF-kappaB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-kappaB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion.
17870551 [How to evaluate the cardiovascular and renal risk at the individual level?]. 2006 Sep The cardiovascular impact of the non-steroidal anti-inflammatory drugs and the higher cardiovas-cular mortality during treatment of inflammatory rheumatism impose a rigorous evaluation of the cardiovascular risk of rheumatic patients. Large epidemiological studies have identified risk factors for cardiovascular diseases such as the age, male gender, family history (infarct, stroke), tobacco consumption, systolic arterial pressure, renal insufficiency, hypercholesterolemia, diabetes mellitis, sedentariness, obesity and "electric" ventricular hypertrophy. Some equations make it possible to evaluate the absolute cardiovascular risk at the individual level, which corresponds to the onset risk of a stroke in the 10 years to come in a subject according to the number and importance of each of his risk factors. It has been demonstrated that the correction of one or more risk factors reduce the overall cardiovascular risk, justifying the strategies for evaluating this risk to define therapeutic intervention thresholds. The impact of a long-term anti-inflammatory treatment or an inflammatory disease such as rheu-matoid arthritis has not been the subject of specific epidemiological study allowing these elements to be included in an equation of the estimation of the cardiovascular risk. However, the introduction of an anti-inflammatory treatment, likely to increase the cardiovascular risk of a patient, certainly justifies an evaluation of the absolute cardiovascular risk.
16830880 Ro52, Ro60 and La IgG autoantibody levels and Ro52 IgG subclass profiles longitudinally th 2006 Congenital heart block occurs in fetuses of Ro/SSA and La/SSB positive women. To investigate the stability of maternal autoantibody levels during pregnancy, we followed Ro52, Ro60 and La autoantibody IgG level variation and Ro52 subclass profiles longitudinally in selected congenital heart block risk pregnancies. Serum samples were obtained from 12 Ro/La positive women diagnosed with a systemic rheumatic disease and followed on average 60 months (range two to 84) which included 13 pregnancies. Seven children were affected by neonatal lupus, whereof four developed complete congenital heart block. Serum was also collected from the babies at birth. Ro52, Ro60 and La IgG as well as subclass antibodies were analysed by ELISA using recombinant antigens. Six Ro/La negative rheumatic patients were included as controls for antibody levels during pregnancy. Ro52, Ro60 and La IgG levels decreased progressively from early to late pregnancy, significantly for Ro52 and Ro60 (P < 0.01). No peaks or persistent elevation of antibody levels were noted in any of the CHB risk pregnancies. Ro52 IgG1 antibody levels were significantly higher than IgG2 (P < 0.01), IgG3 (P < 0.01) and IgG4 (P < 0.05) levels in the mothers during pregnancy. Ro52 IgG1 and IgG4 levels decreased significantly from early to late pregnancy (P = 0.02), while levels of IgG2 and IgG3 were low and the decrease was not significant. All IgG subclasses were transferred to the children. We conclude that maternal levels of Ro52, Ro60 and La autoantibodies tended rather to decrease than to increase during pregnancy.
16849479 Autoimmunity as a result of escape from RNA surveillance. 2006 Aug 1 In previous studies, we detected a frame shift mutation in the gene encoding the autoantigen La of a patient with systemic lupus erythematosus. The mutant La mRNA contains a premature termination codon. mRNAs that prematurely terminate translation should be eliminated by RNA quality control mechanisms. As we find Abs specific for the mutant La form in approximately 30% of sera from anti-La-positive patients, we expected that mutant La mRNAs circumvent RNA control and the expression of mutant La protein could become harmful. Indeed, real-time PCR, immunostaining, and immunoblotting data of mice transgenic for the mutant La form show that mutant La mRNAs are not repressed in these animals and are translated to mutant La protein. In addition to the mutant La protein, we detected a minor portion of native human La in the mutant La-transgenic mice. Therefore, ribosomal frame shifting may allow the mutant La mRNA to escape from RNA control. Interestingly, expression of the mutant La mRNA results in a lupus-like disease in the experimental mice. Consequently, escape of mutant La mRNA from RNA control can have two effects: it 1) results in the expression of an immunogenic (neo)epitope, and 2) predisposes to autoimmunity.
16413168 Sjögren's syndrome in the NOD mouse model is an interleukin-4 time-dependent, antibody is 2006 Mar NOD.B10-H2b and NOD/LtJ mice manifest many features of primary and secondary Sjögren's syndrome (SjS), respectively, an autoimmune disease affecting primarily the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes). A previous study suggested that the T(H2) cytokine, interleukin (IL)-4, plays an integral role in the development and onset of SjS-like disease in the NOD mouse model. To define further the role of IL-4 in onset of murine SjS-like disease, we have examined two IL4 gene knockout (KO) mouse strains, NOD.IL4-/- and NOD.B10-H2b.IL4-/-. Unlike NOD.IL4-/- mice, NOD.B10-H2b.IL4-/- mice are resistant to development of diabetes. The presence of a dysfunctional IL4 gene did not impede leukocyte infiltration of the salivary glands, yet prevented development of secretory dysfunction. Whereas NOD.B10-H2b.IL4-/- mice exhibited many pathophysiological manifestations of SjS-like disease common to the parental strains, these mice failed to produce anti-muscarinic acetylcholine type-3 receptor (M3R) autoantibodies of the IgG1 isotype. Cytokine mRNA expression profiles and adoptive transfers of T lymphocytes from NOD.B10-H2b.Gfp mice into NOD.B10-H2b.IL4-/- mice at different ages suggest IL-4 is required during the pre-clinical disease stage (around 12 weeks of age) to initiate clinical xerostomia. The results of this study indicate that the failure of NOD.IL4-/- and NOD.B10-H2b.IL4-/- mice to synthesize anti-M3R autoantibodies of the IgG1 isotype apparently explains why these mice fail to develop exocrine gland dysfunction, despite exhibiting pre-clinical manifestations of SjS-like disease.
16806593 [Prevalence of Epstein-Barr virus in Sjögren's syndrome in Tunisia]. 2006 Jul PURPOSE: The cause of Sjögren's syndrome is unclear. Several studies suggested the role of Epstein-Barr virus (EBV) in the pathogenesis of this syndrome, but this always remains a subject of numerous controversies. The purpose of this study was to evaluate the prevalence of EBV in Sjögren's syndrome in Tunisia. METHODS: A series of 31 paraffin-embedded biopsies of salivary glands from patients with Sjögren's syndrome were studied in comparison with 19 control glands. EBV was investigated by PCR, EBERs in situ hybridization and by immunohistochemistry for the detection of LMP1, EBNA2 and ZEBRA. RESULTS: EBV DNA was detected by PCR in 3 of 22 PCR beta-globin positive Sjögren's syndrome cases (13.6%) and in 2 of 17 PCR beta-globin positive control glands (11.7%); in situ hybridization positivity was noted in rare lymphocytes in the 3 EBV positive cases of Sjögren's syndrome, but not in control glands; immunohistochemical study was negative in all cases. CONCLUSION: EBV infection does not appear to play a significant role in the pathogenesis of Sjögren's syndrome in Tunisia.
16702740 Long-term outcome of autoimmune pancreatitis after oral prednisolone therapy. 2006 OBJECTIVE: We investigated the long-term outcome of autoimmune pancreatitis (AIP) including morphological changes in the pancreas, pancreatic duct, biliary tract, pancreatic function, and changes in the clinical manifestations after oral prednisolone (PSL) therapy. PATIENTS AND METHODS: We prospectively followed 12 patients for a period of over 12 months (median follow-up period: 41 months; range: from 13 to 133 months). All twelve patients were treated with PSL. The morphological findings consisted of pancreatic enlargement (n=12), an irregularly narrowed main pancreatic duct (n=12), and bile duct stricture (n=10), and salivary gland swelling was observed in six patients. The initial dose of PSL was 30-40 mg/day, and it was subsequently tapered. RESULTS: All 12 patients responded to PSL therapy. The enlargement of the pancreas and the irregularly narrowed main pancreatic duct improved to almost normal. Pancreatic atrophy developed in four of them (4/12, 33%), but no pancreatic calcification was observed in any of the patients. The bile duct stricture improved to various degrees in all 10 patients , but it persisted in the lower part of the bile duct in four of them (4/10, 40%). The salivary gland swelling also improved after PSL therapy. There was no recurrence of enlargement of the pancreas or irregularly narrowed main pancreatic duct after PSL therapy, but the bile duct stricture recurred in one case, and in three cases there was a relapse of salivary gland swelling that required a temporary increase in PSL dose during tapering. No deterioration of pancreatic exocrine function was detected in any of the patients. A malignant tumor was diagnosed in two patients during PSL therapy: early gastric cancer in one and rectal cancer in the other. All patients are alive. CONCLUSIONS: AIP treated with PSL has a favorable long-term outcome based on the morphological findings and assessments of pancreatic function. However, since two of the twelve patients developed a malignancy during PSL therapy, strict follow up should be part of the management of AIP.
16414974 Immunoproteasome subunit LMP2 expression is deregulated in Sjogren's syndrome but not in o 2006 Aug BACKGROUND: The proteasome system has a pivotal role in the control of the immune response, which suggests that it might be involved in the pathogenesis of autoimmune disorders. OBJECTIVE: To investigate the expression profile of selected proteasomal genes in human peripheral blood mononuclear cells in patients with a variety of autoimmune diseases compared with healthy subjects. METHODS: Real time quantitative RT-PCR was used to analyse the mRNA expression pattern of the proteasome activator subunits PA28alpha and PA28beta and of constitutive proteasome and interferon-gamma-inducible immunoproteasome subunits in peripheral blood mononuclear cells. Simultaneously, protein expression of selected proteasome subunits was quantified by immunoblotting. RESULTS: Under systemic inflammatory conditions the proteasome subunits LMP2 (beta1i), LMP7 (beta5i), MECL1 (beta2i), and PA28alpha were expressed abundantly at the protein level in the vast majority of systemic autoimmune disorders. However, simultaneous mRNA and protein quantification showed a characteristic proteasome expression signature in primary Sjögren's syndrome. At the transcript level, the interferon-gamma-responsive subunits LMP2 (beta1i), MECL1 (beta2i), and the proteasome activator subunit PA28alpha were markedly up regulated. In contrast, LMP2 (beta1i) deficiency was evident at the protein level, indicating deregulation of proteasome expression in Sjögren's syndrome. CONCLUSIONS: These data provide evidence for a regulatory defect in the proteasome system in human autoimmune disorders, pointing to a unique role for LMP2 (beta1i) in the pathogenesis of primary Sjögren's syndrome.
16414973 Distinct recognition of antibodies to centromere proteins in primary Sjogren's syndrome co 2006 Aug BACKGROUND: Anticentromere antibodies are characteristically observed in scleroderma but have recently been reported in other autoimmune rheumatic disorders, including Sjögren's syndrome. It is not known whether distinct centromere proteins (CENP) are targeted in primary Sjögren's syndrome (pSS) and scleroderma. OBJECTIVE: To determine whether antibodies to CENP-B and CENP-C are present in these two disorders. METHODS: Sera from 45 patients with pSS and 33 with limited scleroderma were studied. All patients met classification criteria for pSS and scleroderma, respectively. Sera were used to immunoprecipitate in vitro translated CENP-B and CENP-C. The proportions recognising CENP-B or CENP-C were compared. RESULTS: 10 of 45 patients (22%) with pSS and 18 of 33 (55%) with scleroderma had antibodies recognising CENPs (p = 0.004). Seven of 10 (70%) CENP positive patients with pSS recognised CENP-C alone, compared with one of 18 (6%) CENP positive patients with scleroderma (odds ratio (OR) = 40 (95% confidence interval (CI), 3.5 to 450) (p = 0.003). In contrast, the majority (15 of 18 (83%)) of CENP positive scleroderma sera recognised both CENP-B and CENP-C, compared with none of 10 pSS sera (OR = 93 (95% CI, 4.4 to 1979) (p = 0.0001). CONCLUSIONS: The pattern of CENP recognition differs markedly in pSS and limited scleroderma. While patients with pSS predominantly recognise CENP-C alone, dual recognition of CENP-B and CENP-C is most frequent in scleroderma. These findings suggest that obtaining antibodies to specific centromere antigens is useful diagnostically, and imply that distinct mechanisms underlie the unique patterns of centromere autoreactivity in pSS and scleroderma.
16249071 Identification of tear lipocalin as a novel autoantigen target in Sjögren's syndrome. 2005 Nov Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and tissue damage mainly confined to the salivary and lacrimal glands, resulting in dryness of mouth and eyes. Since different epithelial cells of exocrine and non-exocrine tissues are primarily affected, an autoimmune reaction against antigens commonly expressed in epithelial cells is believed to play a pathogenic role. To identify novel autoantigen targets associated with the systemic involvement in SS, we screened a random peptide library with pooled IgG immunoglobulins derived from patients with primary SS. Among the identified peptides, one was recognized by the majority of patients' sera, but not by sera of normal donors and of patients with other autoimmune diseases. The peptide showed homology with an Epstein-Barr Virus (EBV) derived protein and with tear lipocalin, a protein highly expressed in tears and saliva, and with alpha-fodrin, a cytoskeleton protein considered an important autoantigen target in SS. Anti-peptide antibodies affinity purified from patients' sera recognize the viral protein, tear lipocalin and alpha-fodrin. Our findings suggest that EBV infection may be linked to the pathogenesis of SS and that tear lipocalin can be considered a novel and yet unidentified autoantigen in SS.
16537077 Distribution and roles of aquaporins in salivary glands. 2006 Aug Salivary glands are involved in secretion of saliva, which is known to participate in the protection and hydratation of mucosal structures within the oral cavity, oropharynx and oesophagus, the initiation of digestion, some antimicrobial defence, and the protection from chemical and mechanical stress. Saliva secretion is a watery fluid containing electrolytes and a mixture of proteins and can be stimulated by muscarinic and adrenergic agonists. Since water movement is involved in saliva secretion, the expression, localization and function of aquaporins (AQPs) have been studied in salivary glands. This review will focus on the expression, localization and functional roles of the AQPs identified in salivary glands. The presence of AQP1, AQP5 and AQP8 has been generally accepted by many, while the presence of AQP3, AQP4, AQP6 and AQP7 still remains controversial. Functionally, AQP5 seems to be the only AQP thus far to be clearly playing a major role in the salivary secretion process. Modifications in AQPs expression and/or distribution have been reported in xerostomic conditions.
16253713 Secondary renal amyloidosis due to long-standing tubulointerstitial nephritis in a patient 2005 Nov A 53-year-old patient with long-standing primary Sjögren syndrome presented with acute renal failure and nephrotic syndrome caused by secondary (AA) renal amyloidosis. Ten years before, he had been admitted because of exacerbation of the systemic disease. At that time, a pseudolymphoma of the kidney was diagnosed. To our knowledge, this is the first report of a patient with primary Sjögren syndrome and secondary (AA) amyloidosis with amyloid deposition in the kidneys causing nephrotic syndrome.
15640273 Correlation of serum B lymphocyte stimulator and beta2 microglobulin with autoantibody sec 2005 Jul BACKGROUND: In primary Sjögren's syndrome (pSS), extraglandular involvement might result from more intense stimulation of autoreactive B cells. Thus markers of B cell activation could be useful in the clinical assessment of this disease. OBJECTIVE: To investigate the association of serum B lymphocyte stimulator (BLyS) and beta2 microglobulin with autoantibody production and extraglandular involvement in pSS. METHODS: Serum concentrations of BLyS and beta2 microglobulin were analysed in 177 patients with pSS according to the American-European consensus group criteria. Serum beta2 microglobulin was determined serially in 25 patients. RESULTS: Autoantibody secretion (presence of anti-SSA antibody alone or of both anti-SSA and anti-SSB) was associated with increased serum BLyS and beta2 microglobulin. No correlation was found between BLyS and beta2 microglobulin levels (p = 0.36). Serum concentrations of beta2 microglobulin and C reactive protein and positive anti-SSB antibody results were associated with extraglandular involvement on univariate analysis (p<10(-4), p = 0.003, and p = 0.004, respectively). Serum beta2 microglobulin was also significantly increased in patients with extraglandular involvement without autoantibodies (mean (SD): 1.75 (0.7) v 1.39 (0.5) mg/l, p = 0.039). Multivariate analysis showed that extraglandular involvement was associated only with increased serum beta2 microglobulin (p = 0.035, odds ratio = 2.78 (95% confidence interval, 1.07 to 7.22)). Among the 25 patients who had serial determinations of serum beta2 microglobulin, the concentrations were increased in all those with disease flare and decreased in three following treatment. Serum BLyS, gamma globulin, IgG, and rheumatoid factor levels were not associated with features of systemic involvement. CONCLUSIONS: Serum beta2 microglobulin and BLyS reflect B cell activation in different ways in pSS. Serum beta2 microglobulin assessment could be helpful as an activity marker in pSS.
17125142 Role of MHC class II expressing CD4+ T cells in proteolipid protein(91-110)-induced EAE in 2006 Dec MHC class II molecules play a central role in the control of adaptive immune responses through selection of the CD4(+) T cell repertoire in the thymus and antigen presentation in the periphery. Inherited susceptibility to autoimmune disorders such as multiple sclerosis, rheumatoid arthritis and IDDM are associated with particular MHC class II alleles. Advent of HLA transgenic mice has helped us in deciphering the role of particular HLA DR and DQ class II molecules in human autoimmune diseases. In mice, the expression of class II is restricted to professional antigen-presenting cells (APC). However, in humans, class II is also expressed on T cells, unlike murine T cells. We have developed new humanized HLA class II transgenic mice expressing class II molecules not only on APC but also on a subset of CD4(+) T cells. The expression of class II on CD4(+) T cells is inducible, and class II(+) CD4(+) T cells can present antigen in the absence of APC. Further, using EAE, a well-established animal model of MS, we tested the functional significance of these class II(+) CD4(+) T cells. DR3.AEo transgenic mice were susceptible to proteolipid protein(91-110)-induced EAE and showed CNS pathology accompanied by widespread inflammation and demyelination seen in human MS patients, suggesting a role for class II(+) CD4(+) T cells in the pathogenesis.
17054209 Methotrexate for ankylosing spondylitis. 2006 Oct 18 BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown cause, characterised by sacroiliitis and spondylitis. Generally, treatment is limited to the alleviation of symptoms using non-steroidal anti-inflammatory drugs (NSAIDs). Recently, disease-modifying antirheumatic drugs (DMARDs) have been used for patients for whom NSAIDs do not work. Methotrexate (MTX), a widely used DMARD, is effective for rheumatoid arthritis (RA), and so might work for AS too. OBJECTIVES: To evaluate the efficacy and toxicity of MTX for treating AS. SEARCH STRATEGY: We conducted searches in any language in: CENTRAL (The Cochrane Library Issue 4, 2005); MEDLINE (1966 to November 20, 2005); EMBASE (1980 to November 20, 2005); CINAHL (1982 to November 20, 2005), and the reference sections of retrieved articles. SELECTION CRITERIA: Randomised and quasi-randomised trials examining the efficacy of MTX versus placebo, other medication, or no medication, for AS. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed unblinded trial reports for inclusion, assessed methodological quality and entered trial data into RevMan 4.2 using the double-entry facility. Disagreements were resolved by a third reviewer. In the absence of significant heterogeneity, results for continuous data were combined using weighted mean difference or standardised mean difference. Relative risk was used for dichotomous data. MAIN RESULTS: Three trials, involving 116 patients, were included. One 12-month trial compared naproxen plus MTX with naproxen alone. Two 24-week trials compared different doses of MTX with placebo. No statistically significant differences were found for the primary outcome measures of physical function, pain, spinal mobility, peripheral joints/entheses pain, swelling and tenderness, changes in spine radiographs and patient and physician global assessment. Only the response rate in one trial showed a statistically significant benefit of 36% in the MTX group compared to the placebo group (RR 3.18, 95% CI 1.03 to 9.79). This response rate was a composite index that included assessments of morning stiffness, physical well-being, Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), health assessment questionnaire for spondyloarthropathies (HAQ-S), and physician and patient global assessment. However, no single outcome showed a statistically significant difference between the MTX and placebo groups when endpoint results were compared. Therefore, this benefit of MTX is questionable. No serious side effects were reported in these trials. AUTHORS' CONCLUSIONS: There is not enough evidence to support any benefit of MTX in the treatment of AS. High-quality randomised controlled trials of longer durations and with larger sample sizes are needed to clarify the effect(s) of MTX on AS.
17051484 Emergence of Legionella pneumophila pneumonia in patients receiving tumor necrosis factor- 2006 Nov 15 BACKGROUND: Patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists have an increased risk of infection, but infection due to Legionella pneumophila has rarely been described in patients receiving such therapy. METHODS: A registry involving 486 clinical departments in France was designed by a multidisciplinary group (Recherche Axée sur la Tolérance des Biothérapies [RATIO]) to collect data on opportunistic and severe infections occurring in patients treated with TNF-alpha antagonists. All cases are reported to RATIO in accordance with national health authorities and validated by infectious disease experts. The legionellosis rate among patients treated with TNF-alpha antagonists was compared with the rate in France overall. RESULTS: We report a 1-year consecutive series of 10 cases of L. pneumophila pneumonia in France in 2004, including 6 cases treated with adalimumab, 2 treated with etanercept, and 2 treated with infliximab. The median patient age was 51 years (range, 40-69 years). Eight patients were treated for rheumatoid arthritis, 1 was treated for cutaneous psoriasis, and 1 was treated for pyoderma gangrenosum. The median duration of TNF-alpha antagonist treatment at onset of infection was 38.5 weeks (range, 3-73 weeks). Eight patients were receiving concomitant treatment with corticosteroids, and 6 were receiving treatment with methotrexate. The relative risk of legionellosis when receiving treatment with a TNF-alpha antagonist, compared with the relative risk in France overall, was estimated to be between 16.5 and 21.0. We also report a second episode of confirmed legionellosis following the reintroduction of infliximab therapy. CONCLUSIONS: L. pneumophila pneumonia is a potentially severe but curable infection that might complicate anti-TNF-alpha therapy. In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.
16920972 Immune interactions with CD4+ T cells promote the development of functional osteoclasts fr 2006 Sep 1 Dendritic cells (DC) are innate immune effectors and are critically involved in regulating T cell immunity. Osteoclasts (OC) are bone-resorbing cells derived from the monocyte/macrophage lineage in response to receptor activator of NF-kappaB ligand (RANKL). DC and T cells form aggregates in the inflammatory infiltrates at active disease sites in human and in experimental rheumatoid arthritis and periodontitis. We investigated whether DC interactions with T cells in the bone environment can support the development of functional OC. In the present study, we demonstrate that upon proper activation by microbial or protein Ags (namely Actinobacillus actinomycetemcomitans, bovine insulin, and outer membrane protein-1) and during immune interactions with CD4+ T cells in vitro, murine BM-derived and splenic CD11c+ DC (CD11b- F4/80- Ly-6C- CD31-) develop into TRAP+ CT-R+ cathepsin-k+ functional OC in a RANKL/RANK-dependent manner. Rescue and blocking experiments using CD11c+ DC derived from Csf-1(-/-) op/op mice show that M-CSF is required "before" developing such osteoclastogenic potential upstream of RANKL/RANK signaling, suggesting that immature CD11c+ DC can indeed act like OC precursors. In addition, these CD11c+ DC-derived OC are capable of inducing bone loss after adoptive transfer in vivo. These data suggest a direct contribution of DC during immune interactions with CD4+ T cells to inflammation-induced osteoclastogenesis. Therefore, our findings not only provide further evidence for DC plasticity, but also extend the current paradigm of osteoimmunology.