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ID PMID Title PublicationDate abstract
16763456 Matrix metalloproteinase expression in the spondyloarthropathies. 2006 Jul PURPOSE OF REVIEW: Expression of matrix metalloproteinases and their tissue inhibitors has been an active area of investigation in rheumatoid arthritis and osteoarthritis. Only recently have investigators started to study these factors in spondyloarthropathy. The purpose of this review is to summarize these recent findings. RECENT FINDINGS: Multiple matrix metalloproteinases and their tissue inhibitors are expressed in the synovial fluid as well as serum samples of spondyloarthropathy patients. Their degrees of expression in the synovia correlate with parameters of arthritis activity such as cell infiltration. In the synovial fluids, the factor which is expressed in very high level is matrix metalloproteinase-3. Two separate cohorts demonstrate that serum levels of matrix metalloproteinase-3 correlate with disease activity in ankylosing spondylitis. Their usefulness appears to exceed those of erythrocyte sedimentation rate and C-reactive protein. Multiple studies also indicate that serum levels of matrix metalloproteinase-3 are suppressed when patients are treated with the anti-tumor necrosis factor-alpha antibody infliximab. SUMMARY: New biomarkers are in demand for spondyloarthropathy in deciding whether patients would benefit from treatment with tumor necrosis factoralpha blockers, monitoring response to treatment, or predicting potential of joint damage if untreated. Recent studies show that among the matrix metalloproteinase and their tissue inhibitors, serum MMP-3 is the one with potential usefulness.
19076348 RANK/RANKL: regulators of immune responses and bone physiology. 2008 Nov Bone-related diseases, such as osteoporosis and rheumatoid arthritis, affect hundreds of millions of people worldwide and pose a tremendous burden to health care. By deepening our understanding of the molecular mechanisms of bone metabolism and bone turnover, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three tumor necrosis factor (TNF) family molecules, the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor of RANKL, osteoprotegerin (OPG), have attracted the attention of scientists and pharmaceutical companies alike. Genetic experiments revolving around these molecules established their pivotal role as central regulators of osteoclast development and osteoclast function. RANK-RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. In addition, RANKL and RANK have essential roles in lymph node formation, establishment of the thymic microenvironment, and development of a lactating mammary gland during pregnancy. Consequently, novel drugs specifically targeting RANK, RANKL, and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various ailments associated with bone loss, such as arthritis, periodontal disease, cancer metastases, and osteoporosis.
19033264 The effect of plasminogen activator inhibitor-1 -675 4G/5G polymorphism on familial Medite 2009 Jul Familial Mediterranean fever (FMF) is an autosomal recessive disease that is the most common of a rare group of disorders collectively termed familial hereditary periodic fever syndromes, also known as autoinflammatory syndromes. FMF is predominantly affecting people of Mediterranean descent and clinically characterized by intermittent attacks of fever with peritonitis and abdominal pain, pleuritis, arthritis, or erysipelas-like rashes. Amyloidosis due to chronic inflammation progressing to renal failure is one of the most serious potential complications of this disease.Patients with inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, and conditions with chronic subclinical inflammation, like obesity and diabetes mellitus, are now considered to have an increased risk of atherosclerotic cardiovascular complications. FMF is also an inflammatory disease, and it is accepted that even during attack-free periods significant inflammatory reaction continues. However, whether this inflammatory process causes premature atherosclerosis is not known due to a lack of data.Different studies have investigated the association between the fibrinolytic and inflammatory process parameters. PAI-1 is paracrine secretion of pro- and antiinflammatory cytokines, thereby playing a possible role in the adiposity-related inflammation and atherosclerosis. The patients with IRS have higher values of fibrinogen, factor VII, VIII, Von Willebrand factor and Plasminogen Activator Inhibitor (PAI) compared to control subjects. So that we aimed in this study to investigate whether FMF patients with/without amyloidosis and with M694V homozygote mutation, have increased risk for atherosclerotic cardiovascular complications and to determine the strength of association between MEFV gene-mutation types. To our knowledge, this is the first case control and cross-sectional study in the pediatric age groups.
16944081 [Relative value of plain vitamin D and of biologically active vitamin D in the prevention 2006 Sep Vitamin D metabolism has an important role in the pathogenesis of osteoporosis. Vitamin D deficiency is very common in elderly people in central Europe. This leads to secondary hyperparathyroidism and to increased bone resorption, resulting in osteoporosis. Combined with the elevated risk of falling that results from vitamin D deficiency, this increases the frequency of bone fractures. Severe vitamin D deficiency also causes impaired bone mineralization (osteomalacia). Controlled intervention trials with native vitamin D (and calcium) yielded no consistent results in terms of the prevention of extravertebral fractures. It appears likely that treatment with plain vitamin D is effective only in populations with vitamin D deficiency. Treatment with active vitamin D (1-alpha-hydroxylated metabolites such as alfacalcidol) has to be considered a pharmacological intervention that exerts pleiotropic effects on the gut (calcium absorption), bone (stimulation of formation), muscle (decreasing of the risk of falling), and immune system. Target groups are patients with disturbed vitamin D metabolism (renal insufficiency, glucocorticoid therapy, inflammatory disease such as rheumatoid arthritis). Alfacalcidol can prevent glucocorticoid-induced bone loss (high-grade evidence). In comparative studies alfacalcidol was superior to plain vitamin D.
17980637 Development of a scoring system for assessment of outcome of early undifferentiated inflam 2008 Mar BACKGROUND: The current paradigm for early undifferentiated arthritis suggests that persistent synovitis leads to erosive joint damage, which results in functional disability. Discriminating between different forms of early arthritis outcome is relevant for therapeutic decision-making and prevents the occurrence of circularity in diagnostic studies. Implementation of a prognostic model into clinical practice is highly required. OBJECTIVE: To identify the prognostic factors at entry for the persistence of early inflammatory arthritis and to develop a scoring system to assess the outcome in patients presenting with early inflammatory arthritis. METHODS: A cohort of 173 patients with early inflammatory arthritis, were assessed in a special early arthritis clinic. Case definition of synovitis was assessed clinically by the number of tender joint and swollen joint counts as well as symmetry of the affected joints and data were recorded. Baseline HAQ score, serum rheumatoid factor and anti-CCP titre were monitored. Patients satisfying the American College of Rheumatology classification criteria for RA and the European Spondyloarthropathy Study Group criteria for spondylo-arthropathry were excluded, as well as those with a specific rheumatic diagnosis. All the patients were reviewed every 3 months for 24 months period. Ultrasonography for both MCP and PIP joints, both hands, were performed at day of entry and 6 months after initial assessment. All patients had MRI both hands and wrist joints. The arthritis outcome recorded at 1-year follow up represented the gold standard for the diagnosis. Logistic regression analysis was performed to identify the independent factors (predictors) of persistent arthritis and accordingly a scoring system was invented that involved the predictors revealed from the analysis. A ROC curve was set to display the performance of the scoring system and a cut off point was selected taking into consideration a higher sensitivity than specificity, as this model will be mainly used as a screening tool. RESULTS: During the follow up period, 93 patients showed evidence of self-limiting arthritis while 80 showed persistent arthritis. Duration of morning stiffness in minutes, percentage change in HAQ score after 3 months duration and anti-CCP positivity were the predictors of persistent arthritis. ROC curve analysis identified a cut off point of 121 above which the early arthritis patient would be more at risk of developing persistent arthritis. CONCLUSION: Application of a model (scoring system) to stratify patients presenting with early persistent inflammatory arthritis from those with self-limiting disease can be attained. The developed model was found to be valid on the studied cohort. This model is important for standard clinical practice as the value of prediction of persistent arthritis has its great impact not only for identifying the patients but also on the therapeutic outcome as well.
18369459 A genome-wide association study of psoriasis and psoriatic arthritis identifies new diseas 2008 Mar 28 A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11), GWA scan; P = 1.8x10(-30), replication; P = 1.8x10(-39), combined; U.K. PSA: P = 6.9x10(-11)). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26) in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4); U.K. PSA: P = 8.0x10(-4); IL12B:rs6887695, U.S. PS, P = 5x10(-5) and U.K. PSA, P = 1.3x10(-3)) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2x10(-6) for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2x10(-5) for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9x10(-5) for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis).
18601819 [Mid-term results of cementless ultima cups in primary total hip replacement]. 2008 Jun PURPOSE OF THE STUDY: To present the results of primary total hip arthroplasty (THA) with use of the hemispheric threaded Ultima cup at 8.5-year follow-up. MATERIAL: Between 1996 and 1999, a total of 40 Ultima acetabular components were used in 33 patients (15 men and 18 women). The average age at the time of surgery was 61.2 years (range, 45 to 71). By the end of 2006, 36 cups were assessed. Indications for the primary THA procedure included primary arthritis in 32 hips, post-traumatic arthritis in three, post-dysplastic arthritis in two, femoral neck fracture in two and rheumatoid arthritis in one. METHODS: The average follow-up was 8.5 years (range, 7 to 10). The indication criteria for primary implantation were evaluated, i.e., body mass index, patients' activity and their age. THA outcome was evaluated on the basis of clinical rating (Harris hip score) and pain assessment and on radiographic findings on which the acetabulum before and cup position after THA were compared, and potential changes in cup position, acetabular cup loosening or para-articular ossifications were observed. RESULTS: Good outcomes were found in 88.9 % of the hips. In most, cup position was satisfactory. One acetabular component was implanted in a varus position (34 degrees ). An intraoperative complication included fracture of the greater trochanter, which was left untreated for spontaneous healing. The early-postoperative complications were one dislocation, two wounds with serous secretion not requiring revision surgery, and one large haematoma. Stem fracture as a late complication was recorded in two THAs. Radiolucencies were found in six hips and paraarticular ossifications in four. Migration of the cup with protrusion into the acetbulum occurred in one patient 3 years after THA. Four cups showed aseptic loosening within 3 to 7 years of surgery. No infection was recorded in this THA group. DISCUSSION: Information on mid- and long-term outcomes of the use of cementless acetabular cups in the relevant literature is sparse. The Ultima cup is dealt with only in the report by Pazdírek et al., whose results are in agreement with ours, but involve a lower number of implanted cups and a shorter follow-up. In this study, loosening was recorded only in cups larger than 32 mm in diameter. In comparison with our group of cementless BMT acetabular components, the use of cementless Ultima cups gives better results at mid-term follow-up. CONCLUSIONS: At 8.5-year follow-up, 88.9 % of the Ultima acetabular components were without radiographic signs of loosening. Attention should be paid primarily to THA patients with a thin wall acetabulum requiring a larger cup and a 32-mm liner.
16981009 Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune 2006 Oct Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.
17492440 Familial early onset sarcoidosis with bone cysts and erosions. 2007 Sep Early onset sarcoidosis is a granulomatous disease which is characterized by synovitis, polyarthritis, skin and eye involvement. We report the skeletal features of one patient with a family history and clinical symptoms suggestive of early onset sarcoidosis (EOS) which was confirmed by skin biopsy. Radiographs reveal postarthritic deformities of the MCP joints, contractures, a coarsened trabecular pattern at the PIP joints and small bone cysts resembling osteitis cystoides multiplex. Similar lesions were described in radiographs of the older sister and an uncle of our patient. This is the first report demonstrating bone cysts and erosions which could be a diagnostic feature in this rare disease and may help to differentiate other rheumatoid disorders.
17286756 Clinical significance of autoantibodies recognizing Sjögren's syndrome A (SSA), SSB, calp 2007 May The aim of our study was (i) to compare the clinical and biological characteristics of 148 (137 women, 11 men) primary Sjögren's syndrome (pSS) patients at diagnosis as a function of their sex and (ii) to assess the prognostic value of anti-calpastatin and anti-alpha-fodrin autoantibodies. In addition, the presence of anti-nuclear antibodies (ANA), anti-52- and 60-kDa Sjögren's syndrome A (SSA), anti-Sjögren's syndrome B (SSB), anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factors (RF) of IgA, IgG and IgM isotypes was sought in sera collected at pSS onset. Raynaud's syndrome, significantly more frequent in women, was the only systemic manifestation of pSS whose frequency differed significantly as a function of the patient's sex (P = 0.02). ANA (P = 0.001) and anti-60-kDa SSA autoantibodies (P = 0.03) were significantly more common in women, while men never synthesized detectable levels of anti-SSB, anti-calpastatin or IgG anti-alpha-fodrin autoantibodies. In addition, anti-CCP autoantibodies were found in low percentages of pSS patients (4% F/18% M). The absence of autoantibodies does not exclude the diagnosis of pSS in men that will be based mainly on the anatomopathological findings of a minor salivary gland biopsy. Positivity of anti-60-kDa SSA, anti-SSB, anti-calpastatin, IgA and IgG anti-alpha-fodrin antibodies is not associated with pSS clinical and biological severity.
17804554 The clinical significance of IgA antimitochondrial antibodies in sera and saliva in primar 2007 Jun It still remains unclear how antimitochondrial autoantibodies (AMA) are involved with immunopathogenesis of primary biliary cirrhosis (PBC). We have suggested the potential role of IgA-AMA in damage to epithelial cells in PBC. In the current study, we investigated whether IgA-AMA were detectable in sera and saliva of PBC patients, to examine the association between detectable IgA-type autoantibodies in sera or saliva and progression of liver diseases. Fifty-three patients with PBC were enrolled, and IgA-AMA in sera and saliva were sought by immunoblotting using pork heart mitochondria as antigens. The progression of PBC was determined as Scheuer's classification consisting of four histological stages. We found IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP in 43/53 (81%), 37/53 (70%), and 35/53 (66%) sera of patients with PBC, but none of controls. The progression of PBC was statistically associated with presence of IgA-anti-PDC-E2 (P = 0.0124), but neither with IgA-AMA (P = 0.1296) nor anti-IgA-E3BP (P = 0.5973). In saliva, detectable IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP were noted in 12/26 (46%), 6/26 (23%), and 11/26 (42%), respectively. Detection of IgA-anti-PDC-E2 was strongly associated with progression of PBC (P = 0.0002), whereas detection of IgA-AMA and IgA-anti-E3BP were not associated (P = 0.2145 and P = 0.5118). The current findings suggest that the presence of IgA-anti-PDC-E2 in sera or saliva might be associated with progression of PBC, although a prospective study with PBC patients with detectable IgA-anti-PDC-E2 at early stages will be required to conclude the contribution of IgA-anti-PDC-E2 to the progression of PBC.
18681491 Cevimeline. 2008 Cevimeline is an orally administered muscarinic receptor agonist that is indicated for the treatment of symptoms of dry mouth in patients with Sjogren's syndrome. Several well designed placebo-controlled trials demonstrated that 4-12 weeks' therapy with cevimeline 30 mg three times daily improved symptoms of dry mouth in patients with Sjogren's syndrome. Other symptoms, such as dry eye symptoms and overall dryness, also improved to a significantly greater extent with cevimeline than with placebo. Moreover, cevimeline significantly improved the salivary flow rate in patients with Sjogren's syndrome. Increased salivary flow was maintained in the longer term with cevimeline in patients with Sjogren's syndrome and symptoms of dry mouth, according to the results of an open-label 52-week study. From week 20 onwards, rates of patient and investigator satisfaction with the cevimeline dosage were > or =88%. Oral cevimeline 30 mg three times daily was generally well tolerated in patients with Sjogren's syndrome, with many of the most commonly reported adverse events reflecting the pharmacological action of the drug.
18617551 Polymorphism in the 5' regulatory region of the B-lymphocyte activating factor gene is ass 2008 Sep OBJECTIVE: To investigate the association between haplotypes in the 5' regulatory region of the B-lymphocyte activating factor (BAFF) gene, disease susceptibility and serum BAFF (s-BAFF) levels in Caucasian primary SS (pSS) patients. METHODS: Case-control study in an established pSS cohort with PCR-RFLP genotyping for four SNPs (-2841 T-->C, -2704 T-->C, -2701 T-->A, -871 C-->T), which tag a haplotype block in the 5' regulatory region of the BAFF gene and s-BAFF determination by ELISA. RESULTS: s-BAFF levels were elevated in Ro/La-positive pSS patients (n = 85, 1770 pg/ml) compared with both Ro/La-negative pSS patients (n = 27, 1193 pg/ml) and controls (n = 59, 1171 pg/ml), P < 0.001. s-BAFF increased with diversification of the anti-Ro/La antibody response, but was not correlated with age, RF or immunoglobulin G levels. There were four common BAFF haplotypes. While the CTAT haplotype was associated with Ro/La-positive pSS [odds ratio (OR) 2.6; 95% CI 1.7, 4.1; P = 0.00004], the TTTT haplotype was associated with elevated s-BAFF in autoantibody-positive pSS (n = 85; 88% females; P = 0.008). The shared -871 T allele had no independent contribution to disease susceptibility or s-BAFF. CONCLUSIONS: Disease susceptibility for Ro/La-positive pSS is increased with the CTAT haplotype, but not associated with high s-BAFF levels. Elevated s-BAFF levels in pSS are associated with the TTTT haplotype and may be a secondary phenomenon in Ro/La-positive pSS. While both haplotypes carry the -871 T allele, this allele is not independently associated with disease susceptibility.
17467215 Studies on the relationship between electrogustometry and sour taste perception. 2007 Dec OBJECTIVE: Electrogustometry is used as a measurement of taste perception. The prevailing theory is that the anodal current delivered to the tongue mucosa stimulates the sour taste receptors, but this is not universally accepted. Our aim was to evaluate to what extent electrogustometry relates to an ability to detect sour taste--rather than sweet, salt, or bitter. METHODS: We compared automated electrogustometric thresholds with visual analogue scale (VAS) ratings of various tastant solutions in 114 subjects. The whole mouth, and each side of the tongue were tested separately. VAS scores from the strongest set of solutions, and the lowest electrogustometry thresholds for each location were used for statistics. RESULTS: There was a significant correlation between electrogustometry threshold and the whole mouth perception of the salt taste solution. Electrogustometry correlated significantly but weakly for all taste qualities when testing was confined to left and right oral tongue. The positive predictive values of electrogustometry were no better in relation to sour taste perception than to the other taste qualities. CONCLUSIONS: Our results do not support the theory that electrogustometry is mediated by sour taste receptors or even that it reflects the sour taste quality. We postulate that electrogustometry measures a function of taste perception, which is different from that induced by chemical stimuli.
16950808 Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients wit 2007 Mar OBJECTIVE: To investigate the safety and efficacy of rituximab (RTX) for systemic symptoms in patients with primary Sjögren's syndrome (pSS), and changes in B cell biomarkers. PATIENTS AND METHODS: The records of 16 patients with pSS according to the American European consensus group criteria were reviewed retrospectively. RESULTS: Patients, all women, had a median age of 58.5 (range 41-71) years and a disease duration of 9.5 (range 0-25) years. RTX was prescribed for lymphoma (n = 5), refractory pulmonary disease with polysynovitis (n = 2), severe polysynovitis (n = 2), mixed cryoglobulinaemia (n = 5), thrombocytopenia (n = 1) and mononeuritis multiplex (n = 1). The median follow-up duration was 14.5 (range 2-48) months. Three patients experienced adverse events, including one mild serum sickness-like reaction with the presence of human antichimeric antibodies. Efficacy of treatment was observed in 4 of 5 patients with lymphomas and in 9 of 11 patients with systemic involvement. Dryness was improved in only a minority of patients. Corticosteroid dose was reduced in 11 patients. RTX induced decreased rheumatoid factor, gamma-globulin and beta2-microglobulin levels, and the level of B cell activating factor of the tumour necrosis factor family (BAFF) increased concomitantly with B cell depletion. Five patients were re-treated, with good efficacy and tolerance, except for one with probable serum sickness-like reaction. CONCLUSION: This study shows good efficacy and fair tolerance of RTX for systemic features. In addition, RTX allows for a marked reduction in corticosteroid use. Except for BAFF, the level of which increases, serum B cell biomarker levels decrease after taking RTX. Controlled trials should be performed to confirm the efficacy of RTX in pSS.
18067817 [Immunopathology of labial glands of patients with primary Sjögren's syndrome]. 2007 Sep 18 OBJECTIVE: To investigate the expression of CD4+CD25+ regulatory T cell (Treg) in labial gland (SG) of the patients with Sjögren's syndrome (SS). METHODS: Specimens of labial gland were obtained from 25 primary SS patients and 6 healthy controls during biopsy to be made into serial sections. Immunohistochemistry was used to examine the expression of CD25, CD4, CD8, CD68 and Foxp3. RESULTS: Infiltration of a great amount of mononuclear cells and atrophy of part of the labial glands were seen in the specimens from SS patients. The percentage of CD4+ T cells in the infiltrating leucocytes of the SS patients was (44.2 +/- 20.5)%, significantly higher than that of the controls [(9.2 +/- 6.0)%, P < 0.01]. CD25 and Foxp3 were completely absent in the specimens from both the controls and SS patients. CONCLUSION: CD4+CD25+ regulatory T cell lacks in the labial gland of SS patients. CD4+CD25+ regulatory T cells play a key role in the progression of SS.
17127453 Role of B cells in Sjögren's syndrome--from benign lymphoproliferation to overt malignanc 2007 Jan 1 The classical view of B cell biology is that these cells respond to foreign and self antigens and in this way promote protection, primarily by production of antibodies. However, recent studies suggest that B cells have diverse functions within the immune system other than antibody production, which could contribute to autoimmunity. This involves organization of lymphoid tissue, regulation of dendritic cells, antigen presentation, activation of T cells and production of cytokines. Both abnormalities in the distribution of B cell subsets, and recent discovery of clinical benefit after B cell depletion highlight the pivotal role of B cells in autoimmunity. This change in view of the role of B cells will be exemplified in one autoimmune disease namely Sjögren's syndrome.
17075843 Involvement of specific laminins and nidogens in the active remodeling of the basal lamina 2006 Nov OBJECTIVE: To investigate remodeling of the basal lamina of labial salivary glands (LSGs) from patients with Sjögren's syndrome (SS) by analyzing the expression of specific components that participate in its assembly and attachment to acinar and ductal cells. METHODS: Two groups of SS patients with similar levels of remnant glandular tissue but with low and high levels of interacinar fibrosis, respectively, were studied. The expression of laminin alpha1, alpha4, and gamma2 chains and nidogens was examined at the messenger RNA (mRNA) and protein levels. Nidogens 1 and 2 were also studied in situ by immunohistochemistry. RESULTS: Increases in the amount of mRNA and protein for both the processed and unprocessed laminin gamma2-chain were more pronounced in patients with low interacinar fibrosis. Increases in the protein levels of laminin alpha1 and alpha4 chains were observed in patients with low interacinar fibrosis, but not in those with high interacinar fibrosis. Nidogen mRNA and protein levels were similar in SS patients and controls. Interestingly, high levels of nidogen degradation were observed in patients with low interacinar fibrosis. Nidogens were readily detected by immunofluorescence in the basal lamina of the capillaries and stroma in SS patients, but were less apparent in the basal lamina of the acini and ducts. CONCLUSION: These results suggest that the basal lamina of LSGs from patients with SS is undergoing active remodeling, such that alterations are less evident in patients who have advanced morphologic signs of the disease (high interacinar fibrosis). Nidogen proteolysis might account for the disorganization of the basal lamina that is typically observed in LSGs from SS patients, assuming that cleavage impairs their ability to crosslink type IV collagen and laminin networks.
16456020 Epithelial CXCR3-B regulates chemokines bioavailability in normal, but not in Sjogren's sy 2006 Feb 15 Expression of CXCR3-targeting chemokines have been demonstrated in several diseases, suggesting a critical role for CXCR3 in recruiting activated T cells to sites of immune-mediated inflammation. Sjögren's syndrome (SS) is an autoimmune disease characterized by a mononuclear cell infiltrate of activated T cells around the duct in the salivary gland. Analysis of minor salivary gland biopsy specimens from 20 healthy subjects and 18 patients with primary SS demonstrated that CXCR3, in particular, the B form of this receptor, is constitutively expressed by human salivary gland epithelial cells. Salivary gland epithelial cell cultures demonstrated that CXCR3 participate in removing relevant amount of agonists from the supernatant of exposed cells without mediating calcium flux or chemotaxis while retaining the ability to undergo internalization. Although in normal salivary gland epithelial cells, CXCR3 behaves as a chemokine-scavenging receptor, its role in SS cells is functionally impaired. The impairment of this scavenging function might favor chemotaxis, leading to heightened immigration of CXCR3-positive T lymphocytes. These findings suggest that epithelial CXCR3 may be involved in postsecretion regulation of chemokine bioavailability. They also support a critical role for CXCR3 in the pathogenesis of SS and identify its agonists as potential therapeutic targets.
16453388 Phosphorylated and nonphosphorylated epitopes of the La/SSB autoantigen: comparison of the 2006 La/SSB phosphoprotein is the target antigen of autoantibodies in sera of patients with Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). Among other structural and function motifs, four phosphorylation sites are encompassed in the primary sequence of La/SSB. Two of them (Thr-362 and Ser-366) are located within GSGKGKVQFQGKKTKFASDD (346-368) and one (Thr-302) within VTWEVLEGEVEKEALKKI (301-318), which are main B-cell epitopes of La/SSB. With the aim to investigate how phosphorylation, one of the most common posttranslational protein modifications, affects the antigenic and conformational characteristics of the La/SSB epitopes, we synthesized and studied the phosphorylated epitopes La/SSB(346-368)-P, La/SSB(359-368)-P, and La/SSB(301-318)-P with respect to their nonphosphorylated counterparts. Anti-La/SSB positive sera from SS and SLE patients are better recognized by the phosphorylated epitopes compared to their nonphosphorylated counterparts. Conformational analysis by (1)H nuclear magnetic resonance spectroscopy and molecular dynamics showed that the phosphorylated epitopes adopt different structural characteristics from those of the corresponding nonphosphorylated epitopes. It is concluded that phosphorylation can create neoepitopes with altered functions, compared to the nonphosphorylated epitopes, which might be seen from the immune system as "foreign."