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ID PMID Title PublicationDate abstract
17192572 Local amplification of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 and i 2006 Nov Glucocorticoids are widely used to treat chronic inflammatory conditions including rheumatoid arthritis. They promote mechanisms important for normal resolution of inflammation, notably macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) amplifies intracellular levels of glucocorticoids by oxoreduction of intrinsically inert cortisone (in humans, 11-dehydrocorticosterone in mice) into active cortisol (corticosterone in mice) within cells expressing the enzyme. Recently, we have shown in a mouse model of acute inflammation, high expression of 11beta-HSD oxoreductase but not dehydrogenase activity in cells elicited rapidly in the peritoneum by a single thioglycollate injection. 11beta-HSD oxoreductase activity remained high in peritoneal cells until the inflammation resolved. In vitro, the 11beta-HSD1 substrate, 11-dehydrocorticosterone, increased macrophage phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11beta-HSD1: these cells solely expressed the type 1 11beta-HSD isozyme (not 11beta-HSD2), and carbenoxolone, an 11beta-HSD inhibitor, prevented the increase in phagocytosis elicited by 11-dehydrocorticosterone. Macrophages from 11beta-HSD1-deficient mice failed to respond to 11-dehydrocorticosterone. In vivo, 11beta-HSD1-deficient mice showed a delay in acquisition of macrophage phagocytic competence and had an increased number of free apoptotic neutrophils during sterile peritonitis. Importantly, in preliminary experiments, 11beta-HSD1-deficient mice exhibited delayed resolution of inflammation in experimental arthritis. These findings suggest 11beta-HSD1 may be a component of mechanisms engaged early during the inflammatory response that promote its subsequent resolution.
16888149 VIP-PACAP system in immunity: new insights for multitarget therapy. 2006 Jul Our research about VIP/PACAP and the immune system goes back to 1990 when our group described the expression of VIP on lymphocytes for the first time. Since this year, using three models of disease, septic shock, rheumathoid arthritis, and Crohn's disease, we are trying to contribute with new pieces to the puzzle of immunity to approach the use of VIP/PACAP system as a therapeutic agent. In 1999 we established that the first step in the beneficial effect of the VIP/PACAP system exerts consists in its potent anti-inflammatory action. Thus, VIP and PACAP inhibit the expression and release of proinflammatory cytokines and chemokines, and enhance the production of the anti-inflammatory factors. These effects were reported both in vitro and in vivo, are mediated by the presence of PAC1, VPAC1, and VPAC2 receptors, in the three models of diseases used. The next step was that the system favors Th2 responses versus Th1 contributing to the remission of illness as rheumatoid arthritis or Crohn's disease by blocking the autoimmune component of these diseases. Because it appears that inflammatory processes requires more than blockade of a single mediator, new therapies blocking several components of both the infection- and the autoimmunity-induced inflammation cascades should be an interesting focus of attention. In this sense, at present we are trying to dissect new aspects of the potential therapeutic of the VIP/PACAP system in the control of CC and CXC chemokine and their receptors, coagulation factors, adhesion molecules, acute phase proteins, and osteoclastogenesis mediators as well as in the modulation of the expression of Toll-like receptors. Our more recent data open a hopeful door for the therapeutic use of VIP/PACAP in humans.
16009562 Influence of bisphosphonates on the production of pro-inflammatory cytokines by activated 2005 Aug 21 Bisphosphonates have anti-inflammatory effects in rheumatoid arthritis and chondroprotective effects in animal arthritis models but their influence on chondrocytes is not known. The aim of this study is to investigate whether bisphosphonates could influence the production of pro-inflammatory cytokines by activated chondrocytes. Therefore human articular cartilage explants were incubated at 48 h with clodronate, pamidronate or risedronate (10(-6) and 10(-8)mol/L), and dexamethasone (10(-8)mol/L). Subsequently, cultures were stimulated with IL-1, 10 ng/mL (n=6) or 1 ng/mL (n=10) for 48 h. Co-incubation was performed with or without bisphosphonates or dexamethasone. A flow cytometric microsphere-based immunoassay was used for the detection of the pro-inflammatory cytokines IL-6, IL-8, TNF-alpha, IL-1 and the regulatory cytokines IL-12p70 and IL-10 in the supernatants. Stimulation with IL-1 resulted in a dose dependent induction of IL-6 and IL-8, but no production of the other cytokines could be demonstrated. This production of IL-6 and IL-8 was neither inhibited nor enhanced by bisphosphonates. Only dexamethasone caused an inhibition of IL-6 production. In conclusion, there is no evidence on the level of articular cartilage cells that bisphosphonates would suppress or enhance IL-6 and IL-8 mediated joint destruction.
16820986 Minimally invasive implantation of a unicondylar knee system. 2006 Jun OBJECTIVE: Unicondylar medial surface replacement of the knee joint by arthrotomy with short incision and in bone-sparing resection technique. INDICATIONS: Unicompartmental medial arthritis of the joint knee. Unilateral osteonecrosis. Posttraumatic unicompartmental gonarthrosis. CONTRAINDICATIONS: Pangonarthrosis. Rheumatoid arthritis. Knee joint instability. Status following osteotomy of the tibial head. SURGICAL TECHNIQUE: The patient should be placed in the supine position with the knee joint uncovered and freely mobile. Short anteromedial skin incision and arthrotomy. Bone-sparing resection at the tibia and femur. Axial malalignment (varus deformity) is not completely corrected. The implants are centered perpendicular to one another. POSTOPERATIVE MANAGEMENT: Early functional postoperative management adapted to the symptoms with pain therapy, local application of ice, passive mobilization on an electric exercise splint and physiotherapy. Full weight bearing is usually possible from the 2nd postoperative day. RESULTS: 28 Accuris unicondylar knee systems were implanted medially in 26 patients (14 women, twelve men) in minimally invasive technique from March 2003 to July 2004. One patient was not included in the evaluation because the operation was changed to a bicondylar surface replacement due to a deep-seated infection. The patients' average age at the time of the operation was 73.8 years. On average, the operation scar was 8.2 cm long. The average quantity of secretion in the Redon drain was 155 ml. The hemoglobin value fell from 13.3 to 12.3 g/dl. The total HSS (Hospital for Special Surgery) Score increased significantly from 55.5 (34-75) to 87.4 (71-95) points. In the follow-up examination, 21 unicondylar knee systems (77.8%) were evaluated as excellent and six (22.2%) as good.
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.
16088129 Role of magnetic resonance imaging in the clinical diagnosis of the temporomandibular join 2005 Temporomandibular joint (TMJ) abnormalities cannot be reliably assessed by a clinical examination. Magnetic resonance imaging (MRI) may depict joint abnormalities not seen with any other imaging method and thus is the best method to make a diagnostic assessment of the TMJ status. In patients with temporomandibular joint disorder (TMD) referred for diagnostic imaging the predominant TMJ finding is internal derangement related to disc displacement. This finding is significantly more frequent than in asymptomatic volunteers, and occurs in up to 80% of patients consecutively referred for TMJ imaging. Moreover, certain types of disc displacement seem to occur almost exclusively in TMD patients, namely complete disc displacements that do not reduce on mouth opening. Other intra-articular abnormalities may additionally be associated with the disc displacement, predominantly joint effusion (which means more fluid than seen in any asymptomatic volunteer) and mandibular condyle marrow abnormalities (which are not seen in volunteers). These conditions seem to be closely related. Nearly 15% of TMD patients consecutively referred for TMJ MRI will have joint effusion, of whom about 30% will show bone marrow abnormalities. In a surgically selected material of joints with histologically documented bone marrow abnormalities nearly 40% showed joint effusion. Disc displacement is mostly bilateral, but joint effusion seems to be unilateral or with a lesser amount of fluid in the contralateral joint. Abnormal bone marrow is also mostly unilateral. Many patients have unilateral pain or more pain on one side. In a regression analysis the self-reported in-patient TMJ pain side difference was positively dependent on TMJ effusion and condyle marrow abnormalities, but negatively dependent on cortical bone abnormalities. Of the joints with effusion only one fourth showed osteoarthritis. Thus, there seems to be a subgroup of TMD patients showing more severe intra-articular pathology than disc displacement alone, and mostly without osteoarthritis. It should, however, be emphasized that patients with TMJ effusion and/or abnormal bone marrow in the mandibular condyle seem to constitute only a minor portion (less than one fourth) of consecutive TMD patients referred for diagnostic TMJ imaging. The majority of patients have internal derangement related to disc displacement, but without accompanying joint abnormalities. In patients with rheumatoid arthritis and other arthritides TMJ involvement may mimick the more common TMDs. Using MRI it is possible, in most cases, to distinguish these patients from those without synovial proliferation.
15812675 [Blocking adhesion molecules with natalizumab in multiple sclerosis]. 2005 Aug Natalizumab is a humanized, monoclonal antibody, that inhibits adhesion molecules (alpha(4)-integrins) on the surface of immune cells. These adhesion molecules are important for binding of lymphocytes to endothelial cells of blood vessels and infiltration of inflammatory cells into tissues. Natalizumab is currently being tested in large clinical trials for the treatment of multiple sclerosis (MS) and other autoimmune diseases (inflammatory bowel diseases, rheumatoid arthritis). After demonstrating the safety and potential effectiveness of natalizumab in MS therapy during shorter treatment periods (
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.
16082627 Comparison of disease progression and mortality of connective tissue disease-related inter 2005 Aug 15 OBJECTIVE: To compare disease progression and mortality between idiopathic interstitial pneumonia (IIP) and interstitial lung disease (ILD) due to connective tissue diseases (CTD) including scleroderma, rheumatoid arthritis, systemic lupus, polymyositis, dermatomyositis, Sjögren's syndrome, and mixed CTD. METHODS: A case-control study of patients with CTD-ILD (n = 46) and IIP controls (n = 51), seen at the University of Michigan between July 1,1998 and June 30,1999 and followed until March 30, 2002, was conducted. Survival analysis and Cox regression were performed to estimate survival, accounting for demographic and clinical parameters, including pulmonary function tests and high resolution computed tomography (HRCT) diagnosis and scoring. RESULTS: Median followup time was 4.4 person-years. Five-year survival in the IIP group was 51.9% (95% confidence interval [95% CI] 30.8-69.4) versus 43.4% (95% CI 21.1-63.9) in the CTD-ILD group. There were no significant differences among HRCT diagnostic categories between IIP and CTD-ILD. A fibrotic score > or = 2 was associated with decreased survival among the entire group. Age at diagnosis and most recent forced vital capacity were significant predictors of mortality when adjusted for IIP versus CTD-ILD diagnosis, sex, and interstitial score. CONCLUSION: Contrary to expectation, CTD-ILD compared with IIP appears to be associated with a worse prognosis when adjusted for age. A higher fibrotic score is suggestive of decreased survival.
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.
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.
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.
15744117 [Molecular mechanisms of salivary gland destruction in patients with Sjogren's syndrome. ] 2005 Feb IFNgamma plays an important role to induce several functional molecules on salivary epithelial cells, including class II MHC, Fas and CD40 in salivary glands from patients with Sjogren's syndrome (SS). IFNgamma also contributes to the development of lymphocytic infiltrates by inducing T cell attracting chemokines in SS salivary epithelial cells, such as IP-10 (CXCL10), Mig (CXCL9), and I-TAC (CXCL11). IFNgamma dysregulation in SS salivary gland may attribute to the decreased production of TGFbeta from salivary epithelial cells in some patients. Expression of Fas and CD40 was significantly higher in SS salivary epithelial cells than in normal cells after IFNgamma stimulation. Although neither anti-Fas (CH11) nor anti-CD40 mAb alone could induce typical apoptosis, the two together and preincubation with IFNgamma efficiently induced apoptosis in SS salivary epithelial cells. This apoptosis was almost completely blocked by neutralizing anti-Fas mAb (ZB4). c-FLIP, an important inhibitory molecule in the Fas death pathway, was strongly expressed in SS salivary epithelial cells, but its expression was downregulated, at the protein level, by anti-CD40 mAb. CD40 signals promote Fas-dependent death of SS salivary epithelial cells by downregulating c-FLIP expression. The presence of c-FLIP in these cells may explain their resistance to undergo apoptosis in response to either anti-Fas or anti-CD40 mAb, despite their surface expression of both proteins. These findings suggest that SS salivary epithelial cell death requires the cooperation of Fas and CD40.
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."
16396711 Angioimmunoblastic T-cell lymphoma: a relatively common type of T-cell lymphoma in Sjögre 2005 Nov An increased risk of developing lymphoma has been indicated in Sjögren's syndrome (SS), and the lymphomas in SS are usually B-cell type in origin. Interestingly, despite the rather low frequency of T-cell lymphoma in SS, angioimmunoblastic T-cell lymphoma (AILD) constitute the majority of T-cell lymphomas associated with SS. To the best of our knowledge, including our case, at least 11 out of 23 (48%) cases of T-cell lymphoma reported in association with SS, were AILD. The fact that the development of B-cell lymphoma in SS is much more frequent than that of T-cell lymphoma, might be explained by differences in the situation between B and T cells, although the exact mechanism still remains uncertain.
16344495 Immunological consequences of thalidomide treatment in Sjögren's syndrome. 2006 Jan OBJECTIVE: To study the immunological consequences of systemic thalidomide treatment in patients with Sjögren's syndrome. METHODS: Cytokine (tumour necrosis factor alpha (TNFalpha), interleukin (IL) 6) and soluble receptor (sIL2R) levels were measured in patient and control plasma (n = 7), before and after thalidomide treatment. Peripheral blood mononuclear cells were examined by FACS analysis for potential changes in specific cell populations (T cells, B cells, monocytes), and for the expression of activation markers (CD25, HLA-DR), costimulatory molecules (CD40, CD40L), TNF receptors, chemokine receptors, and adhesion molecules (L-selectin (L-sel)). RESULTS: Owing to adverse effects of thalidomide, the treatment interval was limited. None the less, statistically significant changes in markers of cell activation were recorded in the four treated patients. Before treatment, HLA-DR, TNFRI, CXCRI, and CXCRII were raised in the patients compared with healthy controls (p<0.05) and their expression was down regulated after treatment. B cell numbers and expression of the adhesion molecule L-sel also declined with thalidomide. CONCLUSION: Significant changes in measures of cell activation were detected during thalidomide treatment within this limited study, which upon further investigation may offer insight into the underlying immunoregulatory pathways of thalidomide.
16368978 Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pyl 2006 Jan Besides various gastroduodenal diseases, Helicobacter pylori infection may be involved in autoimmune disorders like rheumatoid arthritis (RA) or idiopathic thrombocytopenic purpura. Such autoimmune disorders are often associated with autoreactive antibodies produced by B-1 cells, a subpopulation of B lymphocytes. These B-1 cells are mainly located in the pleural cavity or mucosal compartment. The existence of H. pylori urease-specific immunoglobulin A (IgA)-producing B cells in the mucosal compartment and of their specific IgM in the sera of acutely infected volunteers suggests the possibility that urease stimulates mucosal innate immune responses. Here, we show for the first time that purified H. pylori urease predominantly stimulates the B-1-cell population rather than B-2 cells, which produce antigen-specific conventional antibodies among splenic B220(+) B cells. The fact that such stimulation of B-1 cells was not affected by the addition of polymyxin B indicates that the effect of purified H. pylori urease was not due to the contamination with bacterial lipopolysaccharide. Furthermore, the production of various B-1-cell-related autoreactive antibodies such as IgM-type rheumatoid factor, anti-single-stranded DNA antibody, and anti-phosphatidyl choline antibody was observed when the splenic B cells were stimulated with purified H. pylori urease in vitro. These findings suggest that H. pylori components, urease in particular, may be among the environmental triggers that initiate various autoimmune diseases via producing autoreactive antibodies through the activation of B-1 cells. The findings shown here offer important new insights into the pathogenesis of autoimmune disorders related to H. pylori infection.
15855185 Rheumatological manifestations of hepatitis C: incidence in a rheumatology and non-rheumat 2005 Aug OBJECTIVES: To evaluate hepatitis C virus (HCV)-positive patients followed in a rheumatology department and to compare them with a similar population of HCV-positive patients who had never seen a rheumatologist, in order to describe the rheumatological symptoms present and the effects of methotrexate and interferon-alpha therapy. METHODS: We performed a retrospective study of clinical, radiological and biological data on 21 rheumatology patients (Group I) presenting symptoms consistent with a chronic inflammatory arthritis with a known HCV infection and compared them with 41 members of an HCV support association (Group II). RESULTS: Symptoms of myalgia, sicca syndrome, Raynaud's phenomenon or paraesthesias were similarly frequent in the two groups. However, inflammatory joint pain and joint swelling were more common in Group I. In this group rheumatoid factor was positive in 48%, antinuclear antibodies in 26%, cryoglobulin in 44% and a reduced complement level in 63%. The majority of patients from Group I treated with methotrexate demonstrated an amelioration of the rheumatological symptoms with few negative outcomes. Regarding interferon-alpha therapy and rheumatological symptoms-in Groups I and II respectively 50 and 66% demonstrated a deterioration, 33 and 30% showed no change and 17 and 4% showed an amelioration. CONCLUSION: Rheumatological symptoms are common in patients chronically infected with HCV. It is essential to individualize the role of treatment with interferon-alpha and to consider the use of methotrexate for difficult cases.
18393777 Recent clinical trials of cladribine in hematological malignancies and autoimmune disorder 2006 Jan The purine nucleoside analog - cladribine (2-chlorodeoxyadenosine, 2-CdA) is a cytotoxic agent with high activity in lymphoid and myeloid malignancies. It is also an effective drug in some autoimmune disorders. 2-CdA is usually administered intravenously in continuous or 2-hour infusion. Recently however, new formulation of this agent has been developed for subcutaneous and oral administration. 2-CdA is widely established as first line standard treatment for hairy cell leukemia. Moreover several clinical trials have demonstrated that this agent, used alone or in combination with other cytotoxic drugs, showed good efficacy and acceptable toxicity profile in the treatment of chronic lymphocytic leukemia, Waldenström macroglobulinemia, low-grade non-Hodgkin's lymphoma and acute myeloid leukemia. Moreover, some studies indicate that 2-CdA has some activity in progressive multiple sclerosis and other autoimmune disorders including autoimmune hemolytic anemia, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and in patients with refractory factor VIII inhibitors. This review article will summarize the results of recent clinical trials with 2-CdA in hematological malignancies, multiple sclerosis and other autoimmune diseases.