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ID PMID Title PublicationDate abstract
17259401 PTPN22 R620W functional variant in type 1 diabetes and autoimmunity related traits. 2007 Feb The PTPN22 gene, encoding the lymphoid-specific protein tyrosine phosphatase, a negative regulator in the T-cell activation and development, has been associated with the susceptibility to several autoimmune diseases, including type 1 diabetes. Based on combined case-control and family-based association studies, we replicated the finding of an association of the PTPN22 C1858T (R620W) functional variant with type 1 diabetes, which was independent from the susceptibility status at the insulin gene and at HLA-DR (DR3/4 compared with others). The risk contributed by the 1858T allele was increased in patients with a family history of other autoimmune diseases, further supporting a general role for this variant on autoimmunity. In addition, we found evidence for an association of 1858T allele with the presence of GAD autoantibodies (GADA), which was restricted to patients with long disease duration (>10 years, P < 0.001). This may help define a subgroup of patients with long-term persistence of GADA. The risk conferred by 1858T allele on GAD positivity was additive, and our meta-analysis also supported an additive rather than dominant effect of this variant on type 1 diabetes, similar to previous reports on rheumatoid arthritis and systemic lupus erythematosus.
17196469 Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomiz 2007 Jan 1 Some nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 selective inhibitors, have been associated with increased cardiovascular (CV) events in recent clinical trials or observational studies. To determine whether the cyclooxygenase-2 selective inhibitor celecoxib affects CV risk, the incidence of CV events was analyzed in patients treated with celecoxib, placebo, or nonselective NSAIDs in the clinical trial database for celecoxib using defined Antiplatelet Trialists' Collaboration end points of nonfatal myocardial infarction, nonfatal stroke, and CV death. Patient data were derived from studies in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, low back pain, and Alzheimer's disease. This meta-analysis included (1) 7,462 patients exposed to celecoxib 200 to 800 mg/day for 1,268 patient-years compared with 4,057 patients treated with placebo for 585 patient-years, and (2) 19,773 patients treated with celecoxib 200 to 800 mg/day for 5,651 patient-years compared with 13,990 patients treated with nonselective NSAIDs (diclofenac, ibuprofen, naproxen, ketoprofen, and loxoprofen) for 4,386 patient-years. CV events were adjudicated by a 3-member expert end point committee (WBW, JSB, PBG) blinded to treatment group and study. The incidence rates of the combined CV events were not significantly different between patients treated with celecoxib and placebo or between those treated with celecoxib and nonselective NSAIDs. Event rates were similar for adjudicated and nonadjudicated data. Dose of celecoxib, the use of aspirin, or the presence of CV risk factors did not alter these results. In conclusion, these analyses failed to demonstrate an increased CV risk with celecoxib relative to placebo and demonstrated a comparable rate of CV events with celecoxib treatment compared with nonselective NSAIDs.
16927021 Low dose leflunomide activates PI3K/Akt signalling in erythroleukemia cells and reduces ap 2006 Oct Rheumatoid arthritis (RA) is characterized by persistent joint synovial tissue inflammation. Leflunomide is an immunomodulatory agent that has been approved for treatment of active RA. In the past few years, uses other than RA treatment have appeared. Leflunomide has been reported to show antitumor potential through inhibition of cancer cell proliferation. We thus tested the antiproliferative potential of leflunomide on HEL and K562 erythroleukemia cells. The findings summarized in this report demonstrate for the first time that low dose leflunomide prolonged survival and reduced apoptosis induced by several anticancer agents in erythroleukemia cells. We showed that in treated cells, leflunomide reduced the signalling pathways involved in promoting apoptosis by reducing p38 MAPK and JNK basal activity. On the other hand, leflunomide transiently activated the ERK signalling pathway and induced a sustained activation of Akt. We also showed that leflunomide reduced caspase-3 activity and DNA fragmentation induced by anticancer agents. By using an inhibitory strategy, we showed that inhibition of Akt activation but not ERK abolished the protective effect of leflunomide. Thus our findings suggested that leflunomide reduced apoptosis induced by anticancer agents through PI3K/Akt signalling activation.
16786167 Expression pattern of matrix metalloproteinase and TIMP genes in fibroblasts derived from 2006 Jul Matrix-degrading proteases play a key role in normal development, wound healing, many diseases such as rheumatoid arthritis and, in particular, tumour invasion. In invasive tumours, these enzymes are expressed by fibroblasts of the tumour stroma. Their expression and activity are tightly regulated at several levels, an important one being transcription. Previous in vitro and in vivo findings pointed to a major role of the Ets-1 transcription factor for this level of regulation. In the present study, we tried to prove this role in fibroblasts. We stimulated wild-type mouse fibroblasts with physiological doses of basic fibroblast growth factor (bFGF, known to induce different proteases and expressed by tumour cells) and compared the results to those obtained in Ets-1 -/- fibroblasts derived from Ets-1 knock-out mice. We found that basal Ets-1 levels are necessary not only for a fast induction of MMPs 2, 3 and 13 by bFGF but also for maintenance of the bFGF-induced expression of tissue inhibitors of metalloproteinases (TIMPs) 1, 2 and 3, which are known not only to inhibit but also participate as activators of certain pro-MMPs.
16638798 Decreased CD161+CD8+ T cells in the peripheral blood of patients suffering from rheumatic 2006 Dec OBJECTIVES: Although it has been reported that the numbers of both CD4(-)CD8(-) and CD4(+) natural killer T (NKT) cells are selectively decreased in the peripheral blood of patients with rheumatic diseases, there have been no reports concerning a novel subpopulation of CD8(+) NKT cells. To examine whether CD161(+)CD8(+) T cells, which are closely related to CD8(+) NKT cells, are also decreased in patients with rheumatic diseases, we have investigated the expression of CD161, together with that of CD28, CD25 and CD62L, on T cells in the peripheral blood of these patients. METHODS: The rheumatic diseases evaluated in this study were systemic lupus erythematosus (SLE) (n= 54), mixed connective-tissue disease (MCTD) (n= 15), systemic sclerosis (SSc) (n= 14), polymyositis/dermatomyositis (PM/DM) (n= 13) and rheumatoid arthritis (RA) (n= 24). Healthy donors were examined as controls (n= 18). The expression of CD161, CD28, CD25 and CD62L on T cells was analysed by flow cytometry. RESULTS: Both the frequency of CD161 expression on CD8(+) cells and the absolute number of CD161(+)CD8(+) cells were significantly decreased in patients with SLE, MCTD, SSc and PM/DM. Only the absolute number of CD161(+)CD8(+) T cells was significantly decreased in RA. CD161 expression on CD28(-)CD8(+) T cells was significantly decreased in SLE, MCTD and SSc. The absolute number of CD161(+)CD8(+)CD62L(-) T cells was significantly decreased in SLE, MCTD and SSc. CONCLUSIONS: Both the frequency and the absolute number of CD161(+)CD8(+) T cells were decreased in the peripheral blood of patients suffering from SLE, MCTD, SSc and PM/DM. This result suggests that there is also an abnormality of NKT cells in the CD8(+) population.
16624877 Differential induction of BLT receptor expression on human endothelial cells by lipopolysa 2006 May 2 Leukotriene (LT) B4 is a powerful chemotactic and immune modulating agent that signals via two receptors denoted BLT1 and BLT2. Here we report that BLT1 and BLT2 are expressed at low levels in an apparently silent state in human umbilical vein endothelial cells (HUVEC). However, treatment with LPS leads to a >10 fold increase in the levels of BLT1 mRNA without any significant effects on BLT2 mRNA. In parallel, LPS also increases the amounts of BLT1 protein. Tumor necrosis factor-alpha (TNF-alpha) increases the expression of BLT2 mRNA approximately 6 times above basal levels with only a modest increase in BLT1 mRNA. Interleukin-1beta causes variable and parallel increases of both BLT1 and BLT2 mRNA. The natural ligand LTB4 also increases BLT1, but not BLT2, mRNA and protein expression. Along with the induction of BLT1 and/or BLT2, HUVEC acquire the capacity to respond to LTB4 with increased levels of intracellular calcium and these signals can be blocked by isotype selective BLT antagonists, CP-105696 and LY-255283. In addition, treatment of HUVEC with LTB4 causes increased release of both nitrite, presumably reflecting nitric oxide (NO), and monocyte chemoattractant protein-1. Our data indicate that expression of functional BLT receptors may occur at the surface of endothelial cells in response to LPS, cytokines, and ligand, which in turn may have functional consequences during the early vascular responses to inflammation. Moreover, the results point to BLT receptors as potential targets for pharmacological intervention in LT-dependent inflammatory diseases such as asthma, rheumatoid arthritis, and arteriosclerosis.
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.
18630557 [Prevention and treatment of leg length discrepancy after total hip arthroplasty]. 2008 Jun OBJECTIVE: To explore the prevention and treatment of leg length discrepancy after total hip arthroplasty (THA). METHODS: There were 87 patients who were treated by THA from January 2004 to December 2006, including 36 males and 51 females, with the average age of 60.2 years (ranging from 35 years to 78 years). Among these cases, there were 35 of avascular necrosis of the femoral head, 38 of subcapital femoral neck fracture, 4 of femoral neck tumor, 6 of rheumatoid arthritis and 4 of acetabular dysplasia. In 70 cases, the patients had leg length discrepancy, and the legs shortened from 1 cm to 6 cm. Based on the clinical measurement and radiographic examination, the surgical protocols were designed, the type of the hip prosthesis was chosen, and the neck length of the femoral prosthesis and the position of osteotomy were estimated. By the proper wearing of the acetabula, the best rotation point was found out. The cut plane of the femoral neck was adjusted according to the results of the radiographic and other examinations. The neck length was readjusted after the insertion of the prosthesis so as to achieve intended leg-length equalization. The discrepancy of the leg length was measured and evaluated after operation. RESULTS: Superficial infestation happened in 2 cases 5 days after the operation and was cured by mero-drainage. Luxation happened in 4 cases 4 weeks after the operation, in which 2 cases were cured by operation while the other 2 were cured by manual reduction. All the patients were followed up for 6 months to 36 months, with the average time of 18.3 months. The Harris scores were 34.81 +/- 1.36 preoperatively and 91.50 +/- 1.87 postoperatively (P < 0.05). In the 17 patients with equal legs before the operation, 1 was lengthened 1.5 cm in the leg, while in the 70 patients with shortened legs before the operation, 66 returned to the same length in their legs, and 4 were lengthened or shortened from 1.6 cm to 2.1 cm. The total rate of equal leg length was 94.25%. CONCLUSION: The preoperative measurement, radiographic templating and intraoperative correction, together with postoperative orthopraxy, are effective in prevention and treatment of leg length discrepancy after THA.
20641723 (111)In-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-{Glu-[cyclo(Arg-Gly-Asp-D 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the development of (111)In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-{Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)](2)}(2) ((111)In-DOTA-E-{E-[c(RGDfK)](2)}(2)) for imaging α(v)β(3) receptors in nude mice bearing ovarian carcinoma tumors.
20641712 (99m)Tc(CO)(3)-Bipyridine-cyclo-(Arg-Gly-Asp-D-Tyr-Lys). 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell-cell and cell-matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents and the agonists as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (IC(50), 7-40 nM) but not to α(v)β(5) (IC(50), 600-4,000 nM) or α(IIb)β(3) (IC(50), 700-5,000 nM) integrins. Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). The ready availability and low cost of (99m)Tc led to the development of (99m)Tc-RGD peptides for targeting α(v)β(3) integrins in tumor angiogenesis. (99m)Tc(CO)(3)-Bipyridine-cyclo-(Arg-Gly-Asp-D-Tyr-Lys) ((99m)Tc(CO)(3)-BPy-c(RGDyK)) has been prepared as a single-photon emission computed tomography (SPECT) tracer for imaging α(v)β(3) integrins in tumor (13).
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.
17634901 EGF activates PI3K-Akt and NF-kappaB via distinct pathways in salivary epithelial cells in 2007 Dec Epidermal growth factor (EGF) exerts tropic effects on salivary epithelial cells. We examined EGF-mediated signaling pathways in the salivary epithelial cells of patients with Sjögren's syndrome (SS). We compared the immunohistochemical expression of EGF receptor (EGF-R), phosphatidylinositol 3-kinase (PI3K), Akt and nuclear factor kappa B (NF-kappaB) in the labial salivary glands of SS patients (n = 6) with those of control subjects (n = 2). EGF-mediated signaling pathways were further studied in vitro (n = 3) using primary salivary epithelial cells; NF-kappaB p65 nuclear translocation and Akt phosphorylation were examined by immunofluorescence and western blotting, respectively. The phosphorylation of EGF-R and Akt, and the nuclear expression of NF-kappaB p65, were increased in situ in the salivary epithelial cells of SS patients compared with those of control subjects. Epidermal growth factor induced rapid EGF-R phosphorylation and NF-kappaB p65 nuclear translocation in primary salivary epithelial cells in vitro. However, EGF also induced late Akt phosphorylation (after 12 h). Chemical inhibition of PI3K-Akt by LY294002/wortmannin did not affect EGF-mediated NF-kappaB p65 nuclear translocation; and NF-kappaB inhibition by Bay 11-7082 did not suppress Akt phosphorylation. Our data suggest that EGF stimulates both the PI3K-Akt pathway and NF-kappaB via distinct mechanisms, promoting tropic effects in SS salivary epithelial cells.
19015307 Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sjögren's syn 2008 Nov 24 Although several autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmunity remain unclear. Recently, we found that retinoblastoma-associated protein 48 (RbAp48) induces tissue-specific apoptosis in the exocrine glands depending on the level of estrogen deficiency. In this study, we report that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sjögren's syndrome. CD4(+) T cell-mediated autoimmune lesions were aggravated with age, in association with autoantibody productions. Surprisingly, we obtained evidence that salivary and lacrimal epithelial cells can produce interferon-gamma (IFN-gamma) in addition to interleukin-18, which activates IFN regulatory factor-1 and class II transactivator. Indeed, autoimmune lesions in Rag2(-/-) mice were induced by the adoptive transfer of lymph node T cells from RbAp48-Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-gamma, resulting in loss of local tolerance before developing gender-based autoimmunity.
18209090 Role of sphingosine 1-phosphate in the pathogenesis of Sjögren's syndrome. 2008 Feb 1 Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammatory mononuclear cell infiltration and destruction of epithelial cells of lacrimal and salivary glands. Sphingosine 1-phosphate (S1P) and signaling through its receptor S1P(1) have been implicated in many critical cellular events including inflammation, cancer, and angiogenesis. This study was undertaken to examine the role of S1P(1) signaling in the pathogenesis of primary SS. S1P(1) and sphingosine kinase 1, which converts sphingosine to S1P, were detected in the cytoplasm of inflammatory mononuclear cells, vascular endothelial cells, and epithelial cells in all labial salivary glands by immunohistochemistry. The expression of S1P(1) in inflammatory mononuclear cells was enhanced in advanced stages of primary SS. S1P enhanced proliferation and IFN-gamma production by CD4(+) T cells. The enhancing effect of S1P on IFN-gamma production by CD4(+) T cells was stronger in patients with primary SS than in healthy controls. S1P also enhanced Fas expression and Fas-mediated caspase-3 induction in salivary gland epithelial cells. IL-6 expression was detected in the cytoplasm of inflammatory mononuclear cells and ductal epithelial cells and was enhanced in advanced stages of primary SS. Furthermore, both IFN-gamma and S1P augmented IL-6 secretion by salivary gland epithelial cells. These effects of S1P were inhibited by pretreatment of pertussis toxin. Our data reveal that S1P(1) signaling may modulate the autoimmune phenotype of primary SS by the action of immune as well as epithelial cells.
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.
17672966 [Expression of CD4+ CD25+ regulatory T cells in peripheral blood and salivary gland of pat 2007 Apr 17 OBJECTIVE: To investigate the expression of CD(4)(+) CD(25)(+) regulatory T cells (Tregs) in the peripheral blood and salivary gland of patients with primary Sjögren's syndrome (pSS). METHODS: Samples of peripheral venous blood were collected from 57 newly diagnosed pSS patients, 1 male and 56 females, aged 47 (20 approximately 76), and 46 healthy controls. The levels of CD(4)(+) CD(25)(+) T regulatory cells and CD(4)(+) CD(25)(high) T regulatory cells in the peripheral blood were measured by flow-cytometric assay. Biopsy specimens of labial gland were collected from the 57 patients and 6 healthy person or patients with labial gland cyst. Pathological examination was conducted by light microscopy. Immunohistochemistry was conducted, by using monoclonal mouse anti-human to detect the expression of CD25, CD4, CD8, and CD68. Western blotting was used to detect the levels of IgG, IgM, and IgA. The salivary flow rate was measured. Schirmer's test was used to measure the tear flow rate. RESULTS: The level of CD(4)(+) CD(25)(+) Tregs in the blood of pSS patients was 6.9% (2.84% - 13.50%), significantly lower than that of the healthy controls [10.9% (5.77% - 15.3%), P < 0.001). The level of CD(4)(+) CD(25)(high) Tregs the blood of pSS patients was 0.6% (0.001% - 1.83%), significantly lower than that of the healthy controls [1.1% (0.13% - 2.45%), P < 0.001]. Immunohistochemistry showed that most of the infiltrating lymphocytes in the labial gland of the pSS patients were CD(4)(+) T cells, and there was no CD(25)(+) T cell in both groups. The numbers of peripheral CD(4)(+) CD(25)(+) T cells and CD(4)(+) CD(25)(high) Tregs in the pSS patients were not correlated with the tear flow rate, salivary flow rate, anti-SS-A/SS-B antibodies, and immunoglobulin level. CONCLUSION: The pSS patients show an absence of CD(4)(+) CD(25)(+) T cell in the labial gland of pSS patients, and reduction of the numbers of CD(4)(+) CD(25)(+) and CD(4)(+) CD(25)(high) Tregs in the peripheral blood, which suggests that Tregs play an important role in the pathogenesis of salivary gland destruction in SS.