Rheumatoid Arthritis: Liu X

Chen J, Liu X. · Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 2601, Australia. · Cell Immunol. · Pubmed #18848698 No free full text.

Abstract: Interferon gamma (IFNgamma) plays a central role in the immune response against infection and tumur immune surveillance. Its functions include not only activation of the host immune system to control microbial infections but also repression of autoimmune responses by turning on T-regulatory cells and increasing T effector cell apoptosis. Defects in IFNgamma and IFNgamma receptor genes have been associated with autoimmune diseases such as rheumatoid arthritis, type 1 diabetes and multiple sclerosis. However, treatment of autoimmune diseases by supplementing with IFNgamma has been satisfactory due to its broad biological effects. Instead, its target T-regulatory cells may be used for the clinical treatment of autoimmune diseases. Future study could also focus on promotion of the beneficial effects of IFNgamma and blocking those unwanted IFNgamma-induced activities.

Liu X, Jia R, Zhao J, Li Z. · Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing 100044, China. · J Rheumatol. · Pubmed #19447936 No free full text.

Abstract: OBJECTIVE: Anti-mutated citrullinated vimentin (MCV) antibodies have been reported as a fairly sensitive serological marker of rheumatoid arthritis (RA). We evaluated the diagnostic value of anti-MCV in a large cohort of Chinese patients with early RA. METHODS: One hundred seventy patients with early RA (<1 yr duration), 66 with other rheumatic diseases, 10 with infectious diseases, and 60 healthy individuals were included in our study. Serum anti-MCV and second-generation anti-cyclic citrullinated peptide antibodies (anti-CCP2) were measured by ELISA, and rheumatoid factor (RF) was measured by rate nephelometry. The associated clinical data of patients with early RA were also evaluated. Then disease activity was scored by the formula for Disease Activity Score (DAS)28, and the degree of radiological changes was assessed by Sharp score. RESULTS: The prevalence of serum anti-MCV in patients with early RA (78.2%, 133/170) was significantly higher than that of other rheumatologic patients and patients with infectious diseases. It was 12% (3/25) in systemic lupus erythematosus, 9.5% (2/21) in primary Sjögren's syndrome, 10% (1/10) in systemic sclerosis, 20% (2/10) in ankylosing spondylitis, 12.5% (1/8) in viral hepatitis type B, and 0% (0/2) in tuberculosis. Anti-MCV was not found in the serum of healthy subjects. The sensitivities of anti-MCV, anti-CCP2, and RF tests for early RA were 78.2%, 61.8%, and 72.4%, respectively, and the specificities were 93.4%, 96.3%, and 80.1%. The combination of anti-MCV and anti-CCP2 positivity showed a very high specificity (97.8%) and positive predictive value (97.1%), but a low sensitivity (58.8%). The sensitivity reached 81.2% when the union of anti-MCV and anti-CCP2 positivities was used as one combined criterion. Statistically, anti-MCV had significant correlation with anti-CCP2 (r=0.587, p=0.01, 2-tailed) and RF (r=0.389, p=0.01, 2-tailed). In addition, it had an interesting correlation with radiological assessment (r=0.349, p=0.05, 2-tailed). The anti-MCV had no significant correlation with other factors, such as erythrocyte sedimentation rate, C-reactive protein, antikeratin antibody, antiperinuclear factor, global visual analog scale score for joint pain, IgA, IgG, IgM, C3, C4, hidden rheumatoid factor for IgA (HRFIgA), HRFIgG, and DAS28. CONCLUSION: Anti-MCV is a novel diagnostic marker for early RA. It may be more useful if the anti-CCP2 assay is performed concomitantly to diagnose patients with early RA.

Walker EJ, Hirschfield GM, Xu C, Lu Y, Liu X, Lu Y, Coltescu C, Wang K, Newman WG, Bykerk V, Keystone EC, Mosher D, Amos CI, Heathcote EJ, Siminovitch KA. · University of Toronto, Toronto General Hospital, and Mount Sinai Hospital, Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #19333938 No free full text.

Abstract: OBJECTIVE: The co-occurrence of different autoimmune diseases in patients and their families suggests the presence of shared genetic risk factors. Two compelling candidate autoimmune disease susceptibility genes are those that encode CTLA4 and inducible costimulator (ICOS), immunoregulatory proteins. Associations of CTLA4 polymorphisms with various autoimmune diseases have been reported, but for rheumatoid arthritis (RA) and primary biliary cirrhosis (PBC), the association data are inconsistent and have largely excluded analysis of polymorphisms in the ICOS gene adjacent to CTLA4. We undertook this study to examine whether CTLA4 and ICOS influence RA and PBC susceptibility by testing CTLA4/ICOS polymorphisms for association with these diseases in Canadian subjects. METHODS: Caucasian RA patients (n = 1,140), PBC patients (n = 481), and controls (n = 1,248) were typed for 21 biallelic polymorphisms across the CTLA4/ ICOS genes using a multiplex genotyping array, and the results were analyzed using a false discovery rate method to correct for multiple testing. RESULTS: Significant associations of multiple CTLA4 and ICOS gene polymorphisms with RA and PBC were observed, with the strongest association signals for both diseases coming from a CTLA4/ICOS intergenic single-nucleotide polymorphism, rs17268364 (corrected P [P(corr)] = 6.0 x 10(-4) and P(corr) < 1.0 x 10(-4), respectively). Significant associations, which were common to both diseases, were also observed with other alleles and haplotypes across 3 linkage disequilibrium blocks within the CTLA4 gene, the intergenic region, and the ICOS gene. CONCLUSION: Our results provide evidence for RA and PBC association with the CTLA4/ICOS locus and suggest that the risk allele(s) within this region may be common to both diseases.

Zhang W, Ding T, Zhang J, Su J, Yu J, Li J, Li F, Wang C, Liu N, Liu X, Ma W, Yao L. · Department of Microbiology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China. · J Cell Biochem. · Pubmed #17427955 No free full text.

Abstract: Discoidin domain receptor 2 (DDR2) is a kind of protein tyrosine kinases associated with cell proliferation and tumor metastasis, and collagen, a ligand for DDR2, up-regulates matrix metalloproteinase 1 (MMP-1) and MMP-2 expression in extracellular matrix (ECM). To investigate the role of DDR2 in cartilage destruction in rheumatoid arthritis (RA), we expressed the extracellular domain (ECD) of DDR2 (without signal peptide and transmembrane domain, designated DR) in insect cells, purified and characterized DR, hoping to use it as a specific antagonist of DDR2. By using Bac-To-Bac Expression System with a His tag, we successfully obtained the recombinant bacularvirus containing DDR2 ECD, purified it and characterized its function. The soluble fraction of DR was about 12% of the total fused protein. After chromatographic purification, DR with 92% purity was obtained. Competitive inhibition assay demonstrated that DR blocked the binding between DDR2 and natural DDR2 receptors on NIH3T3 and synovial cells. Results of RT-PCR, Western blotting, and gelatinase zymography showed that DR was capable of inhibiting MMP-1 and MMP-2 secretion from NIH3T3 and RA synoviocytes stimulated by collagen II. For MMP-1, inhibition was displayed at the levels of mRNA and protein, whereas for MMP-2 it was at the level of protein. These findings suggested that the expressed DR inhibited the activity of natural DDR2 and relevant MMP-1 and MMP-2 expression in RA synoviocytes and NIH3T3 cells provoked by collagen II.

Zhang XW, Liu X, Li ZG. · Department of Rheumatology, People's Hospital of Beijing University, Beijing, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #17156671 No free full text.

Abstract: OBJECTIVE: To investigate the clinical features and prognosis of undifferentiated connective tissue disease. (UCTD) METHODS: 1105 connective tissue disease (CTD) patients, including 751 cases of systemic lupus erythrematosus (SLE), 63 cases of systemic sclerosis (SSc), 103 cases of polymyositis/dermatomyositis (PM/DM), 159 cases of primary Sjögren's syndrome (pSS), and 29 cases of overlap syndrome (29), were randomly selected. The clinical data of these patients were analyzed to identify those who displayed the manifestations of UCTD as the onset manifestations so as to summarize the clinical manifestation, immunological parameters, and long term development of UCTD. RESULTS: These 145 patients with UCTD developed SLE, SSc, SS, PM/DM, or overlap syndrome within two to five years. The patients with arthritis and arthralgia often developed into SLE. Raynaud's syndrome was often related to SSc. The patients with rash or face edema were more likely turned out to be PM/DM patients. The patients with dry eyes or dry mouth often developed into pSS patients. CONCLUSION: UCTD can develop into various autoimmune diseases, such as SLE, SSc, pSS or PM/DM. Some clinical features of onset are related with the outcome.

Newman WG, Zhang Q, Liu X, Walker E, Ternan H, Owen J, Johnson B, Greer W, Mosher DP, Maksymowych WP, Bykerk VP, Keystone EC, Amos CI, Siminovitch KA. · University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #17133579 links to  free full text

Abstract: OBJECTIVE: Variants in genes encoding the Fc receptor-like 3 (FcRL-3) and the class II major histocompatibility complex (MHC) transactivator proteins have been associated with an increased risk of rheumatoid arthritis (RA) in Japanese and Nordic populations, respectively. The aim of this study was to investigate these associations in a Canadian Caucasian cohort of RA cases and healthy controls. METHODS: A total of 1,187 RA patients and 462 healthy controls were genotyped for FCRL3 and MHC2TA gene variants associated with RA. Epistasis between the FCRL3 -169C and the PTPN22 1858T variants was also examined. RESULTS: An association was detected between RA and both the FCRL3 -169C allele (OR 1.19, P = 0.023) and the homozygous genotype (OR 1.41, P = 0.027), but association of the MHC2TA promoter region variant (-168G) with RA was not replicated. Stratification of the RA cohort by PTPN22 genotypes revealed the FCRL3 risk variant and RA association was stronger in the patient subgroup lacking PTPN22 1858T variants (P = 0.004) and was not detectable in the subgroup with PTPN22 1858T variants (P = 0.52). The PTPN22 association with RA was greater in the absence than in the presence of the FCRL3 -169C allele (P = 0.0008 versus P = 0.001). The PTPN22 1858T variant also increased the risk of autoimmune thyroid disease (AITD) in the RA patients, whereas the FCRL3 risk variant was protective against AITD. CONCLUSION: Our findings support an association of RA with an FCRL3 functional polymorphism and reveal that this association is stronger in the absence of PTPN22 risk genotypes. These findings support a genetic heterogeneity across RA populations, suggesting that both the FCRL3 and PTPN22 genes play roles in RA susceptibility, but in different individuals.

Zhang W, Ding T, Zhang J, Su J, Li F, Liu X, Ma W, Yao L. · Department of Microbiology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China. · Mol Cell Biochem. · Pubmed #16967187 No free full text.

Abstract: Discoidin domain receptor 2 (DDR2) is a kind of protein tyrosine kinases associated with cell proliferation and tumor metastasis, and collagen, identified as a ligand for DDR2, up-regulates matrix metallloproteinase 1 (MMP-1) and MMP-2 expression in cellular matrix. To investigate the roles of DDR2 in destruction of cartilage in rheumatoid arthritis (RA) and tumor metastasis, we tried to express extracellular domain of DDR2 fused with a His tag to increase protein solubility and facilitate purification (without signal peptide and transmembrane domain, designated DR) in Pichia pastoris, purify the expressed protein, and characterize its function, for purpose of future application as a specific DDR2 antagonist. Two clones of relative high expression of His-DR were obtained. After purification by a Ni-NTA (nitric-tri-acetic acid) chromatographic column, soluble fused His-DR over 90% purity were obtained. Competitive binding inhibition assay demonstrated that expressed His-DR could block the binding of DDR2 and natural DDR2 receptors on NIT3T3 and synovial cell surfaces. Results of RT-PCR, Western blotting, and gelatinase zymography showed that His-DR was capable of inhibiting MMP-1 and MMP-2 secretion from NIT3T3 cells and RA synoviocytes stimulated by collagen II. For MMP-1, the inhibitory effect was displayed at the levels of mRNA and protein, whereas for MMP-2 it was demonstrated at the level of protein physiological activity. All these findings suggested that the fused expressed His-DR inhibited the activity of natural DDR2, and relevant MMP-1 and MMP-2 expression in synoviocytes and NIH3T3 cells provoked by collagen II.

van Oene M, Wintle RF, Liu X, Yazdanpanah M, Gu X, Newman B, Kwan A, Johnson B, Owen J, Greer W, Mosher D, Maksymowych W, Keystone E, Rubin LA, Amos CI, Siminovitch KA. · Ellipsis Biotherapeutics Corporation, Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #15986374 links to  free full text

Abstract: OBJECTIVE: A single-nucleotide polymorphism in the PTPN22 gene encoding the lymphoid protein tyrosine phosphatase (Lyp) has recently been identified as a functional variant associated with susceptibility to rheumatoid arthritis (RA), type 1 diabetes, and systemic lupus erythematosus. To determine whether association of this variant (PTPN22 1858T) with RA is reproducible and is also observed in another autoimmune condition, Crohn's disease, we investigated the association between the PTPN22 1858T allele and RA and Crohn's disease in a Canadian population. METHODS: Two RA case-control cohorts representing a total of 1,234 patients and 791 healthy controls as well as a cohort of 455 patients with Crohn's disease and 190 controls were genotyped for the PTPN22 C1858T polymorphism, and genotype frequencies were compared between patients and controls. RESULTS: Significant association of the PTPN22 1858T allele with RA was detected in both the Toronto-based RA cohort (P = 1.6 x 10(-6), odds ratio [OR] 1.8) and the Halifax-based RA cohort (P = 9.4 x 10(-4), OR 1.94). Association of the risk allele with RA was not affected by sex, age at disease onset, or the presence of either rheumatoid factor or rheumatoid nodules. No association between the PTPN22 risk allele and Crohn's disease was detected. CONCLUSION: These observations confirm the association of RA susceptibility with the PTPN22 1858T allele. However, the data also reveal a lack of association between this variant and Crohn's disease, suggesting that the PTPN22 1858T allele is a risk allele for multiple, but not all, autoimmune diseases.

Wang J, Lü H, Liu X, Deng Y, Sun T, Li F, Ji S, Nie X, Yao L. · Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, People's Republic of China. · J Autoimmun. · Pubmed #12419287 No free full text.

Abstract: In order to know whether any protein tyrosine kinase (PTK) is involved in the over-proliferation and erosiveness of synovial fibroblasts (SF) of rheumatoid arthritis (RA) patients, RT-PCR and RNA dot blotting were done to analyse PTKs profile in RA SF. Platelet-derived growth factor receptor A (PDGFRA), insulin-like growth factor 1 receptor (IGF-1R), Janus kinase 1 (JAK1), TYK2, discoidin domain receptor 2 (DDR2), and Lyn were expressed in SF, and the expression of PDGFRA, IGF-1R, and DDR2 in SF of RA were higher than that of osteoarthritis (OA, as control). Immunoblotting and gelatinase zymography showed that DDR2 in RA SF, which still secreted active matrix metalloproteinase 1 (MMP-1) in vitro, were in active form. Stimulation of collagen II could make NIH-3T3 cells (as control) produce MMP-1, which could be inhibited by soluble extracellular part of DDR2. These results indicated that the over-expression of MMP-1 in RA SF might be related to the activation of DDR2, and collagen II, act as DDR2 ligand, might be one of the stimulators of the over-expression of MMP-1 of RA SF.

Xie M, Wang Z, Liu X, Qiang O, Liu G. · Department of Internal Medicine, First Affiliated Hospital, WCUMS, Chengdu 610041. · Hua Xi Yi Ke Da Xue Xue Bao. · Pubmed #12212057 No free full text.

Abstract: This study was conducted to explore the clinical implication of the relationship between systemic lupus erythematosus (SLE) and peripheral blood lymphocytes (PBL) apoptosis and apoptosis-related gene expression. Terminal deoxynucleotidyl transferase mediated nick end labelling technique and flow cytometry were used to detect the apoptotic cell; immunohistochemistry ABC was used to detect the expressions of bcl-2 and Fas in 29 cases of SLE. The results showed that the rate of apoptosis of PBL in SLE patients was significantly higher than that in normal control (P < 0.001), and that in patients with rheumatoid arthritis (P < 0.001). After 48 hour's culture, the apoptotic rate further increased in SLE patients (33.44%). There was a significant correlation between the SLE activity and the rate of apoptosis in vitro (r = 0.86, P < 0.001). The rate of apoptosis of PBL in SLE-nephritis patients was higher than that in non-SLE-nephritis patients (P < 0.01). Before and after the culture, the expressions of bcl-2 and Fas in PBL of patients with SLE were higher than those in normal control (P < 0.01, P < 0.001). So the authors suggest that increased rate of apoptosis may be used as an index for evaluating the severity of SLE cases.

Wang J, Liu X, Li F, Yao L. · Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China. · Med Hypotheses. · Pubmed #12208180 No free full text.

Abstract: Rheumatoid arthritis is complex and not clear on the mechanism of pathogenesis. On the basis of analysis of the symptom and pathology of rheumatoid arthritis patients, we raised a new hypothesis. The content of the hypothesis is as follows: (A) Collagen II or collagen II-Iike substance in human cartilage is the cross-autoantigen of some infecting virus or bacteria because of the structure's similarity. (B) The inflammation in synovial tissue is auto-immunoreaction to collagen II in cartilage. (C) The proliferation and attachment of synovial tissue to the surface of cartilage is due to the chemotaxis of collagen II in cartilage for the immunocytes in synovial tissue. (D) The collagenase secreted from synovial cells and immunocytes are the direct elements in the destruction of cartilage. The fallen collagen II from cartilage is one of the most important inducer on the synovial cells and immunocytes for the production of collagenase.

Liu X, Lin H, Yuan G, Huang F. · Department of Rheumatology, General Hospital of PLA, Beijing 100853. · Zhonghua Nei Ke Za Zhi. · Pubmed #11798678 No free full text.

Abstract: OBJECTIVE: To investigate the level of interleukin-6 (IL-6) and soluble-IL-6 receptor (sIL-6R) in serum of patients with systemic lupus erythematosus (SLE) and its correlation with disease activity and to explore IL-6 signal transduction pathways in SLE patients. METHODS: By using MTT colorimetry and ELISA, the levels of IL-6 and sIL-6R in serum from 16 patients with SLE (9 active, 7 inactive), 17 with active rheumatoid arthritis (RA) and 29 controls were measured. The expressions of acute phase reaction factor (APRF) in peripheral blood mononuclear cells (PBMCs) were also detected by using electrophoresis mobility shift assays (EMSA) after the PBMCs were isolated and then stimulated by IL-6. RESULTS: Serum IL-6 and sIL-6R levels in active SLE patients were significantly higher than those in normal controls (P < 0.01), but were significantly lower than those in active RA patients (P < 0.01). Serum IL-6 rather than sIL-6R level in active SLE patients was significantly higher than that in inactive ones (P < 0.01). Serum IL-6 was correlated positively with the anti-dsDNA antibody (r = 0.658, P < 0.01), but not with CRP (r = 0.041, P > 0.05). There were no expression of APRF in PMNC from SLE patients and 8 normal controls, whereas PMNC from 11 RA patients expressed APRF activity (11/17). CONCLUSION: The level of IL-6 is a useful parameter for monitoring disease activity of SLE. In active SLE, no significant elevation of serum sIL-6R and no expression of APRF in PMBCs may be responsible for mild CRP elevation.

Liu X, Piela-Smith TH. · Division of Rheumatology, University of Connecticut Health Center, Farmington, CT 06030, USA. · J Immunol. · Pubmed #11046059 links to  free full text

Abstract: It has long been recognized that in most inflamed arthritic joints the coagulation system is activated, leading to the local generation of fibrin, and it has long been hypothesized that the local fibrin deposition promotes inflammation and tissue destruction. However, only recently has the direct effect of fibrin on the inflammatory process been seriously investigated, and specific roles assigned to fibrin or its products as mediators of the inflammatory process. Although fibrin and/or fibrinogen (fibrin(ogen)) is abundantly present in inflamed tissues and joints rich in fibroblastic cells, no significant data on fibrin(ogen)-induced gene expression by fibroblasts have been published. We now demonstrate that coculture of human synovial fibroblasts with fibrin(ogen) results in the up-regulation of ICAM-1 as well as increased production of the chemokines IL-8 and growth-related oncogene-alpha. Increased ICAM-1 expression was fibrin(ogen) dose-dependent and was demonstrated by ELISA, flow cytometry, and functional adhesion assays. Levels of ICAM-1 induced by fibrin(ogen) were comparable to those that could be induced by cytokine stimulation. Fibrin(ogen) stimulation of ICAM-1 could be suppressed by pyrrolidinedithiocarbamate, an inhibitor of NF-kappaB activation. Chemokine production was induced by fibrin(ogen) in cell culture supernatants >100-fold as compared with controls. Thus, through its activation of synovial fibroblasts, fibrin(ogen) deposition may promote the recruitment (via chemokines) and retention (via adhesion molecules) of lymphocytes within the arthritic joint.