Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
8568334 Pancreatic involvement in patients with Sjögren's syndrome and primary biliary cirrhosis. 1995 Feb Serum pancreatic enzyme activities, exocrine pancreatic function, and pancreatic ductal morphology were evaluated in patients with one or both of Sjögren's syndrome and primary biliary cirrhosis. Ten of 20 patients with Sjögren's syndrome (50%), 6 of 17 patients with primary biliary cirrhosis (35%), and 4 of 11 patients with both diseases (36%) had an elevated level of at least one pancreatic enzyme, including elastase-1, lipase, and trypsin. Diminished excretion of N-benzoyl-L-tyrosyl-para-aminobenzoic acid was observed in 3 of 17 patients with Sjögren's syndrome (18%), 4 of 16 with primary biliary cirrhosis (25%), and none of 7 with both diseases. Endoscopic retrograde pancreatograms demonstrated an abnormal pancreatic ductal configuration in 3 of 11 patients with Sjögren's syndrome (27%), 2 of 9 with primary biliary cirrhosis (22%), and 3 of 4 with both diseases (75%). Only minimal changes in branches of the pancreatic duct were observed in the pancreatogram. Finally, 9-30% of patients with Sjögren's syndrome and/or primary biliary cirrhosis had a mild and intermittent abdominal pain. These findings support the concept of a disease complex, "autoimmune exocrinopathy," in patients with Sjögren's syndrome, primary biliary cirrhosis, and chronic pancreatitis.
1323968 Are endogenous retroviruses involved in human autoimmune disease? 1992 Apr A role for viruses in the etiopathogenesis of human autoimmune diseases has long been suspected but has not yet been proven. In Sjögren's syndrome (SS), there is continuing experimental support for the possible involvement of Epstein-Barr virus. Since the advent of AIDS, there is also great interest in retroviruses and autoimmune disease. We previously reported that 30% of SS patients and 36% of systemic lupus erythematosus (SLE) patients have serum antibodies to the p24 gag protein of HIV-1. We now report that two mechanisms classic for retroviruses (molecular mimicry and immunosuppression) may be operative in SS and SLE. The p24 gag protein shares a proline-rich epitope with the Sm nucleoprotein to which many SLE patients have antibodies. The impaired lymphocyte activation seen in peripheral blood T cells in SS patients is also seen in a human T cell line infected with an A-type retroviral particle linked to SS. Many studies suggest that endogenous retroviral sequences are important in immunoregulation. We now suggest that endogenous retroviral sequences may also be important in the etiology and pathogenesis of SS and SLE.
8894617 S-substituted isothioureas are potent inhibitors of nitric oxide biosynthesis in cartilage 1996 Oct 3 Nitric oxide (NO.) is a multifunctional messenger molecule generated by a family of enzymes, the nitric oxide synthases, and is overproduced in osteoarthritis and rheumatoid arthritis. Chondrocytes are the major native source of NO. in diarthrodial joints. Chondrocytic inducible nitric oxide synthase induced by inflammatory cytokines and bacterial cell wall fragments mediates many of the catabolic events in arthritis. Agents which specifically inhibit chondrocyte inducible NO. synthase, may thus have a role in the management in arthritis. We evaluated a novel class of potential inducible NO. synthase inhibitors, the S-substituted isothioureas, for their ability to inhibit inducible NO. synthase activity in cultured bovine chondrocytes and explants of cartilage from patients with osteoarthritis. Two isothioureas, S-methyl isothiourea and S-(aminoethyl) isothiourea were 2-4 times more potent than NG-monomethyl-L-arginine monoacetate, 5-10 times more potent than aminoguanidine and over 300 times more potent than N omega-nitro-L-arginine and N omega-nitro-L-arginine methyl ester. The rank order of potency of the NO. synthase inhibitors was S-(aminoethyl) isothiourea > S-methyl isothiourea > NG-monomethyl-L-arginine > aminoguanidine > N omega-nitro-L-arginine = N omega-nitro-L-arginine methyl ester. The order of potency was reversed (N omega-nitro-L-arginine methyl ester = N omega-nitro-L-arginine > NG-monomethyl-L-arginine = S-methyl isothiourea > S-(aminoethyl) isothiourea > aminoguanidine) when evaluating the same compounds ability to inhibit constitutive NO. synthase activity in bovine endothelial cells. In comparison to conventional arginine based analogs, the isothioureas represent a more potent and relatively specific class of inhibitors of inducible NO. synthase in cartilage and thus may be beneficial in the management of arthritis.
8864830 Autoantibody repertoire to Ro/SSA and La/SSB antigens in patients with primary and seconda 1996 Aug Autoimmune diseases are characterized serologically by the presence of antibodies to specific autoantigens. Antibodies to the two antigens Ro/SSA and La/SSB are found in patients with primary (pSS) and secondary Sjögren's syndrome (sSS). To explore if differences in the fine specificity of these autoantibodies could be distinguished in sera from patients with primary (n = 17) and secondary (n = 20) Sjögren's syndrome, sera were analysed by immunoblotting and ELISA using recombinant antigens and synthetic peptides. Minor differences were detected when the frequencies of the Ro 60 kD, Ro 52 kD and La autoantibody specificities to full-length proteins in the pSS and sSS groups were compared. However, when reactivity to different parts of the Ro 60 kD antigen was analysed, including recombinant fragments encompassing amino acid (aa) 1-134, aa 181-320 and aa 397-525, only two sera, both from pSS patients, reacted to the aminoterminal fragment aa 1-134, and 3/4 sera that reacted with the carboxyterminal aa 397-525 fragment derived from sSS patients. Of all the anti-Ro 60 kD positive sera, 80% reacted with the middle fragment encompassing aa residues 181-320. The fine specificity of the autoantibodies reacting with this 181-320 aa region was further mapped with synthetic peptides, and a peptide (VSLVCEKLCNEKLLKKARIH) recognized by 8 out of 16 sera from both pSS and sSS patients was identified.
8575139 CD4+ T-lymphocytopenia without HIV infection: increased prevalence among patients with pri 1995 Sep OBJECTIVE: Primary Sjögren's syndrome (1 degree SS) is an autoimmune disease, usually accompanied by manifest immune hyperactivity. In some cases the disease converts to malignant neoplasia. On the other hand, there are clinical similarities to HIV infection. Since the rare phenomenon of persistent depletion of CD4+ T-lymphocytes in peripheral blood without HIV infection was recently defined as idiopathic CD4+ T-lymphocytopenia (ICL), we have used the ICL criteria to investigate the prevalence of this phenomenon among 1 degree SS patients. METHODS: During the period 1988-94, 115 caucasian patients (10 males), mean age 57.8 (range 19-82) years, with 1 degree SS were prospectively studied. Lymphocyte subsets were investigated by means of monoclonal antibodies and flow cytometry. For the detection of HIV and HTLV antibodies, we used an enzyme immunoassay (for HIV-1 and HIV-2), Western blot techniques (HIV-1, HIV-2, HTLV-I and HTLV-II), and the polymerase chain reaction procedure (HIV-1, HTLV-I and HTLV-II). HIV antigens were tested for with the HIV-1 p-24 Ag test. RESULTS: Six patients with 1 degree SS fulfilled the criteria for ICL. While the clinical condition of 5 of those six patients remained stable, one patient developed malignant lymphoma three years after her disease was classified as a case of ICL. The prevalence of ICL among our 115 patients with 1 degree SS was 5.2%, which is significantly higher than the rates reported for any other patient or population group. We have estimated the relative risk of ICL in 1 degree SS patients to vary from 3.4 to 6,000 (P values of 0.0001-0.025). CONCLUSION: We suggest that subjects with ICL should be carefully examined for 1 degree SS and, if its presence is confirmed, that they should be followed with regard to the possible complications of this disease, including the development of malignant lymphoma.
8882417 Characterization of T cell receptor repertoire and anti-Ro/SSA autoantibodies in relation 1995 Non-obese diabetic (NOD) mice develop sialadenitis which morphologically resembles the exocrinopathy in human Sjögren's syndrome (SS). The sialadenitis is characterized by focal infiltrates of inflammatory cells. Immunoenzyme staining (ABC-technique) and monoclonal antibodies defining CD4, CD8, CD11b, TCR alpha/beta, gamma/delta, V beta 2, V beta 4, V beta 6, V beta 7, V beta 8.1, 2, V beta 10b and V beta 11 were used to examine the infiltrating mononuclear cells (MNC) in salivary glands of NOD mice. TCR alpha beta + cells dominated clearly over TCR gamma delta + cells in the salivary glands. A predominance of CD4+ T-cells was identified, while a small population of CD8+ cells was found in the salivary gland infiltrates. CD11b+ mononuclear cells were sporadically seen within the salivary gland lesions. All different TCR V beta:s which were analysed appeared to be utilized at the site of MNC infiltration in salivary glands; although with various frequencies. The frequency pattern of V beta gene expression in salivary glands was V beta 8.1,2 (15%) > V beta 6 (12%) > V beta 4 (11%) > V beta 10b (5%) > V beta 11 (5%) = V beta 2 (5%) > V beta 7 (3%). Analysis of the TCR V beta utilization in corresponding lymph nodes revealed a quite similar frequency pattern as found in the salivary glands. Serum samples were also tested for anti-Ro52, Ro60 and anti-La antibodies with Western blot. Autoantibody production was limited to anti-Ro/SSA and 3/37 (8%) of the mice were found to produce anti-Ro52 kD antibodies. The degree of sialadenitis (focus score) appeared not to influence reactivity to the Ro52 kD protein.
7964483 One gene, two transcripts: isolation of an alternative transcript encoding for the autoant 1994 Dec 1 A cDNA library was prepared from peripheral blood lymphocytes of an autoimmune patient with primary Sjögrens' syndrome. The cDNA library was screened with the patients own autoimmune serum being monospecific for the nuclear autoantigen La/SS-B. Thereby an alternative type of La mRNA was identified that differed from the known La mRNA due to an exchange of the exon 1. Sequencing of the genomic region between the exons 1 and 2 showed that the alternative 5'-end is a part of the intron. In addition, the presence of an alternative promoter site, which exists within the intron downstream of the exon 1, became evident. In consequence, the alternative La mRNA is the result of a promoter switching combined with an alternative splicing mechanism. In the intron, further transcription factor binding sites, including a NF-kappa B element, were identified leading to the suggestion that the expression of the gene encoding for the nuclear autoantigen La/SS-B alters in dependence on disease conditions.
1634351 Impact of androgen therapy in Sjögren's syndrome: hormonal influence on lymphocyte popula 1992 Jul Recent research has demonstrated that androgen treatment dramatically curtails lymphocyte infiltration in the lacrimal glands of a mouse model of Sjögren's syndrome. The purpose of the current study was to determine whether this androgen action involves the selective suppression of specific lymphocyte populations or Ia expression in lacrimal tissue. Autoimmune female MRL/Mp-lpr/lpr mice were administered placebo- or testosterone-containing compounds for 0, 17, or 34 d. Then lacrimal glands were obtained and processed for immunohistochemical evaluation. Results demonstrated that in pretreatment mice, lacrimal lymphoid foci were composed predominantly of Thy 1.2+ cells, bearing L3T4 (helper T cell) or B220 surface antigens. In contrast, suppressor T cells (Lyt 2+) and surface IgM-bearing B cells represented minority populations in the immune infiltrates. Class II antigen (Ia) expression was observed on over 40% of the infiltrate lymphocytes and occasionally on epithelial cells close to the lymphoid focus. During the experimental time course, the extent of lymphocyte infiltration increased in glands of placebo-treated mice. This cellular accumulation was associated with an elevation in the frequency of B220+ cells, but not that of other lymphocyte subclasses. Testosterone administration induced a striking diminution in the area encompassed by all immune cell populations. Moreover, hormone therapy significantly reduced the frequency of B220+ cells in focal infiltrates. Overall, these findings demonstrate that androgen exposure stimulates a decrease in the quantity, but not necessarily the entire lymphocyte composition, of lymphoid aggregates in lacrimal glands of MRL/lpr mice.
1313502 Salivary gland 99mTc-scintigraphy: a grading scale and correlation with major salivary gla 1992 Feb Sequential salivary gland scintigraphy with 99mTc-technetium pertechnetate (Tc-99) is a safe, minimally invasive test for study of major salivary glands. However, its relationship to salivary function has not been investigated in detail. We have investigated the relationship between major salivary gland flow rates and Tc-99 scans and developed a new rating scale using scans of a control group with normal salivary function. Salivary flow rates and Tc-99 scans were obtained from healthy, non-medicated subjects (n = 33) and from xerostomic patients (n = 22). There were significant differences between the groups for salivary flow rates and Tc-99 ratings. Significant correlations were found between salivary flow rates and Tc-99 ratings in the control and xerostomic groups. The Tc-99 rating scale proved reliable in assessing salivary dysfunction, and showed a high inter-examiner correlation. These results demonstrate the usefulness of salivary gland scintigraphy in assessing major salivary gland flow rates and the utility of a new rating scale.
9022322 [Sjögren's syndrome complicated by thymoma]. 1996 Dec A 43-year-old woman with a history of Sjögren's syndrome was admitted to our hospital because of dyspnea due to anemia. Her chest X ray film on admission revealed an anterior mediastinal tumor. We diagnosed this tumor as a thymoma based on a chest CT scan and magnetic resonance imaging. Because the latter indicated that the thymoma may have involved the mediastinal great vessels, preoperative chemotherapy with cisplatin, doxorubicin hydrochloride, vincristine sulfate and cyclophosphamide. Thereafter the tumor was successfully resected along with part of the right pleura. Thymoma as a complication of Sjögren's syndrome is rare. Here we also discuss the treatment of thymoma and the combination of these two diseases.
8757639 Autoimmune Sjögren's-like lesions in salivary glands of TGF-beta1-deficient mice are inhi 1996 Aug 1 The targeted disruption of the TGF-beta1 gene in mice (TGF-beta1 -/-) leads to extensive inflammation in vital organs, cachexia, and death within 3 to 4 wk. Significant inflammatory lesions develop initially in the periductal regions of the salivary glands and escalate as the animals become symptomatic. These inflammatory sites, characterized by lymphocytic infiltration and increased proliferation, cytokine mRNA expression, and IgG-positive cells, resemble lesions of Sjögren's syndrome. Moreover, the inflammatory pathology, enhanced MHC expression, and Ab production are consistent with an autoimmune-like etiology. Glandular atrophy and loss of acini with reduced saliva production appear to contribute to the wasting syndrome characteristic of the TGF-beta1 -/- mice. To determine whether the structural and functional defects were developmental due to the absence of TGF-beta1 or secondary to the inflammation, TGF-beta1 -/- mice were treated with synthetic fibronectin peptides, which block leukocyte infiltration. Daily systemic injections of RGD, CS-1, and/or peptides derived from the heparin-binding region of the A chain not only prevented leukocyte infiltration in the salivary glands of the TGF-beta1 -/- mice, but also reversed the acinar and ductal derangements. These data suggested that salivary gland development is not jeopardized in the absence of TGF-beta1, but that the extensive infiltration of inflammatory cells compromises glandular structure and function. The essential nature of TGF-beta1 in controlling inflammatory and immune processes is confirmed by these studies. Moreover, these TGF-beta1 -/- mice provide an important model of autoimmune disease that can be used in the design of therapeutic interventions.
8964596 Differential interleukin (IL)-10 and IL-13 gene expression in vivo in salivary glands and 1996 Jan Primary Sjögren's syndrome (PSS) is an autoimmune inflammatory disorder characterized by lymphocytic infiltration of exocrine glands, B cell hyperactivity and autoantibody production. The aim of this study was to determine the presence of IL-10 and IL-13 in this disease. We studied the IL-10 and IL-13 gene expression in vivo by peripheral blood mononuclear cells and minor salivary glands from PSS patients. We found a high expression of the IL-10 gene and its product by their peripheral blood mononuclear cells (PBMC) as well as by their salivary glands. Peripheral blood B cells and monocytes were responsible for 89% of total IL-10 secretion. IL-13 gene expression was not observed in PBMNC from either PSS patients or healthy controls, and was confined to PSS salivary glands. Our results suggest that IL-10 and IL-13 contribute to the pathogenesis of PSS and might explain the B cell abnormalities and the development of lymphoma observed in this autoimmune disease.
8523198 Central nervous system disease in a child with primary Sjögren syndrome. 1995 Dec A 9-year-old girl had hemiparesis, and a diagnosis of primary Sjögren syndrome was made. The neurologic dysfunction was multifocal, involving both the brain and spinal cord, and was recurrent; the findings mimicked multiple sclerosis. Corticosteroid treatment during episodes of acute neurologic dysfunction appeared to be beneficial.
8392093 Characterization of the primary structure of T cell receptor beta chains in cells infiltra 1993 Jul Infection with HIV-1 occasionally results in a sicca syndrome, termed the diffuse infiltrative lymphocytosis syndrome, characterized by infiltration of the salivary glands with a predominance of CD8 T cells. This response is strongly associated with certain MHC class I and class II alleles. To define the salivary gland T cell receptor (TCR) repertoire, the primary structure of the TCR beta-chains was determined using in situ cDNA synthesis followed by the "anchored" polymerase chain reaction. The sequences of 59 beta-chains from five individuals with diffuse infiltrative lymphocytosis syndrome shared structural features suggesting antigenic clonal selection. Certain combinations of V beta J beta gene segments were selectively overrepresented in the repertoire sample, demonstrating a common restricted usage of certain V beta and J beta gene segments. The beta-chains derived from these overrepresented V beta J beta combinations revealed a preference for specific amino acids at position 97 in the third complementarity-determining region, a residue postulated to contact peptide antigen. Moreover, the nucleotides encoding this position were not germline in origin. TCR beta-chains in nonoverrepresented V beta J beta combinations did not exhibit preferential usage of selected somatically encoded residues. The pattern of TCR beta-chains expressed in the salivary gland of a control person with primary Sjögren's syndrome was considerably more heterogeneous and different from that found in diffuse infiltrative lymphocytosis syndrome.
8048093 [The role of mumps in the development of chronic salivary gland diseases]. 1993 Jan Examinations of 47 patients with various forms of chronic sialadenitis have demonstrated that the epidemic parotitis virus is not the principal factor in the development of this condition. Analysis of the epidemiologic anamnesis and comprehensive examinations carried out after abatement of the acute process help eliminate diagnostic errors. Both epidemic parotitis and chronic sialadenitis may run a latent course.
8809447 Expression of ductal Fas antigen in sialoadenitis of Sjögren's syndrome. 1996 May OBJECTIVE: The expression of Fas antigen on ductal epithelial cells of sialoadenitis was examined in patients with Sjögren's syndrome (SS) and in normal subjects. METHODS: Minor salivary glands from the SS patients were examined by an immunohistochemical method using a new monoclonal antibody to the Fas antigen. RESULTS: In two patients with severe sialoadenitis, Fas was strongly expressed on the ductal epithelial cells. By contrast, the Fas antigen was not seen in the minor salivary glands of normal subjects nor in those with mild sialoadenitis. CONCLUSION: This finding suggests that the Fas antigen may play a role in the pathogenesis of sialoadenitis in SS by providing a specific target for cytotoxic T cells expressing the Fas ligand.
8908282 Elevated levels of soluble Fc epsilon RII/CD23 and antibodies to Epstein-Barr virus in pat 1996 To clarify how Epstein-Barr virus (EBV) infection is responsible for Sjögren's syndrome (SjS) we measured both IgG and IgM antibodies to viral capsid antigen (VCA) of EBV in the sera of normal healthy subjects and patients with SjS. Anti-VCA IgG was detectable in all controls and patients however, anti-VCA IgG titers in the sera of SjS patients were significantly higher than those of the controls (p < 0.01). No anti-VCA IgM was detected in the sera of controls whereas anti-VCA IgM was detected in the sera from 10 out of the 13 patients with SjS. This suggests that SjS might be associated with EBV. The serum levels of sCD23 (IgE-binding factor) were also measured to assess the differential state in patients with SjS. The sCD23 level of normal individuals was 211.26 +/- 12.01 micrograms/L (value is mean +/- SE), and was 443.77 +/- 71.94 micrograms/L in the 13 patients with SjS. The mean sCD23 level in the 9 patients with SjS without any complication was 360.67 +/- 35.63 micrograms/L. In the patients with SjS, sCD23 levels were significantly higher than those in the normal individuals (p < 0.01).
8775196 The pronator quadratus interposition transfer: an adjunct to resection arthroplasty of the 1996 Jan Ulnar head resection for treatment of painful traumatic and arthritic conditions of the distal radioulnar joint has been performed for over 100 years. Although this is a time-honored procedure, several negative sequelae of the operation have been described. Most of these problems have been due to the instability of the ulna remnant with respect to surrounding structures, including the radius and extensor tendons. This report describes an operative technique to prevent and treat this problem. The pronator quadratus origin is transferred to the dorsum of the ulna, placing the muscle belly between the radius and the ulna remnant. Theoretically, this may provide a soft tissue cushion to prevent ulnoradial impingement. We have been performing this operation since 1985 and report here the results on 16 wrists in 15 patients who underwent surgery between 1985 and 1989. Patients included in this study had pain in the distal radioulnar joint due to osteoarthritis, post-traumatic arthritis, or incongruity. No patients with rheumatoid or other autoimmune arthritis were included. The average follow-up period was 8 years, with a range of 5-9 years. Two groups of patients were studied, including seven who had failure of prior ulna head resection and eight who underwent this procedure (one on both wrists) concomitantly with ulnar head resection.
8558027 The role of BALB/c donor CD8+ lymphocytes in graft-versus-host disease in (BALB/c x A/J)F1 1996 Feb 1 To investigate the role of donor T lymphocyte subsets in the development of chronic graft-vs-host disease (GVHD) induced in (BALB/c x A/J)F1 (CAF1) mice by injecting BALB/c lymphoid cells, we analyzed the effect that CD8+ cell removal from donor inoculum has on the manifestation of the disease. Compared with age- and sex-matched CAF1 mice injected with whole lymphocyte inoculum, CAF1 mice injected with CD8(+)-depleted inoculum exhibited: 1) a higher incidence and exacerbation of nephritis by immunocomplexes; 2) higher (five- to sevenfold) spontaneous IL-4 production; 3) higher frequency titer and precocity of anti-dsDNA, anti-histone, and IgM and IgG rheumatoid factors; 4) a dramatic change in the frequency and titer of anti-U1 small nuclear ribonucleoprotein Abs; and 5) a markedly decreased engraftment (10- to 15-fold) on BALB/c donor lymphocytes. In contrast, rheumatoid arthritis-like disease, a later clinical manifestation of the GVHD in CAF1 + BALB/c model, is not present in the CD8(+)-depleted model (CAF1 + CD8-BALB/c). Considered together, these data suggest that CD8+ donor T lymphocytes play an important role in the degree of chimerism, modulation of the response to autoantigens, and clinical aspects developed in the GVHD model presented here.
8838510 Direct suppression of human synovial cell proliferation in vitro by salazosulfapyridine an 1996 Jan OBJECTIVE: The mechanism of disease modifying antirheumatic drugs (DMARD) is incompletely understood. We investigated in vitro the effect of DMARD such as bucillamine (Buc), salazosulfapyridine (SASP), and D-penicillamine (D-Pen) on the proliferation of human synovial cells in patients with rheumatoid arthritis (RA). METHODS: We evaluated the inhibitory effect of DMARD on [3H]-thymidine incorporation and cytokine production in synovial cells from patients with RA. Moreover, the expression of cytokine and protooncogene mRNA in synovial cells was determined by reverse transcription polymerase chain reaction methods. RESULTS: The proliferation of synovial cells and interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) production of synovial cells were significantly inhibited by Buc and SASP in the concentration range of 1 to 100 microM in a dose dependent manner. In contrast D-Pen had no apparent effect at the same concentrations. Subsequently, the inhibitory effects of these compounds on transcriptional regulation of IL-1 beta, IL-6, and c-fos, which are well known to play an important role in synovial cell proliferation, were clarified. Overexpression of c-fos mRNA was inhibited by Buc and SASP. Moreover, the combination of low dose Buc and SASP inhibited synovial cell growth and transcriptional regulation of these mRNA. CONCLUSION: DMARD may have a direct inhibitory effect on rheumatoid synovial cell proliferation without the involvement of other cellular factors, which may be a mechanism of clinical remission induced by DMARD in patients with RA.