Browse

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

ID PMID Title PublicationDate abstract
8181531 The Y chromosome-linked "autoimmune accelerating" yaa gene suppresses collagen-induced art 1994 May The Y-linked autoimmune accelerating gene mutation (yaa), first discovered in the BXSB mouse strain, is known to accelerate spontaneous autoantibody production and subsequent development of lupus disease. We have investigated the role of the yaa gene in the development of the type II collagen (CII)-induced arthritis (CIA), which is used as a model for rheumatoid arthritis. In contrast to the accelerating effects on development of lupus autoimmunity we can show that the presence of BXSB Y chromosome carrying the yaa gene block development of CIA in F1 crosses with three normally CIA-susceptible strains, DBA/1, C3H.Q and B10.Q. Backcross experiments showed an additional modulatory effect from other BXSB genes or possibly from DBA/1 X chromosome. To evaluate the effect mediated by the yaa gene alone, the BXSB Y chromosome was bred into the DBA/1 gene background. The DBA/1 congenic DBA/1.yaa male mice were less susceptible to arthritis development than their DBA/1 counterparts. (B10.QxDBA/1.yaa)F1 acquired resistance to arthritis development similar to that of DBA/1.yaa, indicating a role for the yaa gene alone. The serum levels of autoantibodies to CII were significantly suppressed in all strains carrying yaa. In DBA/1.yaa mice a reduced number of T cells were found to produce interferon-gamma after in vitro stimulation with CII. Thus, although autoreactive B cells are important in both diseases they play different roles in murine lupus and in CIA.
8783759 Screening for coeliac disease in Dutch children with associated diseases. 1996 May Our objective was to assess the frequency of coeliac disease in children with associated disorders in the province of "Zuid-Holland". The Netherlands. We therefore screened 115 children with Down's syndrome, 62 children with juvenile rheumatoid arthritis (JRA) and 46 children with diabetes mellitus for CD using the IgA-class of antigliadin, antiendomysium and antireticulin antibodies in serum, and a functional sugar absorption test. The antiendomysium antibody test was the screening test that performed the best. Every patient who has at least one positive test underwent a jejunal biopsy for the diagnosis of CD. No association could be demonstrated between CD and diabetes mellitus. The frequency of CD in Down's syndrome was 7.0%, which is much higher than that found from screening the general population. CD was found in one child with JRA (1.5%), who also had Down's syndrome. We recommend screening for CD in all persons with Down's syndrome using at least the antiendomysium antibody test.
1567557 Mapping rheumatoid factor binding sites using genetically engineered, chimeric IgG antibod 1992 Apr We are using chimeric IgG antibodies consisting of murine variable regions joined to human constant regions as rheumatoid factor (RF) binding substrates to localize and map IgM RF binding sites on IgG. Using chimeric antibodies in a modified RF ELISA, we showed that RFs from rheumatoid arthritis (RA) and Waldenstrom's macroglobulinemia (WMac) patients differ in their binding specificities for IgG3, although some of these RFs share common specificity for IgG1, IgG2, and IgG4. By shuffling constant region domains between IgG3 and IgG4, we showed that sequence variation in the CH3 domain is responsible for WMac-derived RF differentiation of IgG3 and IgG4. By making site-directed mutations in the wild-type IgG3 or IgG4 human gamma constant genes, we showed that His-435 is an essential residue in RF binding to IgG for most WMac RFs. The allotypic polymorphism in IgG3 at 436 is not responsible for differences in previous reports of high-frequency IgG3 binding by WMac RFs. A amino acid loop in the CH2 domain of IgG4 proximal to the CH2-CH3 interface is important in WMac RF binding to IgG; a more distal CH2 loop in CH2 has a more variable effect on WMac RF binding. To evaluate the contribution of the N-linked carbohydrate moiety at Asn-297 to RF binding sites on IgG, we measured RF binding to aglycosylated IgG antibodies produced by mutating the glycosylation signal Asn-297 to another amino acid. Of all four IgG subclasses, only aglycosylated IgG3 was a better RF binding substrate than its glycosylated subclass counterpart.(ABSTRACT TRUNCATED AT 250 WORDS)
8603538 Comparative microbicidal activity of synovial fluid on arthritogenic organisms. 1996 Apr There is strong circumstantial evidence to support the concept that local microbial antigens play a key role in the synovitis of reactive arthritis (ReA) patients. It is not at all clear whether these antigens reflect the sequelae of previously viable organisms once resident in the joint. To address the microbicidal activity of synovial fluid (SF) we performed quantitative cultures of arthritogenic organisms (Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae) and controls (Escherichia coli, Staphylococcus aureus) in the presence of SF from patients with ReA. There was a dramatic inhibitory effect of SF on the Gram-negative organisms (mean 1.35x10(5) organisms at 3h; 0 organisms at 24 h) in contrast to Staph. aureus (1.61x10(5) at 3h; 5.70x10(5) at 24 h). This SF bactericidal phenomenon was observed in 11/11 ReA patients, 5/8 rheumatoid arthritis (RA) patients and 1/8 osteoarthritis (OA) patients. Using a sandwich ELISA, we measured SF levels of bactericidal/permeability-increasing protein (BPI). BPI was detectable in all ReA SF (range 4.6-333ng/ml)) and RA SF (range 343-2570ng/ml), but was absent in 5/6 OA SF tested. Anti-BPI antibodies, however, did not fully neutralize the bactericidal activity of inflammatory SF. In contrast to the SF effects observed on Gram-negative bacteria, Chlamydia trachomatis cultured within HeLa cells thrived in the presence of SF. Indeed extracellular Chlamydia could easily be passaged through cultured synovial fibroblasts in the presence of SF. These findings indicate that the potent microbicidal activity of SF may account for the failure to recover viable organisms from the joint in ReA. Chlamydia alone amongst these organisms demonstrates resistance to microbicidal effect of SF, which may relate to the pathogenesis of Chlamydia-induced arthritis.
7957574 Transfer of Sjögren's syndrome-like autoimmune lesions into SCID mice and prevention of l 1994 Nov We describe the successful transfer of murine Sjögren's syndrome-like autoimmune lesions from MRL/lpr mice (H-2k) to severe combined immunodeficiency (SCID) mice (H-2d) and prevention of lesions by anti-CD4 and -T cell receptor V beta 8 antibody treatment. Mononuclear cells (1 x 10(6)) isolated from the inflamed submandibular salivary gland tissues of MRL/lpr mice were transferred intraperitoneally into SCID mice. Autoimmune lesions resembling those seen in Sjögren's syndrome developed in the salivary and lacrimal glands of SCID mice 8 weeks after the injection, whereas other organs did not show any lesion. This pathology resembles Sjögren's syndrome in humans involving both the salivary and lacrimal glands. Immunohistochemically, a major proportion of these infiltrating cells in transferred SCID mice were CD4+ and V beta 8+. When the spleen cells from MRL/lpr mice were injected, severe inflammatory lesions, probably resulting from a graft-versus host reaction, were observed in multiple organs of SCID mice. The disease could not be induced by intraperitoneal administration of the sera from MRL/lpr mice, or of the spleen cells from C3H/He (H-2k) and BALB/c (H-2d) mice. We detected autoantibody production specific for the salivary gland tissue in sera from transferred SCID mice. Moreover, we found that the lesions were prevented by administration of the isolated cells treated in vitro with anti-CD4 and anti-V beta 8 monoclonal antibodies. These results suggest that CD4- and V beta 8-bearing T cells are involved in recognizing an autopeptide and triggering autoimmunity in the salivary and lacrimal glands, and therapies designed with anti-CD4 and anti-V beta 8 antibodies may prove effective in treating the murine autoimmune disease.
7799344 T cell receptor V alpha repertoire of infiltrating T cells in labial salivary glands from 1994 Sep OBJECTIVE: To analyze the T cell receptor (TCR) V alpha repertoire of infiltrating T cells in labial salivary glands of patients with Sjögren's syndrome (SS). METHODS: TCR V alpha genes of infiltrating T cells in lips from 2 patients with SS were examined, using the double step inverse polymerase chain reaction. Four and 7 clones encoding the VJC alpha region were established and sequenced, respectively. RESULTS: All 4 clones used the V alpha 17.1 gene in one patient, while 3 (42.8%) of 7 clones from the other patient used the V alpha 2 family gene (V alpha 2.1, V alpha 2.2, V alpha 2.4), and the other 3 clones used the V alpha 11.1 family gene. A comparison using labial salivary glands and peripheral blood showed that the predominant expression of V alpha 2, V alpha 11.1, and V alpha 17.1 gene segments is specific in the salivary glands. CONCLUSION: The TCR V alpha repertoire of infiltrating T cells from the lips of 2 patients with SS was relatively restricted in individual patients, thereby suggesting the limited heterogeneity of these cells in salivary glands.
1482299 [A case of sarcoidosis associated with Sjögren's syndrome]. 1992 Oct A 49-year-old woman, who has had a past history of Raynaud's phenomenon since 1981, dry mouth since 1987 and dry eyes since 1990, was admitted to our hospital complaining of general fatigue, bilateral gonalgia, and shortness of breath in April 1991. Physical examinations revealed bilateral parotid gland enlargement and bilateral uveitis. Her family history included mixed connective tissue disease in her eldest daughter. Laboratory findings indicated an elevated erythrocyte sedimentation rate, hypergammaglobulinemia, and elevation of serum lysozyme and angiotensin converting enzyme levels. Antinuclear antibodies, anti-SSA antibodies, anti-SSB antibodies were positive, while tuberculin test was negative. Chest X-rays showed bilateral hilar lymphadenopathy and small nodular shadows in both lung fields. Increases in lymphocytes and the CD4/CD8 ratio of T cells were noted in alveolar lavage fluid. Renal biopsy revealed non-caseous granulomas. Other remarkable findings included positive Schirmer's test, apple tree lesions by sialography and chronic sialoadenitis by biopsy of the labial minor salivary gland. On the basis of all these findings, we diagnosed her as suffering from sarcoidosis with Sjögren's syndrome. After oral administration of prednisolone, her shortness of breath, hilar lymphadenopathy and small nodular shadows in the lung field disappeared, but the patient was transferred to the department of urology due to the onset of hydronephrosis. This case is noteworthy because sarcoidosis associated with Sjögren's syndrome has been reported in only 11 cases in the literature.
1565490 Lacrimal and salivary gland inflammation in the C3H/Ipr autoimmune strain mouse: a potenti 1992 Apr Sjögren's syndrome is an autoimmune inflammatory disease that affects the lacrimal and salivary glands. To identify a potential animal model for study of Sjögren's syndrome, an evaluation was made of lacrimal and salivary glands in the C3H/Ipr autoimmune strain mouse at ages before (2 months) and after (5 months) systemic autoimmune disease onset at 3 to 4 months. Quantitative and qualitative analyses of C3H/Ipr lacrimal and salivary (parotid, submandibular, and sublingual) gland histopathology were performed using age-matched C3H/HeJ nonautoimmune mice to control for inflammation of nonautoimmune origin. No lacrimal or salivary gland inflammation was seen in either of the strains at 2 months of age and measures of systemic autoimmune disease were negative. At 5 months of age, the nonautoimmune C3H/HeJ controls showed a slight increase in lacrimal gland inflammation, but this was not significantly different from the 2 month old controls. A significant increase in lacrimal gland inflammation was found in the 5 month old C3H/Ipr autoimmune mice in a histologic pattern similar to that of Sjögren's syndrome in human beings. Furthermore, the degree of inflammation was positively correlated with serum immune complexes and spleen weight. Sporadic inflammation of the submandibular gland was seen in both autoimmune and control mice, but this was neither statistically significant nor correlated with measures of autoimmunity. No significant inflammation was seen in the parotid or sublingual glands.
8364849 The optical pedobarograph. 1993 Jul The optical pedobarograph has proven to be very helpful in studying foot pressure abnormalities in a variety of clinical conditions and especially in diabetes mellitus and rheumatoid arthritis. Studies using this device have provided a very good insight into the etiopathogenesis and natural history of foot disorders. It has also allowed the conduction of intervention trials which assess the efficacy of new treatment. The main advantages of the pedobarograph include accuracy, reliability and high spatial resolution. Its drawbacks are its size and that it can only measure pressures between the foot-floor interface.
8722201 Autoimmune diseases and monoclonal gammopathies. 1996 Jan Rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome are nonorgan-specific autoimmune diseases in which serum monoclonal immunoglobulins (MIg) have been identified repeatedly. Conversely, autoimmune traits have been detected in a number of patients with lymphoproliferative disorders such as multiple myeloma, Waldenström's macroglobulinemia and chronic lymphocytic leukemia. The latter cells have even shown to produce multispecific autoantibodies. One connection between connective tissue diseases and Iymphoid malignancies might be established by a limitedfraction of B Iymphocytes expressing the CD5 marker.
7584656 The management of leg ulcers in a patient with ulcerative colitis. This case study details 1995 Oct Pyoderma gangrenosum is a rare condition which is sometimes associated with ulcerative colitis and Crohn's disease. The pathological basis is not completely understood but it may be caused by vasculitis. The lesions are typically said to have purple overhanging edges and a necrotic base. The condition may also occur with rheumatoid arthritis, multiple myeloma and leukaemia. The treatment of choice is systemic steroids but it may also respond to azathioprine, minocycline or clofazimine.
8415881 Rhythms in the immune system. 1993 This report reviews the evidence that cells within the immune system are subject to rhythmic influences that affect numbers of circulating cells and their function both in vitro and in vivo. It is concluded that, although periodicity has clearly been demonstrated for numbers of immunocompetent cells in the circulation, significant functional changes have not been consistently observed. A number of neuroendocrine hormones, which modulate immune responsiveness in vitro and which are released in a rhythmic manner, are considered as mediators of the observed effects on the immune system and this is related to changes in expression and activity of immune-mediated diseases such as rheumatoid arthritis.
1589908 Therapeutic potential of cytokine manipulation. 1992 Apr Interleukin 1 is just one of a large, growing, collection of potent cytokines that are produced by a variety of cells and have a myriad of overlapping activities. Many of these cytokines have important pathophysiological actions in diseases ranging from rheumatoid arthritis to AIDS. Selective inhibition of the synthesis or of the action of specific cytokines may have therapeutic benefit. In this review, Brian Henderson and Simon Blake discuss the ways in which cytokine function could be manipulated pharmacologically for therapeutic benefit.
22959043 Total shoulder arthroplasty with a tissue-ingrowth glenoid component. 1992 Mar A newly designed, uncemented, tissue-ingrowth glenoid component with a porous surface was used in association with the Neer humeral head prosthesis for 32 total shoulder arthroplasties in 29 patients. The diagnoses for the shoulders were osteoarthritis in 17, rheumatoid arthritis in eight, and traumatic arthritis in seven. Follow-up evaluations averaged 51 months (range, 29 to 80 months). Five complications occurred, necessitating four reoperations: two for glenoid component dissociation, one for humeral loosening, and one for infection. Little or no pain was experienced after the operation in 27 (96%) of the 28 shoulders that required no additional surgery. Average active abduction was 145°, average external rotation was 59°, and median internal rotation was to 112. Three glenoid components had probable loosening on radiographic examination. Eight shoulders had some degree of instability; a complication related to the glenoid component (polyethylene dissociation) or probable loosening not yet requiring reoperation developed in four of these (p < 0.02). These data support the continuing use of an uncemented, tissue-ingrowth glenoid component in arthritic shoulders with adequate bone support. Joint instability must be avoided to lessen complications and the need for revision surgery.
7653940 Autoimmune sialadenitis: a form of onset of Sjögren's syndrome? 1995 We analyzed phenotype, activation factors and adhesion molecules in minor salivary glands of patients with incomplete Sjögren's syndrome (SS) criteria and those with autoimmune diseases without defined SS criteria who presented non-specific sialadenitis. These data were correlated with those observed in patients with established SS. A total of 76 minor salivary gland biopsies were analyzed. Twenty-five patients had defined SS, 23 probable SS and 28 had diffuse infiltrates without forming foci (12 had probable SS and 16 had autoimmune disease without associated SS). When a group of 23 patients with focal infiltrates ("focal sialadenitis") and probable SS was compared with another of 25 with defined SS, no significant differences were detected in the phenotype, activation or adhesion molecules studied or in HLA-DR expression in epithelium. In patients with diffuse infiltrate ("non-specific sialadenitis"), no differences were found in phenotype cell activation molecules expression was observed in the lymphocytes of some biopsies of patients with autoimmune disease without SS, though without statistical significance. Statistically significant differences were found in HLA-DR expression in epithelium.
8398611 New developments in Sjögren's syndrome. 1993 Sep The growing number of conditions associated with sicca manifestations and focal sialadenitis has shed further light on the heterogeneity of Sjögren's syndrome. Viral and retroviral infections, lymphoproliferative disorders, as well as various autoimmune syndromes, target the lacrimal and salivary glands and incite a local immune response. This awareness has not only intensified the search for a viral or retroviral cause of Sjögren's syndrome, but it has also provided a daunting challenge to investigators who are striving to improve diagnostic testing and classification. A better understanding of Sjögren's syndrome is needed to develop innovative and more effective therapies.
8912510 Lymphocyte apoptosis and apoptosis-associated gene expression in Sjögren's syndrome. 1996 Nov OBJECTIVE: To study the mechanism and regulation of apoptosis in peripheral blood T and B lymphocytes from patients with Sjögren's syndrome (SS). METHODS: The mode of in vitro lymphocyte death in the peripheral blood of patients with SS was determined by fluorescence microscopic analysis, terminal deoxynucleotidyl transferase assay, and DNA fragmentation analysis. Apoptotic cell death of T and B cells was determined at 48 hours of culture by fluorescence-activated cell sorter analysis of propidium iodidestained cells. Messenger RNA (mRNA) expression of bcl-2, bcl-x, bax, and c-myc in T and B cells was determined by enzyme-linked immunosorbent assay-polymerase chain reaction (ELISA-PCR). Expression of bcl-xL and bcl-xS was determined by Southern blot analysis of PCR products. Gene expression was calculated as the ratio of each gene message to the message of the GAPDH gene. Bcl-2 protein levels in SS T cells were determined by ELISA. RESULTS: SS T cells showed increased in vitro apoptosis compared with normal T cells (mean +/- SD 12.3 +/- 4.5% versus 7.3 +/- 2.0%; P < 0.01). Freshly isolated SS T cells showed increased expression of bcl-2 mRNA compared with normal controls (mean +/- SD 1.50 +/- 0.65 versus 0.88 +/- 0.23; P < 0.05). There was no significant difference in levels of bax or c-myc mRNA in T cells and B cells between SS patients and normal controls. When SS T lymphocytes were cultured in vitro for 72 hours, Bcl-2 protein levels decreased with time. CONCLUSION: SS T cells showed accelerated apoptosis in vitro. Freshly isolated SS T cells had increased expression of bcl-2. An increase in death-promoter signals and decrease in death-suppressor signals in vitro may have been responsible, in part, for the apoptosis in SS T lymphocytes.
8934921 Sjögren's syndrome: immunobiology of exocrine gland dysfunction. 1996 Apr Sjögren's syndrome is an autoimmune disorder characterized by dryness of the eyes and mouth. The frequency of this disorder remains controversial, due to absence of a universally accepted classification system. In the San Diego and San Francisco classification systems for primary Sjögren's syndrome, evidence for an autoimmune process and focal lymphocytic infiltration of the salivary or lacrimal gland is required for diagnosis. This paper reviews the genetic and environmental factors that have been associated with the autoimmune process in Sjögren's syndrome. Key immunopathologic features include: (a) an increased prevalence of particular HLA-DR/DQ alleles; (b) induction of HLA-DR/DQ proteins on the epithelial cells in salivary and lacrimal gland biopsies; (c) infiltration of the glands by CD4+ T-cells that transcribe IL-2 and IFN-gamma; (d) induction of granzyme A and perforin in CD4+ T-cells, suggesting a mechanism of cellular destruction of the glands; (e) clonal expansion of B-cells that use a particular light chain within the salivary gland; (f) production of autoantibodies against nuclear antigens SS-A (60 and 52 kDa) and SS-B (48 kDa), indicating a failure of normal tolerance mechanisms; and (g) increased frequency of B-cell non-Hodgkin's lymphoma. Indirect evidence has suggested a potential role for viruses (especially members of the herpesvirus and retroviral family) as co-factors.
7999742 Bilateral parotid MALT lymphoma and Sjögren's syndrome. 1994 Oct A patient with Sjögren's syndrome who developed bilateral parotid lymphoma is described. The management is discussed emphasising difficult aspects of the diagnosis and treatment.
7952145 Pathogenesis of Sjögren's syndrome-like autoimmune lesions in MRL/lpr mice. 1994 Aug Sjögren's syndrome in humans is a chronic inflammatory disease with a presumed autoimmune etiology of the exocrine organs, involving in particular the salivary and lacrimal glands. The pathogenesis of this syndrome remains unclear, but the majority of infiltrating cells in the salivary glands are CD4+ T cells both in humans and rodents. Since many cytokines are involved in the development of T cell-mediated autoimmunity, local cytokine gene expression was analyzed in vivo using an animal model for Sjögren's syndrome in MRL/lpr mice. Overexpression of interleukin-1 (IL-1)beta and tumour necrosis factor (TNF) was detected before the onset of inflammatory lesions in the salivary gland, and the upregulation of IL-6 mRNA was also found in accordance with autoimmune sialadenitis in MRL/lpr mice. The inflammatory cytokines such as IL-1 beta, TNF, and IL-6 have proved to play important roles as regulatory proteins inducing autoimmune phenomena. In addition, the expression of T cell antigen receptor beta (TCR) beta transcripts in the salivary gland tissues was analyzed. Transcript for V beta 8 was predominantly detected in the T cells infiltrating sialadenitis from the onset of the disease, suggesting that CD4+ T cells bearing TCR V beta 8 play an essential role in recognizing unknown autopeptide in the autoimmune sialadenitis of MRL/lpr mice. Furthermore, Sjögren's syndrome-like autoimmune lesions were successfully transferred into severe combined immunodeficiency (SCID) mice, and these lesions were prevented by administration of anti-CD4, and anti-V beta 8 monoclonal antibodies. This article will review recent observations of these pathogenetic analyses of autoimmune sialadenitis as it occurs in MRL/lpr mice.