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ID PMID Title PublicationDate abstract
7849389 T cell abnormalities in mixed connective tissue disease complicated with Klinefelter's syn 1994 Nov We report a 28-year-old Japanese with Klinefelter's syndrome who developed mixed connective disease (MCTD) and Sjögren syndrome. Previously being well, he presented with Raynaud's phenomenon, dry eye, fever and polyarthralgia. Clinical examinations revealed anti-nRNP autoantibody, leukopenia and lung fibrosis. Then he was found to have Klinefelter's syndrome. Flow cytometric analysis showed a relative increase of peripheral CD8+ T lymphocytes carrying either HLA-DR or CD57. Lymphocyte IL-2 production induced in vitro by concanavalin A was decreased. Such T cell abnormalities may be implicated in the development of autoimmune disease in Klinefelter's syndrome.
9068010 Role of the ICAM-1/LFA-1 pathway during the development of autoimmune dacryoadenitis in an 1996 We have analyzed the role of cell adhesion molecules during the development of autoimmune dacryodenitis in an NFS/sld mouse model for primary Sjögren's syndrome. The expression of cell adhesion molecules was assessed by RT-PCR and immunohistochemistry. We detected an up-regulation of local cell adhesion molecule genes (ICAM-1, LFA-1, CD44 and Mel-14) in the course of autoimmune lacrimal gland diseases. Immunohistochemically, ICAM-1 was localized exclusively in the endothelial cells of variously sized blood vessels before the onset of disease, and LFA-1, CD44 and Mel-14, expressing infiltrating cells, were found within these lesions. When the therapeutic effects of blocking cell adhesion molecules in vivo were examined, antibodies to ICAM-1 in combination with anti-LFA-1 prevented the development of autoimmune lacrimal gland diseases in NFS/sld mice. These data suggest that in Sjögren's syndrome-like autoimmune dacryoadenitis in NFS/sld mutant mice, the ICAM-1/LFA-1 pathway may play a crucial role in the development and subsequent progression of T-cell-mediated autoimmunity in the lacrimal glands.
7789062 Cogan's syndrome: a new possible complication of antiphospholipid antibodies? 1995 Mar A 55-year-old woman with a six-year history of Sjögren's syndrome (SS) and the positivity of IgG and IgM antiphospholipid antibodies (aPL) developed a sudden onset of sensorineural hearing loss associated with vertigo. This suggested the presence of an atypical Cogan's syndrome (CS), which might be a focal, neurological complication of aPL.
8203230 Diagnostic specificity of anti-neutrophil cytoplasmic antibodies (ANCA) in otorhinolaryngo 1994 The incidence and titer of ANCA were examined with 871 sera from patients with otorhinolaryngological diseases at our hospital. The cytoplasmic pattern of ANCA (c-ANCA) whose titer was more than 16 was detected only in the sera of patients with Wegener's granulomatosis (WG). The incidence of c-ANCA in active WG was more than 90%. The perinuclear staining pattern of ANCA (p-ANCA) was detected in almost 40% of patients with Sjögren's syndrome, 2.0% of inflammatory diseases and 1.0% of tumorous diseases. A high diagnostic value of c-ANCA in WG was found in patients with otorhinolaryngological diseases.
8440071 Rheumatoid factor isotypes in serum and salivary fluid of patients with primary Sjögren's 1993 Jan Salivary fluid and serum levels of immunoglobulin and rheumatoid factor (RF) isotypes were measured in patients with primary Sjögren's syndrome (SS) as well as in patients suspected of the syndrome in whom the diagnosis could be excluded (NON-SS) in order to investigate the site of RF production in primary SS and to determine the diagnostic value of determination of salivary fluid levels of RF. Increased salivary fluid levels of IgA-RF were found in 46% of 39 primary SS patients, 14% of 42 NON-SS patients, and in 2% of 41 healthy controls. Salivary fluid levels of other RF isotypes were not increased in the patient groups. The frequency of elevated titers of IgA-, IgG-, and IgM-RF in serum of primary SS patients was 51, 7, and 59%, respectively. The levels of IgA, IgG, and IgM in salivary fluid of primary SS patients were increased in 36, 31, and 23%, respectively. Comparison of RF levels in samples of serum and saliva from primary SS patients after correction for immunoglobulin levels indicated local production of IgA-RF in salivary glands. Significant positive correlations were found between IgA-RF levels in serum and saliva but not between the levels of immunoglobulin isotypes in the two compartments. The results of this study show that (1) increased levels of IgA-, but not IgG- and IgM-RF occur in saliva of primary SS patients; (2) IgA-RF is locally produced in the salivary glands; (3) the stimuli for IgA-RF production in the systemic and secretory compartment may be similar; and (4) measurement of both IgA- and IgM-RF in serum may be used as adjunctive diagnostic procedure for primary SS.
1348286 Expression of the CD54 (ICAM-1) and CD11a (LFA-1) adhesion molecules in oral mucosal infla 1992 Feb Previous studies of chronic dermatoses have suggested that expression of the CD54 cell surface antigen (intercellular adhesion molecule-1, ICAM-1) by keratinocytes is a feature of chronic inflammation. However, whether such expression is a prerequisite for intraepithelial migration of lymphocytes is unclear. The present study evaluated the expression of CD54 and its ligand, CD11a (lymphocyte function-associated antigen, LFA-1) in oral lesions of lichen planus, recurrent aphthous stomatitis, secondary Sjögren's syndrome and traumatic ulceration using an immunoperoxide technique. In 33 of 56 lesions examined, substantial numbers of CD11a + cells were present within oral mucosal epithelium despite an absence of detectable keratinocyte CD54 antigen expression. Consequently, CD54/CD11a adhesion interactions may not be critical in the initiation of oral mucosal inflammation.
8748946 Microvascular architecture and exchange in synovial joints. 1995 Sep The microcirculation of the synovial lining of joints displays many fascinating adaptations to function. One primary function is to supply nutrients to the avascular cartilage, whose chondrocytes are metabolically active but are relatively vast distances from the nearest capillary (> 1 cm in the center of a human knee). Exchange is facilitated by a high density of fenestrated capillaries situated very close to the synovial surface (an arrangement disrupted in rheumatoid synovium) with fenestrations preferentially oriented toward the joint cavity. Even so, diffusion alone is too slow to supply central chondrocytes with glucose. The problem is solved by the synovial microcirculation generating intra-articular fluid (synovial fluid) that transports glucose by convection during joint movement. Synovial fluid is a plasma ultrafiltrate into which hyaluronan has been secreted, and it also serves to lubricate the joint. The joint cavity offers unusually easy access to the interstitial side of the microcirculation because the synovial cell layer is discontinuous, with an interstitial matrix between capillary and joint cavity. This allows the experimental study of the effect of the extravascular Starling "forces" (hydraulic and colloid osmotic pressure) on fluid exchange. One unexpected outcome has been the finding that a substantial part of the hydraulic resistance to fluid transport between blood and joint cavity resides in the series interstitial layer rather than in the capillary wall. Another is that, under appropriate boundary conditions (joint angle, etc.) fluid can simultaneously filter into the cavity in some regions (synovium directly overlying capillaries) and out of the cavity into subsynovium in other regions (synovium in the mesh space between capillaries) to produce a turnover of synovial fluid.
8343190 Connective tissue activation. XXXVI. The origin, variety, distribution, and biologic fate 1993 Aug OBJECTIVE: To determine the origin, distribution, and biologic fate of platelet-derived connective tissue activating peptide-III (CTAP-III), to define the relative amounts of the antigen forms (CTAP-III, beta-thromboglobulin [beta-TG], neutrophil activating peptide-2 [NAP-2]) in plasma of normal persons and those with rheumatic or end-stage renal disease, and to define the isoforms of CTAP-III in platelets, plasma, transudates, and tissue deposits. METHODS: CTAP-III in plasma was measured by enzyme-linked immunosorbent assay, and growth promoting activity of CTAP-III isoforms was tested in synovial and peritoneal cell cultures by measuring increased synthesis of 14C-glycosaminoglycan (14C-GAG) and 3H-DNA. Isolated CTAP-III was characterized by Western blotting, microsequencing, and mass spectrometry. RESULTS: CTAP-III was the primary isoform of this antigen family in normal platelets and platelet-rich plasma; beta-TG and NAP-2 accounted for < 1% of CTAP-III isoforms. Previously undescribed isoforms, i.e., CTAP-III des 1, des 1-2, des 1-3, and a phosphate adduct of CTAP-III, were observed in varying amounts. Elevated plasma levels of CTAP-III antigen were found in a substantial fraction of rheumatic disease patients: 24% of those with rheumatoid arthritis, 36% of those with systemic sclerosis, and 15% of those with systemic lupus erythematosus. All 10 patients with end-stage kidney disease had marked elevations of plasma CTAP-III levels, which stimulated DNA and GAG synthesis by peritoneal cells in culture. Only large isoforms (such as CTAP-III) were detected in venous plasma of normal subjects, rheumatic disease patients, and patients receiving long-term dialysis. Normal human spleen and kidney contained substantial (micrograms/gm) amounts of CTAP-III and traces of an isoform with the electrophoretic mobility of CTAP-III des 1-15/NAP-2. Liver, lung, and urine contained lesser (ng/gm) amounts of CTAP-III. CONCLUSION: These data show that, among the 10 known isoforms, intact CTAP-III itself was the major circulating isoform (> 90%), and beta-TG was the most rare (0-1%). Deposition of CTAP-III in tissues, such as synovium, spleen, and kidney, is associated with partial processing to NAP-2-like isoforms and the potential to induce neutrophil and fibroblast activation in patients with rheumatic or end-stage renal disease.
7964507 Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection o 1994 Dec 1 Intraperitoneal injection of pristane (2,6,10,14 tetramethylpentadecane) is a standard technique for obtaining monoclonal antibody-enriched ascitic fluid. However, pristane also induces plasmacytomas and an erosive arthritis resembling rheumatoid arthritis in BALB/c mice, probably as a consequence of enhanced interleukin 6 production. We report here that the production of autoantibodies characteristic of systemic lupus erythematosus (SLE) is a further consequence of injecting pristane in BALB/c mice. Anti-Su antibodies appeared as early as 1-2 mo after a single injection of 0.5 ml pristane, followed by anti-U1RNP and anti-Sm antibodies after 2-4 mo. Within 6 mo of pristane injection, 9 of 11 BALB/c mice had developed anti-Su, anti-U1RNP, anti-U2RNP, anti-Sm, and possibly anti-U5RNP antibodies. Autoantibodies were not produced by 20 BALB/c mice of the same age and sex that were not injected with pristane. Thus, autoantibodies characteristic of lupus were induced in mice that are not usually considered to be genetically susceptible to the disease. The induction of autoantibodies associated with SLE by pristane may be relevant to understanding the role of abnormal cytokine production in autoantibody production and the pathogenesis of autoimmune disease. Furthermore, the induction of high titer autoantibodies by pristane dictates caution in the use of ascitic fluid as a source of monoclonal antibodies, since the polyclonal antibodies induced by pristane may copurify with the monoclonal antibody secreted by an injected hybridoma.
7684683 Restricted T cell receptor expression by human T cell clones specific for mycobacterial 65 1993 Jun We have examined the T cell receptor (TcR) expression of clones specific for epitopes of mycobacterial 65-kDa heat-shock protein (hsp65) in the context of two different HLA molecules, and used this system as a model to assess the selection of T cells responsive to this antigen in vivo. DR3-restricted clones were raised from both the synovial fluid (SF) and peripheral blood (PB) of a patient with reactive arthritis in three separate cloning events. Five of five SF-derived clones tested expressed either V beta 5.2 or a closely related beta chain, V beta 5.6. The alpha chains expressed by V beta 5.2+ and V beta 5.6+ clones were from different families, V alpha 2.4 and V alpha 23.2, respectively. Nine of ten clones derived from two cloning procedures on PB taken 3 years later also expressed either V beta 5.2 or V beta 5.6. This suggests that the TcR repertoire for recognizing this major histocompatibility complex/peptide complex is relatively restricted and favors the use of V beta 5. Conservation of the beta chain third complementarity-determining region (CDR3) sequence was not evident, however. Sequencing alpha and beta chains of representative V beta 5.2+ and V beta 5.6+ PB-derived clones revealed TcR which were identical to those utilized by the SF-derived clones, showing that the repertoire for recognition of this antigen is stable over time. Similar studies of TcR expression were carried out on hsp65-specific, DP4-restricted clones derived from the SF of a patient with rheumatoid arthritis by two independent cloning procedures. There was conservation of alpha chain usage, since all clones expressed a member of the V alpha 1 family, but again CDR3 sequence conservation was not apparent. beta chain usage was not restricted since different clones expressed V beta 6.7, V beta 22.3 and V beta 12. Subtle differences in epitope specificity were detected for two clones with differing TcR. Once more, T cell clones with identical alpha and beta TcR chains were obtained from the separate cloning procedures, suggesting oligoclonalty of T cells with this defined specificity in the patient's SF.
8578313 Vasculitides in hairy cell leukemia. 1995 Oct Forty-two cases of vasculitis coincident with hairy cell leukemia (HCL) have been reported, of which 17 had panarteritis nodosa (PAN), 21 had cutaneous leukocytoclastic vasculitis (LCV), and 4 had vessel wall infiltration by hairy cells. PAN generally occurred after the diagnosis of HCL, splenectomy, and infection. HBs antigen was detected in 3 of 12 patients tested, whereas immune complexes were positive in 3 of 4 patients tested. LCV was often preceded by infection and was frequently detected before HCL. Serum immunoglobulin levels were generally elevated when measured. Cryoglobulins, complement, rheumatoid factor, and antinuclear antibodies showed no clear association with vasculitis in HCL. These reports suggest a role for infection and splenectomy as contributing factors to vasculitis.
7584125 A recombinant adenoviral vector expressing a soluble form of VCAM-1 inhibits VCAM-1/VLA-4 1995 Sep Intra-articular injection of recombinant adenovirus has been shown to be a feasible approach to the introduction of genetic reagents into synovial tissues in vivo. Rheumatoid arthritis (RA) is an autoimmune disorder characterized by the infiltration of lymphocytes and monocytes into inflamed synovium. It has been hypothesized that the recruitment of T lymphocytes/monocytes into sites of chronic inflammation is mediated by enhanced binding of very late antigen-4 (VLA-4) to vascular cell adhesion molecule-1 (VCAM-1) expressed on microvascular endothelial cells. Additional evidence suggests that VLA-4 binding continues to be important within the inflamed synovial membrane, where it appears to play a role in T cell retention and activation. A feasible therapeutic strategy for RA could be to utilize a soluble congener of the VCAM-1 molecule to block VLA-4 binding. In order to test this concept, a recombinant serotype Ad5 human adenovirus encoding a secreted form of VCAM-1 (Ad.CBsVCAM) was constructed. Human synoviocytes were readily infected in vitro with Ad.CBsVCAM, and sVCAM-1 expression and processing were analyzed by immunoprecipitation studies. Secretion of transgenic sVCAM was identified by ELISA of tissue culture supernatants, and biological activity was demonstrated with cell adhesion assays. In vivo, transgenic sVCAM-1 expression was determined by immunohistochemical analysis and in situ hybridization of synovial tissue, and secretion of transgenic sVCAM-1 was demonstrated by ELISA of tidal knee lavage fluid. The results showed that recombinant adenovirus can mediate the expression of a biologically active sVCAM-1 by synoviocytes in vivo and suggest that this strategy may be useful for inhibiting T lymphocyte retention and activation within rheumatoid synovium.
7825408 Topical cyclosporin treatment of keratoconjunctivitis sicca in secondary Sjögren's syndro 1994 Aug Topical cyclosporin 2% in olive oil was investigated for its possible immunoregulatory role on the dry eye state in patients with secondary Sjögren's syndrome. The study was a randomized, double-masked, placebo-controlled trial. Thirty eyes of 15 patients were randomized to undergo treatment with topical cyclosporin in olive oil and 30 eyes of the other 15 patients received a placebo, which was the sterile olive oil used as a vehicle for the cyclosporin. The effect of the 2-month long treatment with either medication on the status of the dry eye state was measured by Schirmer-I test, tear film break-up time and rose bengal staining. There was a significant increase in the break-up time and a significant decrease in rose bengal staining score between the cyclosporin and control groups at the end of the 2-month study period (p < 0.01). Schirmer-I test remained unaffected (p > 0.05). These results probably indicate that topical cyclosporin modulates the goblet cell function in secondary Sjögren's associated keratoconjunctivitis sicca and through this mucus enhancing action or some other mechanism not yet known, helps to maintain the structural integrity of the epithelium.
1626074 Anti-La antibodies. 1992 May Anti-La antibodies usually occur in sera with anti-Ro antibodies and represent important serologic markers of Sjögren's syndrome and neonatal lupus erythematosus. In addition to their diagnostic and prognostic significance, anti-La antibodies have proved valuable reagents for molecularly characterizing its antigenic target, which is a 47 kD ribonucleoprotein located in the nucleus and cytoplasm of mammalian cells. The isotype distribution and fine specificity of the anti-La response as well as its associations with HLA-DR and DQ loci suggest that these autoantibodies arise by a T cell-dependent, antigen-driven mechanism. Further insights into the mechanisms of anti-La production in humans may be gained by studying experimental animal models that develop these antibodies spontaneously or through induction by various immunization protocols.
1604418 [A case of systemic lupus erythematosus (SLE) developing pan-dysautonomia]. 1992 Feb A 43-year-old woman who had been diagnosed as primary Sjögren's syndrome since 1986 developed severe constipation, urinary retention, dizziness at standing and polyarthralgia in February, 1990. Laboratory tests revealed proteinuria, hypocomplementemia and high titer of anti-DNA antibody. Diagnosis of SLE was made and she was admitted to our hospital on April 2, 1990. Physical examination on admission showed that she also had asymmetric pupils, impairment of sweating, orthostatic hypotension, neurogenic bladder, gastro-intestinal dysmotility and the diminution of R-R interval variability during deep breathing on the electrocardiogram. These findings suggested that she had pan-dysautonomia but there were no signs of motor and sensory disturbance. Because other diseases such as diabetes mellitus and amyloidosis which induced dysautonomia could be ruled out, her pan-dysautonomia seemed to be due to SLE. After the treatment with steroid pulse therapy, most of her dysautonomia improved rapidly. However, some of the disturbance had persisted for a long time. Pan-dysautonomia has been rarely reported as a complication of SLE, and high dose of steroid therapy at the early stage should be considered.
8722202 Sjögren's syndrome, mixed cryoglobulinaemia and the monoclonal gammopathies. 1996 Jan Sjögren's syndrome (SS) represents a pathological model of the evolution from polyclonal B lymphocyte activation to oligo-monoclonal B cell expansion, which may culminate in the development of a true lymphoproliferative disease. The different phases of this process are usually marked by the appearance of type II mixed cryoglobulins in which the monoclonal component is commonly represented by an IgM with rheumatoid factor activity. A similar mechanism exists in mixed cryoglobulinaemia (MC), a different pathological entity in which hepatitis C virus infection has been demonstrated to play an important etiopathogenetic role. Although there are significant differences between SS and MC, they also share many clinical and immunological characteristics, which suggest that common pathogenetic mechanisms may underlie both disorders.
8835241 Histopathology of renal biopsies with correlation to clinical findings in primary Sjögren 1995 Nov OBJECTIVE: To characterise the renal histopathological lesions in patients with primary Sjögren's syndrome and to correlate the findings with the clinical manifestations. METHODS: Kidney and labial salivary gland biopsies from ten patients with primary Sjögren's syndrome were studied. The protocol included semiquantitative assessments of the inflammatory focus scores and the levels of atrophy, interstitial fibrosis, glomerular sclerosis and vessel wall thickening. RESULTS: No statistically significant correlation was found between the kidney and labial inflammatory scores; this was probably the result of observation of the lesions at different stages. The level of chronic tubulointerstitial nephritis was correlated to the glomerular filtration rate and to the extent of glomerular sclerosis but not to vessel wall thickening. These findings indicate a primary injury of the tubules in primary Sjögren's syndrome that secondarily compromises the glomeruli. CONCLUSION: A semiquantitative approach to the assessment of histopathological features, as used in this study, appears to be valuable for characterising the lesions in kidney biopsies.
8531348 [Production and role of B cell growth factor (BCGF) in Sjögren's syndrome]. 1995 Oct Sjögren's syndrome (SS) is characterized by polyclonal B cell hyperactivity in exocrine glands and peripheral blood. The number of CD20+ B cells is significantly increased in peripheral blood of twenty patients with SS in our study. LMW-BCGF (12 KD) cloned by Sharma in 1987 was reported to associate with DNA synthesis and to give the progressive signal of B cell cycle which develop G1 stage to S stage. In our bioassay using Ks-3, F. 10 cells which respond only to BCGF and proliferate, T cells from SS patients showed increased production of BCGF, whether or not T cells were stimulated with PHA. It was suggested that BCGF may play an important role in the polyclonal activation of B cells in SS.
8531346 [Aberrant expression of HLA-DR antigens on acinar and ductal epithelial cells of salivary 1995 Oct The major histocompatibility complex (MHC) class II antigens have been reported to play an important role in antigen presentation to T cells and influence the susceptibility to several autoimmune diseases, including Sjögren's syndrome (SS). In this paper, an aberrant expression of MHC class II antigens, especially HLA-DR antigens, on salivary glands of SS is described. HLA-DR antigens were immunohistochemically detected on acinar and ductal epithelial cells of SS patients but not those of healthy controls. This expression was observed in proximity to the periphery of dense lymphocytic infiltrates but sometimes not associated with lymphocytic infiltrates. These results are consistent with recent findings of HLA-DR antigen expression on target organs of various autoimmune diseases. Finally, we discussed a pathogenic role of HLA-DR antigens, aberrantly expressed on target organs of SS.
8189070 Cytokine mRNA expression in salivary gland biopsies of Sjögren's syndrome. 1994 Jun 1 Sjögren's syndrome is a human autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands, hypergammaglobulinemia, and specific autoantibodies. The accessibility of the salivary gland to biopsy provides an opportunity to study cytokine mRNA expression at the site of organ-specific immune damage. Using reverse transcriptase and a quantitative PCR to measure cytokine mRNA, we found Sjögren's syndrome: 1) salivary gland CD4+ T cells produce over 40-fold more IL-2, IFN-gamma, and IL-10 mRNA than peripheral blood CD4+ T cells from the same patient or from normal controls; 2) salivary gland CD4+ T cells produced little IL-4 and IL-5 mRNA immediately after elution from the salivary gland, although these mRNAs could be induced by mitogen stimulation of Sjögren's syndrome salivary gland lymphocytes in vitro; 3) salivary gland epithelial cells produced over 40-fold more IL-1 alpha, IL-6, and TNF-alpha mRNA than epithelial cells from individuals with histologically normal salivary glands. Increased levels of IL-1 alpha, IL-6, IL-10, TNF-alpha, and IFN-gamma cytokines were found by ELISA assay in the saliva of Sjögren's syndrome patients, indicating that the elevated mRNA levels detected in their glandular tissue by PCR correlate with local protein synthesis. Our results demonstrate that CD4+ cells in the salivary glands of Sjögren's syndrome patients exhibit mRNA expression that is distinct from previously described Th1 and Th2 lymphocytes in mice or cytokines reported in other human autoimmune or allergic diseases. Also, we found that salivary gland epithelial cells may participate in the pathogenesis of Sjögren's syndrome biopsy by producing cytokines (IL-1 alpha, IL-6, and TNF-alpha).