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ID PMID Title PublicationDate abstract
9629233 Corticotropin-releasing hormone and inflammation. 1998 May 1 Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis (HPA) and principal coordinator of the stress response. As in stress, intracerebroventricular administration of CRH suppresses the immune system indirectly, via glucocorticoid and/or sympathetic system-mediated mechanisms. Also, during inflammatory stress, the cytokines TNF alpha, IL-1, and IL-6 stimulate hypothalamic CRH and/or vasopressin secretion as a way of preventing the inflammatory reaction from overreacting. Recently, CRH receptors were described in peripheral sites of the immune system, and CRH was found to promote several immune functions in vitro. We demonstrated a direct role of CRH in the inflammatory immune process in vivo, by first studying the effect of systemic CRH immunoneutralization in an experimental model of carrageenin-induced aseptic inflammation in Spague-Dawley rats. We extended these observations to other forms of experimental inflammation, including streptococcal cell wall polysaccharide- and adjuvant-induced arthritides and peptide R16 (epitope of the interphotoreceptor retinoid-binding protein)-induced uveitis in Lewis rats. We also studied human disease states, including rheumatoid arthritis, Hashimoto thyroiditis, and ulcerative colitis. Inflamed tissues contained large amounts of IR CRH, reaching levels similar to those observed in the hypophyseal portal system. We also demonstrated the presence of CRH mRNA and CRH receptors in inflammatory cells and identified the mast cells as a major immune target for CRH. In addition to production by immune cells, the peripheral nervous system, including the postganglionic sympathetic neurons and the sensory fibers type C, appears to contribute to IR CRH production in inflammatory sites. The production of CRH from the postganglionic sympathetic neurons may be responsible for the stress-induced activation of allergic/autoimmune phenomena, such as asthma and eczema, via mast cell degranulation. Antalarmin, a novel nonpeptide CRH receptor antagonist, displaced 125I-labeled ovine CRH binding in rat pituitary, frontal cortex, and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmin significantly inhibited CRH-stimulated ACTH release and carrageenin-induced subcutaneous inflammation in rats. Thus, antalarmin and other related compounds that antagonize CRH at the level of its own receptor have therapeutic potential in some forms of inflammation directly mediated by type 1 CRH receptors and promise to enhance our understanding of the many roles of CRH in immune/inflammatory reactions.
9626133 Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum 1998 Jun Interleukin-6 (IL-6) is one of the pathogenetic elements in inflammatory and age-related diseases such as rheumatoid arthritis, osteoporosis, atherosclerosis, and late-onset B cell neoplasia. In these diseases or during aging, the decrease in production of sex hormones such as dehydroepiandrosterone (DHEA) is thought to play an important role in IL-6-mediated pathogenetic effects in mice. In humans, we investigated the correlation of serum levels of DHEA, DHEA sulfate (DHEAS), or androstenedione (ASD) and IL-6, tumor necrosis factor-alpha, or IL-2 with age in 120 female and male healthy subjects (15-75 yr of age). Serum DHEA, DHEAS, and ASD levels significantly decreased with age (all P < 0.001), whereas serum IL-6 levels significantly increased with age (P < 0.001). DHEA/DHEAS and IL-6 (but not tumor necrosis factor-alpha or IL-2) were inversely correlated (all patients: r = -0.242/-0.312; P = 0.010/0.001). In female and male subjects, DHEA and ASD concentration dependently inhibited IL-6 production from peripheral blood mononuclear cells (P = 0.001). The concentration-response curve for DHEA was U shaped (maximal effective concentration, 1-5 x 10(-8) mol/L), which may be the optimal range for immunomodulation. In summary, the data indicate a functional link between DHEA or ASD and IL-6. It is concluded that the increase in IL-6 production during the process of aging might be due to diminished DHEA and ASD secretion. Immunosenescence may be directly related to endocrinosenescence, which, in turn, may be a significant cofactor for the manifestation of inflammatory and age-related diseases.
9366446 Inhibition of IL-12 production by thalidomide. 1997 Nov 15 The immunomodulatory properties of thalidomide are currently being exploited therapeutically in conditions as diverse as erythema nodosum leprosum, chronic graft-vs-host disease, rheumatoid arthritis, and sarcoidosis. The relevant mechanism of action of thalidomide in these diseases remains unclear. The important role recently ascribed to IL-12, a cytokine critical to the development of cellular immune responses, in the pathogenesis of several of these conditions led us to examine whether thalidomide affects the production of IL-12. Thalidomide potently suppressed the production of IL-12 from human PBMC and primary human monocytes in a concentration-dependent manner. Thalidomide-induced inhibition of IL-12 production was additive to that induced by suboptimal inhibiting doses of dexamethasone, and occurred by a mechanism independent of known endogenous inhibitors of IL-12 production. These results suggest that thalidomide may have therapeutic utility in a wide range of immunologic disorders that are characterized by inappropriate cellular immune responses.
9300936 Elevated serum concentrations of soluble adhesion molecules in coronary artery disease and 1997 Sep 29 OBJECTIVES: Adhesion molecules are involved in a number of chronic conditions and diseases like rheumatoid arthritis, tumor growth and wound repair. Soluble adhesion molecules (SAM) play an important role in angiogenesis which is a common aspect of the conditions mentioned above and atherosclerosis. The aim of the present study was to assess the prevalence and the impact of elevated soluble adhesive molecule plasma concentrations in patients with atherosclerosis. DESIGN AND SUBJECTS: In this study, we measured the soluble forms of intercellular adhesive molecule (sICAM), endothelial adhesive molecule (sELAM) and vascular adhesive molecule (sVCAM) using a sandwich ELISA technique in plasma of patients with acute myocardial infarction (AMI), coronary heart disease (CHD) and in healthy subjects (HS). RESULTS: Patients suffering from CHD and AMI showed significant higher plasma concentrations of sICAM (p <0. 05 and p <0.005), sELAM (p <0.01 and p <0.001) and sVCAM (p <0.001 and p <0.005) than HS. In patients with fatal outcome of myocardial infarction the plasma concentrations of sICAM, sELAM and sVCAM were significantly elevated compared to surviving patients (p <0.005; p <0.005; p <0.05). In patients undergoing thrombolytic therapy there were no significant differences of plasma adhesive molecule concentrations. The levels of SAM were not related to other risk factors like diabetes, nicotin abuse, hyperlipidemia, hypertension and a familiary history of cardiovascular disease. CONCLUSIONS: Elevated levels of SAMs are found in patients with coronary heart disease. High SAM levels in plasma seem to be a prognostic factor in acute myocardial infarction. This effect is independent from other concomitant risk factors. Our results suggest that SAMs are involved both in acute phase of myocardial infarction and chronic process of atherosclerosis. It seems that similiar to other chronic inflammatory diseases, atherosclerosis seems to be modulated by soluble forms of adhesive molecules.
9133643 Effect of L-fucose and D-glucose concentration on L-fucoprotein metabolism in human Hep G2 1997 Apr 17 L-Fucose is a monosaccharide that is present at low concentrations in serum and is a normal constituent of glycoproteins. In some pathological conditions, such as cancer, rheumatoid arthritis, and diabetes, there is an abnormal fucosylation of acute phase serum proteins. Because most serum proteins are produced in the liver, we have examined L-fucose accumulation, metabolism, and secretion of L-fucose-containing proteins in human Hep G2 liver cells. Accumulation of L-fucose by Hep G2 cells approached 3.5 nmol/mg protein after a 48 h incubation. This accumulation appears similar to accumulation in other cells, which we have shown occurs via a specific transport protein. Exogenous L-fucose was incorporated into protein in both O- and N-linked glycosidic linkages. After a 48 h incubation, 61% of the accumulated L-fucose was incorporated into protein and secreted into the medium, whereas 39% of the L-fucose remaining in the cells was incorporated into integral membrane proteins. Utilizing reverse-phase high-performance liquid chromatographic separation of L-[5,6-(3)H]fucose-containing proteins and detection by scintillation counting, we determined that two major fucoproteins and numerous minor fucoproteins were produced and secreted by normal Hep G2 cells. This elution profile was unchanged when glucose-conditioned cells were examined. By size-separating secreted proteins by nondenaturing HPLC we determined that the size of the two major fucoproteins were approximately 60 and approximately 100 kDa. In these studies we also examined the effect of diabetes on hepatic fucosyltransferase and serum alpha-L-fucosidase activity and found that the activity of these enzymes is increased by 40 and 100%, respectively in diabetic rats.
11232392 Hypermobility of the first ray. 2000 Sep Hypermobility of the first ray is one of the causative components in common foot problems (such as hallux valgus) with a large intermetatarsal angle and metatarsus primus varus. Although not always associated with hallux valgus, hypermobility is a predisposing factor for this deformity, especially in conjunction with extrinsic factors, such as disruption of the plantar first metatarsal cuneiform ligament and tendon-muscle imbalance. Hypermobility is also frequently found in adolescents with hallux valgus, especially when associated with a large intermetatarsal angle. Motion at the first metatarsocuneiform joint occurs in the sagittal and transverse planes. Most studies agree that greater than 4 degrees and greater than 8 degrees, respectively, constitutes excessive motion. Clinically, hypermobility is evaluated by determining sagittal motion (the grasping test) and transverse motion (the clinical squeeze test) and by identifying signs such as the presence of a dorsal bunion, intractable plantar keratosis beneath the second metatarsal head, and arthritis of the first and second metatarsocuneiform joint. Radiographically, hypermobility is evaluated by measurements from the modified Coleman block test (for sagittal motion) and the radiographic squeeze test (for transverse motion) and by the identification of signs, such as cortical hypertrophy along the medial border of the second metatarsal shaft, a cuneiform split, the presence of os intermetatarseum, and the round shape and increased medial slope of the first metatarsocuneiform joint. Usually, treatment for hypermobility of the first ray is operative, but surgery is contraindicated for patients less than 20 years of age (especially when the epiphysis is not closed) and for patients with generalized ligamentous laxity, short first metatarsal, and arthritis of the hallux MTP joint. The authors' surgical treatment of choice is arthrodesis of the tarsometatarsal joint (as part of the hallux valgus correction), exostectomy, capsulorraphy, and distal soft tissue release to correct and stabilize the first metatarsal at the apex of the deformity. The authors have found it unnecessary to include the base of the second metatarsal. The main complications associated with the Lapidus procedure and its modifications are nonunion, malunion, and dorsal elevation of the first metatarsal. Although radiographic nonunion is the most frequent complication, only 25% of the patients with this condition have associated clinical findings; the results have been defined as good or excellent in two series. These results closely equal those in rheumatoid or sedentary patients managed with newer, modified, less traumatic techniques that stabilize the first metatarsocuneiform joint with screws rather than with arthrodesis.
9362038 Sialadenitis in IQI/Jic mice: a new animal model of Sjögren's syndrome. 1997 Oct Focal infiltration of lymphocytes with parenchymal destruction was noted in both salivary and lacrimal glands of IQI/Jic mice. The sialadenitis was found in more than 80% of female mice at all ages examined. The lesion progressed after 6 months and became more prominent with age. In contrast, male mice had slight and stable salivary lesions independent of age, though the incidence increased with age. Infiltrating lymphocytes consisted of both T and B cells. The dominant lymphocytes in small foci were CD4+ cells, but the majority of infiltrating cells were B cells (B220+), followed by CD4+ T cells in larger lesions. The ductual epithelium in the foci aberrantly expressed MHC class II antigen. Eight of 24 15-month-old female mice with sialadenitis produced speckled-type IgG antinuclear autoantibody. These findings are similar to those in patients with Sjögren's syndrome. IQI/Jic mice could be a novel animal model of Sjören's syndrome.
10540173 CD4 cytotoxic and dendritic cells in the immunopathologic lesion of Sjögren's syndrome. 1999 Oct The existence of CD4+ T lymphocytes with cytotoxic activity in minor salivary gland (MSG) biopsies from Sjögren's syndrome (SS) patients was investigated using in situ double immunohistochemistry technique. The presence of dendritic cells (DC) in SS lesions was examined by using single and double immunohistochemistry methods and a panel of different MoAbs to specific cell surface markers (i.e. CD3, CD11c, DRC). Furthermore, the ultrastructural morphology of DC was characterized by electron microscopy (EM). Immunogold labelling technique using the DRC surface marker was also applied. Finally, we investigated the existence of germinal centres (GC) in the salivary gland lesions of SS patients. Seven patients with primary SS and five patients with non-specific sialadenitis were the subjects of this study. Our results indicate the existence of a CD4+ cytotoxic cell population that utilizes perforin-mediated cell destructions as they expressed perforin mRNA. Quantitative analysis of these cells revealed that they comprised approximately 20% of the existing T lymphocytes. We also identified a population of CD4+ T cells that expressed the CD11c activation marker. Furthermore, we observed a distinct cell subtype which expressed the DRC cell surface marker. These cells had the characteristic ultrastructural morphology of DC and were DRC+ when examined by immunoelectron microscopy. Finally, the formation of GC structures in the histopathologic lesions of the salivary glands was observed. The above findings indicate that both CD4+ cytotoxic T lymphocytes (CTL) and DC may be involved in the initiation and perpetuation of SS pathogenesis. Moreover, the formation of GC in the lesions reveals a possible mechanism for in situ differentiation and proliferation of activated B lymphocytes.
9890453 Anti-cytoplasmic autoantibodies reactive with epithelial cells of the salivary gland in se 1999 Jan To test whether the autoantibodies reactive with epithelial cells of the salivary gland in sera from Sjögren's syndrome (SS) patients are specific for the organ and the disease, tissue reactivities of serum IgG obtained from the patients with SS and oral lichen planus (OLP), another immune-mediated oral mucosal disease, were examined by immunohistochemistry and Western blotting. IgG purified from the sera of SS patients specifically localized not only on the nuclei but also on the cytoplasm of the salivary gland epithelial cells. On the other hand, no convincing staining of the epithelial cells was observed when IgG purified from the sera of OLP patients or those from healthy controls were used for immunohistochemistry. No cytoplasmic staining was observed when sections of kidneys and pancreas were stained with SS patients' IgG. In Western blotting performed by using lysates of a submandibular gland as antigens, all the IgG prepared from the SS patients reacted prominently with several protein bands, including those specific for the disease and the organ. These results suggest that production of autoantibodies reacting with the cytoplasm of salivary gland epithelial cells is a characteristic of SS, and may play a role in the pathogenesis of the sialadenitis.
11710719 Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells 2001 Nov OBJECTIVE: To test the hypothesis that the formation of ectopic germinal center (GC)-like structures in Sjögren's syndrome (SS) is associated with the ectopic expression of the constitutive lymphoid tissue-homing chemokines B cell-attracting chemokine 1 (BCA-1; or, CXCL13) and stromal cell-derived factor 1 (SDF-1; or, CXCL12). METHODS: Immunohistochemical and immunofluorescence analysis was used to determine the expression of the constitutive chemokines BCA-1 (CXCL13) and SDF-1 (CXCL12) in salivary glands from 5 SS patients and 3 non-SS patients. In addition, the expression of their respective receptors (CXCR5 and CXCR4) was examined on infiltrating lymphocytes. Human tonsil was used as a positive control for secondary lymphoid tissue. RESULTS: BCA-1 (CXCL13) was expressed within lymphoid aggregates in SS, which shared many structural features with GCs in tonsil. BCA-1 (CXCL13) was completely absent in control biopsy samples from patients who did not have SS. High levels of BCA-1 (CXCL13) were also found on endothelial cells in salivary glands from SS patients. Diseased SS tissue was infiltrated by CXCR5-expressing B cells which organized into GC-like clusters. In complete contrast, SDF-1 (CXCL12), a constitutive chemokine involved in leukocyte retention within lymphoid tissue, was expressed by epithelial cells in both diseased and control samples. The chemokine receptor for SDF-1, CXCR4, was expressed on T cells that accumulated in a periductal distribution in diseased tissue. CONCLUSION: The ectopic expression of BCA-1 (CXCL13) on endothelial cells and within GC-like structures, together with the strong expression of SDF-1 (CXCL12) on ductal epithelial cells, is a unique feature of inflamed glands in SS. By creating a local microenvironment supportive of focal B cell aggregation and differentiation, with structural features that are remarkably similar to GCs, BCA-1 (CXCL13) and SDF-1 (CXCL12) may contribute to the excessive production of high-affinity, class-switched autoantibodies and to the high incidence of B cell lymphomas classically associated with SS.
11334493 Hepatitis C and D, retroviruses and autoimmune manifestations. 2001 May Chronic infections with hepatitis C virus (HCV) are associated with various autoimmune manifestations, i.e. mixed cryoglobulinemia, membranoproliferative glomerulonephritis, autoimmune thyroid diseases, sporadic porphyria cutanea tarda and B cell lymphoma. Since exacerbation of hepatitis occurs in 5-10% of HCV patients receiving interferon-alpha treatment and may be successfully treated by immunosuppression afterwards, hepatitis C was also suspected to be associated with autoimmune hepatitis. LKM3 autoantibodies in chronic hepatitis D virus (HDV) infection and epitope recognition are discussed. Lately, endogenous and exogenous retroviruses have been investigated for the induction of autoimmune diseases. Human A type retroviral particles (HIAP), reverse transcriptase activity and anti-HIAP autoantibodies were detected in patients with Sjögren's syndrome. Anti-HIAP and anti-HIV p24 autoantibodies are seen in systemic lupus erythematosus, primary biliary cirrhosis and multiple sclerosis. Multiple sclerosis was even associated with a new human retrovirus called multiple sclerosis associated retrovirus (MSRV). In diabetes long terminal repeats (LTR) were detected in the HLA DQB1 locus, which was shown to associate with an increased risk of diabetes. A second retrovirus called IDDMK(1,2)22 was reported to code for a superantigen, which was implicated as a potential cause of diabetes. This hypothesis, however, was challenged repeatedly. Until now it is unknown whether endogenous retroviruses are aetiological agents of autoimmune diseases or an epiphenomenon, induced by coinfecting viruses (e.g. herpes viruses) and inflammatory processes.
10711864 Relationship between red cell mean corpuscular volume and 6-thioguanine nucleotides in pat 2000 Mar Azathioprine (AZA) is characterized by high interindividual differences in bioavailability and metabolization. The aim of the present study was to analyze, in patients treated with AZA for various immune system disorders, whether the variation in red blood cell mean corpuscular volume (deltaMCV) could be used as an indirect estimation of the level of the active immune modifier metabolite 6-thioguanine nucleotides (6-TGN). In 43 consecutive patients treated with a stable dose of AZA for at least 6 months who were not initially anemic, the erythrocyte 6-TGN levels with routine hematologic parameters were determined two to four times at 1-month intervals. In most patients MCV significantly increased after 3 months of therapy and stabilized after 6 months. The correlation between the daily dose of AZA and the 6-TGN level was mild (r = 0.51; P<.001). A weak correlation was also found between the dose of AZA and the deltaMCV after at least 6 months of therapy (r = 0.36; P<.05). The correlation between deltaMCV and 6-TGN level, however, was much better (r = 0.74; P<.001). The lack of a significant increase in MCV after 3 to 4 months of AZA therapy reflects low 6-TGN levels, sometimes a result of undertreatment. A determination of the 6-TGN level during the first months after AZA therapy is begun will allow more accurate adaptation of the effective dose. We observed that deltaMCV could be used as an indicator of 6-TGN levels after 6 months of AZA treatment. An increase in MCV of at least 6 fL is expected to reflect a 6-TGN level of about 175 pmol/8x10(8) red blood cells (probably being within a therapeutic value).
9787134 Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and a 1998 Nov 1 Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of the Fas gene in 150 cases of non-Hodgkin's lymphoma. Overall, mutations were identified in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant-negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with somatic Fas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity.
9344336 Detection of antibodies to a recombinant gag protein derived from human endogenous retrovi 1997 To investigate whether human endogenous retroviruses (HERV) contribute to autoimmune diseases, we prepared a recombinant p30gag protein derived from clone 4-1 of the HERV family, using a baculovirus-vector system. This p30gag protein (CA41B) was approximately 30 kDa, as expected, and reacted with antibodies for p30gag purified from both murine and feline leukemia virus. This result suggested that the antigenic determinant for p30gag was well conserved in CA41B. Analysis of serum antibodies to p30gag in patients with autoimmune diseases was done by Western blotting. CA41B detected anti-p30gag antibodies in 48.3% of systemic lupus erythematosus (SLE) patients, 35.0% of Sjögren's syndrome (SS) patients, and 33.3% of mixed connective tissue disease (MCTD) patients, whereas no anti-p30gag antibodies were found in healthy subjects. This suggested that HERV p30gag or other retroviral p30gag proteins possessing the same antigenic determinant as CA41B may play a role in these diseases. Although detection of antibodies to HERV p30gag in autoimmune diseases is indirect evidence that HERV proteins are involved, this study showed that patients with autoimmune diseases have antibodies to HERV p30gag using a recombinant HERV protein rather than synthetic peptides based on HERV or retroviral proteins of other species.
10793067 Severe destructive autoimmune lesions with aging in murine Sjögren's syndrome through Fas 2000 May When we evaluated the age-associated changes in autoimmune exocrinopathy in a NFS/sld murine model for primary Sjögren's syndrome (SS), severe destructive autoimmune lesions developed in the salivary and lacrimal glands in the aged mice, compared with those observed in the younger model. We detected a decreased secretion of saliva and tear flow in the aged group. A significant increase of TUNEL(+)-apoptotic epithelial duct cells in the salivary glands was detected in the aged SS animal model. A higher proportion of mouse salivary gland cells bearing Fas was found in the aged group, whereas no significant changes were seen on tissue-infiltrating CD4(+) T cells bearing FasL in the salivary glands from young and aged mice. We detected an increased cleavage product of organ-specific autoantigen, 120-kd alpha-fodrin, in the aged salivary gland tissues on immunoblotting, and an increase in serum autoantibody production against 120-kd alpha-fodrin by enzyme-linked immunosorbent assay. An increase in the proliferative response of splenic T cells against organ-specific autoantigen was observed, whereas nonspecific concanavalin A responsiveness was decreased in the aged mice. In addition, a decrease in Fas expression was found on splenic CD4(+) T cells in the aged mice, and anti-Fas mAb-stimulated apoptosis was down-regulated on CD4(+) T cells. These results indicate that age-associated dysregulation of CD4(+) T cells may play a crucial role on acceleration of organ-specific autoimmune lesions in a murine model for primary SS through Fas-mediated apoptosis.
10787003 Mixed cryoglobulinemia: new concepts. 2000 The most documented extrahepatic manifestation of hepatitis C virus (HCV) infection is mixed cryoglobulinemia (MC). MC is characterised by the presence of temperature-sensitive protein complexes: in type II MC, cryoglobulins are composed of a monoclonal rheumatoid factor (usually, IgMkappa) against polyclonal IgG. In type III MC, all components are polyclonal. The presence of microheterogeneity and other new types of cryoglobulins is a novel and recent observation. The production of different autoantibodies and circulating immune complexes, including the cryoglobulins, are responsible for systemic vasculitis and various organ damage. In a limited number of MC patients, a malignancy, that is B-cell non-Hodgkin's lymphoma or hepatocellular carcinoma, may also develop. Finally, results of interferon and/or ribavirin treatments in MC patients represent an indirect proof for the pathogenetic link between MC and HVC infection. The discovery of the relation between HCV infection and MC shows the striking association between a viral infection and an autoimmune disease and, thus, a potential link between the systemic autoimmune and lymphoproliferative disorders.
10587729 [Autoimmune deafness]. 1999 Nov 6 A REAL ENTITY: Deafness resulting from an autoimmune mechanism is suggested by a growing number of clinical and experimental arguments. The audio-vestibular system is known to be involved in a certain number of systemic diseases, particularly Cogan's disease. In other cases, the inner ear alone is involved; deafness may be the first manifestation of a systemic disease or result from a possible immunological mechanism. CLINICAL ASPECTS: Autoimmune deafness is very invalidating. Bilateral perception deafness is observed in 80% of the cases and vestibular involvement is found in 70% DIAGNOSIS: No one simple reliable test is known which can establish the diagnosis of autoimmune deafness. Other causes must be ruled out by appropriate clinical and complementary explorations. For humoral immunity, the western blot method has given promising results suggesting a possible role of the heat shock protein in the underlying immunological mechanism. TREATMENT: Immediate care is needed but no standard treatment has been defined. High-dose corticosteroids can provide symptom relief, particularly in case of abnormal immunological tests. The role of immunosuppressive therapy, sometimes proposed in case of corticosteroid resistance, remains to be defined.
10451125 Lectin binding studies of parotid salivary glycoproteins in Sjögren's syndrome. 1999 Jul Human parotid salivas were collected from patients with secondary Sjögren's syndrome and controls without disease or with drug-induced xerostomia. Parotid glycoproteins were separated by gradient sodium dodecyl sulphate gel electrophoresis (SDS-PAGE), electroblotted onto nitrocellulose membrane and probed with biotinylated lectins of characterised sugar specificities. The binding patterns of lectins from Maclura pomifera (MPA) and Arachis hypogaea (PNA) indicated that many parotid glycoproteins have sialylated O-linked glycans and that sialylation is not affected by disease. Binding by lectins from Ricinus communis (RCA-1), Limax flavus (LFA), Lotus tetragonolobus (LTA) and Ulex europaeus (UEA-1) appeared unaltered in secondary Sjögren's syndrome, suggesting no obvious change in N-glycosylation of parotid glycoproteins. Variations in binding patterns of most lectins was attributable to subject-to-subject variations in recognised polymorphic proteins. Dolichos biflorus agglutinin (DBA) consistently showed increased binding to a 75 kDa (Mr) protein in salivas from patients with secondary Sjögren's syndrome. The binding protein was identified as lactoferrin but found not to contain N-acetylgalactosamine, the sugar to which DBA binds. Binding of DBA to lactoferrin was dependent upon its saturation with iron, modified SDS-PAGE under nonreducing conditions resolved iron-free and iron-saturated lactoferrins and demonstrated increased levels of the iron-saturated form in secondary Sjögren's syndrome. Lectin binding studies of purified lactoferrins from saliva, milk, and polymorphonuclear neutrophils suggested that raised levels of lactoferrin in saliva originate from salivary cells and not from inflammatory cells. These results suggest that DBA binding provides greater specificity as an indicator of salivary gland disease than measurement of lactoferrin levels alone.
10340964 Expression of mitogen activated protein kinases in labial salivary glands of patients with 1999 Jun OBJECTIVE: The expression of CD40 and CD40 ligand (CD40L) in mononuclear cells (MNCs) infiltrating the salivary glands of patients with Sjögren's syndrome (SS) has recently been reported. This study determined the expression of mitogen activated protein kinase (MAP kinase) superfamilies, which act as downstream effector molecules of CD40, in MNCs infiltrating labial salivary tissues in SS patients. METHODS: Six HTLV-I seronegative SS patients and 10 HTLV-I seropositive patients including five HTLV-I associated myelopathy (HAM) patients were examined. The expression of MAP kinase superfamilies in labial salivary glands was examined by immunohistochemistry containing the mirror section technique. RESULTS: Both active forms of c-Jun N-terminal kinase (JNK) and p38 were found in salivary infiltrating MNCs of SS patients. Only minimal expression of the active form of extracellular signal regulated kinase (ERK) was observed in these tissues, however, co-expression of active JNK and active p38 was confirmed by the mirror section technique. Furthermore, these protein kinases were co-expressed in CD40(+) MNCs. No difference in expression levels of active JNK and p38 was found in patients who were positive or negative for anti-HTLV-I antibody. CONCLUSION: These results indicate that JNK and p38, but not ERK, function as downstream effector molecules of CD40 in salivary infiltrating MNCs in SS patients, and suggest that these molecules may be involved in the pathological process of chronic sialadenitis in SS.
9787115 Ca2+ signaling by cholinergic and alpha1-adrenergic agonists is up-regulated in lacrimal a 1998 Nov Innervation of the lacrimal gland of MRL/Mp-Fas-lpr/lpr (MRL/lpr), a murine model for Sjögren's syndrome, is unaltered with the onset or progression of the lymphocytic infiltration. To determine whether lacrimal and submandibular gland cells are able to respond to external stimuli, acini were prepared from MRL/lpr (diseased) and MRL/Mp-+/+ (MRL/+, control) mice at 4, 8, and 12 weeks of age and loaded with the fluorescent dye fura-2 to monitor changes in the intracellular Ca2+ concentration ([Ca2+]i) in response to cholinergic and alpha1-adrenergic stimulation, two major stimuli of lacrimal gland protein secretion. Cholinergic-induced [Ca2+]i increase was up-regulated 3- and 4-fold in lacrimal gland acini isolated from 8- and 12-week-old MRL/lpr mice, respectively, compared to 4-week-old animals, but was not up-regulated in age-matched MRL/+ control mice. Similarly, alpha1-adrenergic-induced [Ca2+]i increase was up-regulated 7- and 12-fold in acini isolated from 8- and 12-week-old MRL/lpr mice, respectively, compared to 4-week-old animals, but was not up-regulated in MRL/+ mice. Cholinergic-induced [Ca2+]i increase in submandibular gland acini of MRL/lpr and MRL/+ mice was the same at all ages. In contrast, alpha1-adrenergic-induced [Ca2+]i increase was up-regulated 3-fold in acini from 12-week-old MRL/lpr mice, compared to 4-week-old mice, but was not up-regulated in age-matched MRL/+ mice. We conclude that the Ca2+ signaling portion of cholinergic and alpha1-adrenergic pathway in the lacrimal gland and the Ca2+ signaling portion of alpha1-adrenergic pathway in the submandibular gland is up-regulated with the onset and progression of the lymphocytic infiltration in the MRL/lpr murine model of Sjögren's syndrome.