Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 7932104 | [Highly sensitive analytical procedure for methotrexate and its main metabolite 7-hydroxym | 1994 Aug | Recently, methotrexate (MTX) low dose therapy (5-10 mg/m2) has been used for the treatment of patients with rheumatoid arthritis. Hence a practical and sensitive high-performance liquid chromatographic method for the determination of MTX and its main metabolite 7-hydroxymethotrexate (7-OH-MTX) in human serum has been studied. After deproteinization with perchloric acid followed by the addition of pH 5.0 acetate buffer, the serum sample was purified by solid-phase extraction on a Sep-Pak C18 cartridge. The analyte was chromatographed on a reversed-phase Inertsil ODS-2 column using a phosphate buffer-acetonitrile at pH 3.0 system as the mobile phase, and the effluent from the column was monitored at 303 nm. Gradient elution was employed to increase the sensitivity for 7-OH-MTX. A good linear relationship between peak height and concentration was found for the two compounds in the range 2.5 to 100 ng/ml of the human serum, and the detection limits were about 1 ng/ml for the two compounds. The day-to-day coefficients of variation assay were 2.3% (20 ng/ml) and 4.4% (100 ng/ml) for MTX and 4.6% (20 ng/ml) for 7-OH-MTX. The present method was successfully applied to the analysis of the serum after a single oral administration of MTX 2.5 mg tablet to male dogs. MTX was rapidly absorbed, reached to the maximal level at about 1.4 h and thereafter decreased monoexponentially with a half-life of about 1.4 h. A metabolite, 7-OH-MTX was not detected in the serum up to 24 h post dose. | |
| 8161219 | Arg-Gly-Asp-Ser peptide analogs suppress cartilage chondrolytic activities of integrin-bin | 1994 Apr | We have reported that Fn fragments (Fn-f), which have been detected in synovial fluids of osteoarthritis and rheumatoid arthritis patients, can potently cause cartilage chondrolysis and depress proteoglycan (PG) synthesis in cartilage tissue cultured as explants. Amino-terminal 29-kDa, gelatin-binding 50-kDa, and integrin-binding 140-kDa Fn-f are active. In order to investigate the mode of action and devise means of blocking the damage mediated by all Fn-f, we have tested the effects of various analogs resembling the integrin binding sequence, Arg-Gly-Asp-Ser, on blocking Fn-f-mediated chondrolysis. The analog peptides, Gly-Arg-Ala-Asp-Ser-Pro-Lys and Arg-Phe-Asp-Ser, at concentrations as low as 1 microM, blocked the effects of all three Fn-f on cartilage degradation, while the native sequence peptide, Arg-Gly-Asp-Ser, had very low Fn-f-blocking activity and by itself caused cartilage damage. Random sequence peptides dissimilar to the analog sequences were inactive as inhibitors as well as was a sequence analog, Phe-Asp-Arg-Ser, related to the Arg-Phe-Asp-Ser inhibitor. The analog inhibitory peptides decreased rates of Fn-f-mediated PG degradation and release from cartilage and decreased Fn-f-mediated PG synthesis depression. The analog inhibitory peptides alone had no detectable effect on cartilage PG degradation or PG synthesis rates. These data show that the chondrolytic activities of integrin-binding and nonbinding Fn-f can be blocked by synthetic peptide analogs of the Arg-Gly-Asp-Ser sequence and suggest that these peptides may be useful for blocking other activities of Fn-f. | |
| 8297198 | Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of ri | 1994 Feb 14 | BACKGROUND: Hospitalizations for acute liver injury in the absence of a viral infection or any other well-defined pathologic finding that could have caused it is rare. In this study, we included both outpatients and hospitalized patients with acute liver injury to estimate the risk of clinically important acute liver injury associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to study the role of certain risk factors. METHODS: This was a retrospective cohort study with secondary case-control analysis. The study included 536 general practitioners' practices in England and Wales for the period October 1987 through August 1991. A total of 625,307 persons who received more than 2 million prescriptions for one of 12 NSAIDs were followed up to estimate the risk of newly diagnosed acute liver injury. RESULTS: There were 23 cases of acute liver injury. The incidence of acute liver injury was 3.7 per 100,000 NSAID users or 1.1 per 100,000 NSAID prescriptions. None of the cases had a fatal outcome. Sulindac was the only NSAID with a substantially greater risk than that for the overall NSAID group. Users of NSAIDs who had rheumatoid arthritis had a 10-fold increased risk of acute liver injury compared with NSAID-treated patients with osteoarthritis. Concomitant exposure to other hepatotoxic medications also increased the risk. Transient minor increases in liver test values were not a useful predictor of diagnosed NSAID-associated acute liver injury. CONCLUSIONS: Although NSAIDs have been found to be associated with acute liver injury in a small number of persons, the risk is sufficiently small as to be of minimal concern for most NSAIDs. | |
| 8143505 | Expression levels of IL-6 mRNA in PBMNCs from patients with IDDM, NIDDM and normals by RT- | 1993 Dec | Although it has been confirmed that insulin dependent diabetes mellitus (IDDM) is a kind of autoimmune disease, islet cell autoantibodies (ICAs), insulin autoantibodies (IAA) and anti-GAD-glutamic acid decardaxylase antibodies have been found in the sera of patients with IDDM and immunotherapies have been used in some patients with IDDM, yet the manner in which the dysfunctional immunosystem acts on beta cells and causes damage to them remains to be clarified. Recently, possible involvement of the abnormal production of IL-6 in autoimmune symptoms was suggested in patients with cardiac myxomas, Castleman's disease and rheumatoid arthritis. However reports of IL-6 abnormal production in patients with IDDM are rare. In the present study, we examined whether or not an abnormal expression of IL-6 mRNA was present in mononuclear cells (PBMNCs) of the peripheral blood of patients with IDDM. We devised a highly sensitive, specific and semiquantitative protocol, ie, reverse transcription and polymerase chain reaction (RT-PCR). We have used such an assay to measure the relative expression levels of IL-6 mRNA in PBMNCs from 12 early IDDM patients (duration < 6 mon, 8.20 +/- 3.85 yr), 29 newly-diagnosed NIDDM patients (54.85 +/- 9.12 yr), 23 normal children (8.20 +/- 3.26 yr) and 12 normal adults (31.92 +/- 11.22 yr). In this assay significantly high expression levels of IL-6 mRNA were found in PBMNCs from patients with IDDM (P < 0.05). The relative levels were 0.91 +/- 0.19; 0.10 +/- 0.06; 0.43 +/- 0.08; 0.10 +/- 0.07, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 7691738 | Abnormal glycosylation of alpha 2-macroglobulin, a non-acute-phase protein in patients wit | 1993 Aug | Previous studies from this and other laboratories have shown that abnormal glycosylation of several acute-phase proteins can be detected in various pathological conditions including autoimmune diseases. In the present study, we have investigated if abnormal glycosylation is limited to acute-phase proteins. We used the concanavalin A (Con A) blots in conjunction with the peptide mapping techniques to analyze serum samples and cerebrospinal fluids (CSF) obtained from patients with autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), scleroderma (SCL), Sjögren's syndrome (SS), and polymyositis (PM); diseases of probable autoimmune origin: hepatopathies (HP); diseases of suspected autoimmune origin: schizophrenia and Alzheimer's disease (AZ); and conditions not related to autoimmunity: pregnancy (PG) and elevation of the carcinoembryonic antigen (CEA), in comparison to normal donors (NHS). We have micropurified two human proteins; alpha 2-macroglobulin, a non-acute-phase protein and beta-chain of haptoglobin, a known acute-phase protein, from serum samples of individual patients with SLE, RA, MCTD, SCL and SS, and from PG and NHS for analysis. The identity of the purified proteins was confirmed by immunoblots using either monospecific polyclonal or monoclonal antibodies, and by direct N-terminal amino acid sequencing. Peptide maps for each of these proteins were generated using Staphylococcus aureus protease V8, a Glu-C endopeptidase. When the peptide fragments of alpha 2-macroglobulin were resolved by SDS-PAGE and visualized using silver staining, no differences were noted between patient samples and controls. However, when they were examined by lectin blots using Con A, the Con A-reactive fragments increased specifically and significantly in samples derived from patients of SLE, SCL, MCTD, and RA. Similarly when the peptide fragments of the beta-chain of haptoglobin were visualized by silver staining, no differences were noted; however, the Con A reactivity of specific fragments increased in SLE, RA, SCL, and SS patients. Analysis of these results indicated that there has been a selective increase in Con A-reactive fragments in both acute-phase and non-acute-phase proteins in autoimmune conditions. Thus, the study of changes in glycosylation patterns in selected serum proteins may be a valuable diagnostic approach to define the pathophysiology of inflammatory and autoimmune disorders. | |
| 1597488 | Brefeldin A-resistant mutants of human epidermoid carcinoma cell line with structural chan | 1992 Jun 5 | We have isolated brefeldin A (BFA)-resistant cell lines, KB/BF-1 and KB/BF-2, from the human epidermoid carcinoma KB cell line. The BFA-resistant phenotypes have been stably maintained for more than 3 months in the absence of BFA. KB/BF-1 and KB/BF-2 showed 10-30-fold higher resistance to cytotoxicity of BFA but were 2-3-fold more sensitive to monensin and nigericin, than KB cells. KB/BF-1 showed aberrant structures of the Golgi complex with poorly developed cisternae surrounded by many small vesicles. Immunocytochemical studies were done with antibodies against a Golgi-specific antigen (chronic rheumatoid arthritis antigen) and a coatomer subunit (beta-subunit for coat proteins of non-clathrin-coated vesicles). Golgi-specific markers were distributed into the small vesicles which were localized diffusedly in cytoplasm of KB/BF-1 cells. Such Golgi markers were observed in a strictly confined perinuclear region of the parental KB cells, whereas in the mutant cells the markers were distributed more diffusedly in dot-like structures at perinuclear regions. In addition, when exposed to BFA, the mutant and parental cells showed a different distribution of these markers. Synthesis and maturation of low density lipoprotein receptor showed apparently slower rates in processing of low density lipoprotein receptor in KB/BF-1 and KB/BF-2 cells than those observed in their parental KB cells. Protein secretion in KB/BF-1 and KB/BF-2 cells was about 30% less than that in KB cells. Much less inhibition by BFA on the secretion was observed in KB/BF-1 and KB/BF-2 cells. A BFA-resistant mutation in BFA-resistant KB cell lines appears to affect assembly of the Golgi apparatus as well as some Golgi-specific functions. | |
| 1374422 | Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in b | 1992 May | T cell sensitization to two myelin components, myelin basic protein (MBP) and myelin proteolipid protein (PLP), may be important to the pathogenesis of multiple sclerosis (MS). Using the limiting dilution assay, we demonstrated that the blood of MS patients had an increased frequency of MBP-reactive T cells compared with normal subjects and patients with other neurological diseases (OND) and rheumatoid arthritis. There was no difference in T cell frequency to a synthetic peptide, PLP139-151, or Herpes simplex virus. Within cerebrospinal fluid (CSF), 37% of IL-2/IL-4-reactive T cell isolates from MS patients responded either to MBP or PLP139-151 while only 5% of similar isolates from OND patients responded to these myelin antigens. The mean relative frequency of MBP-reactive T cells within CSF from MS patients was significantly higher than that of OND patients (22 x 10(-5) cells versus 1 x 10(-5) cells) and was similar to that of MBP reactive T cells within the central nervous system of rats with experimental autoimmune encephalomyelitis. These results lend new support to the hypothesis that myelin-reactive T cells mediate disease in MS. | |
| 1345796 | The effect of sulfasalazine on bovine endothelial cell proliferation and cell cycle phase | 1992 Jan | Sulfasalazine is used in the treatment of chronic inflammatory states, for example, in inflammatory bowel disease and to a lesser degree in rheumatoid arthritis. In chronic inflammation, the formation of new blood vessels may play a key role in maintaining the inflammatory state. This process is dependent on the activation and proliferation of the endothelial cells. To investigate the possible role of sulfasalazine and its metabolites, sulfapyridine and 5-aminosalicylic acid, we examined the effect of these drugs on vascular endothelial cell proliferation in vitro. Cultures of bovine aortic endothelial cells were incubated with sulfasalazine and its metabolites. At 24 hours of incubation, sulfasalazine inhibited tritiated thymidine incorporation and cell proliferation and had already slowed S-phase progression at a concentration greater than 0.125 mmol/L. After 3 hours of incubation, sulfasalazine inhibition of tritiated thymidine incorporation into the DNA of endothelial cells was observed. This inhibition was completely reversible 24 hours after the drug was removed. One of the possible mechanisms for the inhibition of endothelial cell proliferation is interference with the de novo synthesis of thymidine that depends on folate-dependent enzymes. The effect of deoxyuridine and tetrahydrofolate on tritiated thymidine incorporation into cellular DNA, as well as release of tritium to water by [5-3H]-labeled deoxyuridine on methylation to thymidine, were used as probes for the de novo synthesis of thymidine. Deoxyuridine and tetrahydrofolate, when added to cells either individually or together for 3 hours, suppressed incorporation of tritiated thymidine into DNA through an increase in de novo thymidine synthesis. Sulfasalazine, but not its metabolites, reduced this suppression.2+ culture is inhibited by sulfasalazine and olsalazine but not by their metabolites. This inhibition appears to depend partly on the reduction of de novo synthesis of thymidine that is folate dependent. | |
| 7790026 | Comparison of the suppressive effects of interleukin-10 and interleukin-4 on synovial flui | 1995 Apr | This study determined the potential capacity of interleukin-10 (IL-10), compared with IL-4, to control the production of tumour necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-1 receptor antagonist (IL-1ra) and the expression of major histocompatibility complex (MHC) class II antigens by monocytes/macrophages isolated from synovial fluid of patients with rheumatoid or other forms of chronic inflammatory arthritis. Mononuclear cells were isolated from synovial fluid and peripheral blood and incubated with or without lipopolysaccharide (LPS), and with or without IL-10 (100 U/ml, 10 ng/ml) or IL-4 (10 ng/ml) for 22 hr. TNF-alpha, IL-1 beta and IL-1ra levels were measured by enzyme-linked immunosorbent assay (ELISA) in the culture supernatants, and MHC class II expression was examined on the monocytes/macrophages by flow cytometry. IL-10, unlike IL-4, decreased TNF-alpha production by LPS-stimulated synovial fluid cells to the same extent as by LPS-stimulated peripheral blood cells from the same patients. IL-10 and IL-4 suppressed equally IL-1 beta production by the same cells. However, only IL-4 significantly increased IL-1ra production by synovial fluid mononuclear cells. Synovial fluid cells expressed increased levels of MHC class II antigen, and these levels were not as efficiently suppressed by IL-10 as they were for peripheral blood cells. Because IL-10 and IL-4 differentially regulate TNF-alpha and IL-1ra production by synovial fluid mononuclear cells, selective use of either IL-10 or IL-4 in the treatment of chronic inflammatory conditions will depend on whether TNF-alpha or IL-1, respectively, is established as primarily responsible for the maintenance of the chronic inflammatory condition. | |
| 9275485 | [Expression of cytokines in labial gland of Sjögren's syndrome]. | 1996 Jun | OBJECTIVE: To explore the role of cytokines in the process of inflammation and destruction of minor salivary gland in Sjögren's Syndrome. (SS) METHODS: Using in situ non-isotope double hybridization method, we detected the mRNA of the following cytokines: TNF alpha, IL-1 beta, IL-6, PDGF alpha and PDGF beta in 24 labial gland biopsied sections. RESULTS: No cytokine could be detected in the normal labial glands sections. The positivity of all cytokine expression was higher in the pSS and sSS patients than that in the control. The intensity of TNF alpha expression was 3-4 fold increase in pSS compared with sSS. The different cytokines were expressed with the different grade of lymphocytic focus. The site of different cytokines was also expressed differently. The coexpression of mRNA of TNF alpha and IL-1 beta or TNF alpha and IL-6 was only seen in the inflammatory mononuclear cells but not others. The expression of TNF alpha in aciniar cells could occur earlier than the infiltration of lymphocytes in the interstitial region. It was found that the IL-6 positive group had higher positivity of serum ANA compared with the IL-6 negative group according to Ridit statistical analysis (P < 0.05). The serum anti-SSA and anti-SSB antibody had an increase tendency in the IL-6 positive group. CONCLUSION: We hypothesize that the development of SS may be secondary to some trigger agents, which activated the aciniar cells in exocrine gland of predisposed individuals. The activated acini cells secreted TNF alpha, then TNF alpha induced other cytokine expression, followed by the lymphocytes infiltration, which led to autoimmne reaction and the destruction of the exocrine gland. | |
| 7616459 | Anti-salivary antibodies in primary Sjögren's syndrome. | 1995 May | Earlier studies have described an antibody that recognized salivary ductal epithelium in sera from 15-50% of patients with primary Sjögren's syndrome; however, the specific salivary antigen in those studies was not identified. The present study further investigated this unknown salivary antigen. Twenty-nine of 31 patients (94%) with primary Sjögren's syndrome demonstrated IgG antinuclear antibodies that bound to an epithelial cell line with ductal characteristics derived from a human salivary gland. Seventy-seven percent of these patients had serum antibodies that bound to ductal cells of normal human parotid tissue after formalin fixation. Western blots of cell extracts, immunofluorescence, and adsorption studies indicated that SS-A/Ro and SS-B/La were the antigens recognized in the salivary cell line. The pattern of fluorescence seen when anti-SS-B/La bound to normal parotid tissue was identical to the fluorescence pattern of the anti-salivary ductal antibodies described in earlier literature. | |
| 7520377 | The immunoreactive region in a novel autoantigen contains a nuclear localization sequence. | 1994 Sep | Antibodies in the serum of patients with autoimmune diseases have been used to identify human autoantigens. Because autoantibodies often recognize active sites within corresponding protein antigens, autoantibodies have facilitated the functional characterization of these polypeptides. In the present study, serum from a patient with Sjögren's syndrome was used to identify a novel autoantigen which was designated Ge-1. Using the patient's serum, a 4.8-kb cDNA encoding Ge-1 was identified. Fragments of the cDNA were ligated into prokaryotic expression vectors, expressed in Escherichia coli, and used to produce recombinant Ge-1 fusion proteins. Fusion proteins containing different portions of Ge-1 were used to identify a 58 amino acid immunoreactive region within the protein. This immunoreactive region contained the protein's putative nuclear localization sequence (NLS). To demonstrate that the immunoreactive region was capable of functioning as a NLS, a eukaryotic expression plasmid was constructed to encode the immunoreactive region fused to the cytoplasmic protein, chicken muscle pyruvate kinase. After transfection of this plasmid into COS-1 cells, the fusion protein was detected in the nucleus. The presence of the NLS motif within the immunoreactive region of Ge-1 and other nuclear autoantigens suggests that the NLS may be a target of human autoantibodies. | |
| 7937032 | [Diffuse connective tissue diseases (DCTD)--a review]. | 1994 | The diffuse connective tissue diseases constitute a group of inflammatory diseases with the potential of involvement of many organ systems. The etiopathogenesis is thought to be multifactorial, involving the interaction between particular genetic background and exogenous agents. Recently theories regarding inherited defects in the clearing of immune complexes have been put forward. Serological markers are important diagnostic tools in many of these diseases and emphasize the role of autoimmunity. Epidemiological studies have demonstrated an increase in incidence in some of these diseases and because of selection bias many epidemiological studies may overestimate the severity of these diseases. Therapy aims at modulating and suppressing inflammation. A step towards more directed immune modulation is the use of cyclosporin A and monoclonal antibodies against various surface antigens and mediators in inflammation. | |
| 7833885 | [Rheumatic manifestations of chronic hepatitis C and response to the treatment with interf | 1994 | Chronic hepatitis C can be responsible for a broad range of autoimmune manifestations, including cryoglobulinemia and Sjögren's syndrome. We report our experience with six patients (five women and one man; mean age 55.6 years) in whom hepatitis C was diagnosed during evaluation of joint symptoms. Polyarthralgia was the main symptom and was often accompanied with myalgia; a polyalgic syndrome was seen in some patients. Isolated cytolysis was consistently found, although, in some instances, liver enzyme elevations were moderate and postdated the onset of the clinical symptoms. The diagnosis of hepatitis C was confirmed by recombinant immunoblot assay (RIBA) in every case. The polymerase chain reaction (PCR) detected hepatitis C virus RNA in five of the six patients. Histological findings were characteristic of chronic hepatitis. All six patients had immunological test abnormalities, which included presence of rheumatoid factors (2 of 6), positive antinuclear antibodies without anti-DNA antibodies (3 of 6) and low serum complement levels (3 of 6). A cryoprecipitate was found in four of the six patients. Four patients reported symptoms of sicca syndrome and two had Chisholm grade III lesions upon examination of salivary gland biopsy specimens. Four patients were given a six-month course of interferon alpha. In three of these four patients, evaluation at the end of the treatment showed abatement or resolution of symptoms, normal liver function tests, unchanged or diminished antinuclear antibody titers, and normal serum complement levels. In the remaining patient, no changes in symptoms or transaminase levels occurred during interferon alpha treatment. In conclusion, rheumatic symptoms can be the most prominent manifestation of chronic hepatitis C.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 7693746 | Specific cellular immune responses to pancreatic antigen in chronic pancreatitis and Sjög | 1993 Jul | The specific cellular immune response to the partially purified pancreatic antigen was studied by the peripheral blood lymphocyte proliferation assay in patients with chronic pancreatitis, Sjögren's syndrome, and primary biliary cirrhosis. A significant positive result (stimulation index > 2.0) was observed in 7 of 21 patients with idiopathic chronic pancreatitis (33%; P < 0.05), 6 of 7 patients with Sjögren's syndrome-associated chronic pancreatitis (86%; P < 0.0005), and 6 of 11 patients with Sjögren's syndrome (55%; P < 0.01), compared to normal controls whose stimulation index was 0.94 +/- 0.28 (mean +/- SD; n = 14; range, 0.56-1.60). On the other hand, patients with alcoholic chronic pancreatitis (17%; n = 12), stone-related chronic pancreatitis (0%; n = 7), primary biliary cirrhosis-associated chronic pancreatitis (33%; n = 3), primary biliary cirrhosis (0%; n = 4), systemic lupus erythematosus (17%; n = 6), and autoimmune thyroiditis (0%; n = 6) showed no significant difference from normal controls. Furthermore, in patients with idiopathic chronic pancreatitis who had positive results, a lymphocyte proliferative response to the pancreatic antigen was observed in T cells, especially in the CD4+ T cell subpopulation. These results suggest that the pancreatic antigen plays a role in the pathogenesis of a part of idiopathic chronic pancreatitis and Sjögren's syndrome in association with T cell responses and, also, suggest that autoimmunity may be a possible etiological factor in chronic pancreatitis. | |
| 8397718 | Predominance of IgG1 subclass of anti-Ro/SSA, but not anti-La/SSB antibodies in primary Sj | 1993 Jun | We have developed isotype-specific enzyme-linked immunosorbent assays to assess anti-Ro/SSA and anti-La/SSB IgG subclasses in 31 patients with primary Sjögren's syndrome. The anti-Ro/SSA antibody production was largely but not totally restricted to IgG1, whilst the anti-La/SSB subclass distribution varied from one patient to another. IgG2 and IgG3 anti-La/SSB was more frequent in those patients with extraglandular manifestations. In addition, there were more increases in the IgG2 and IgG4 contribution to anti-La/SSB activity in the 16 DR3-positive patients than in the remaining 10. | |
| 8423457 | Chronic progressive sensory ataxic neuropathy: clinicopathological features of idiopathic | 1993 Jan | Eleven patients with chronic progressive sensory ataxic neuropathy were examined clinicopathologically. Three cases were associated with primary Sjögren's syndrome (SS-SAN) and the others were considered to be idiopathic (ISAN). The major clinical symptom in both was loss of proprioceptive and kinesthetic sensation with some impairment of superficial sensation, with multifocal and asymmetrical distribution and progression. The truncal and trigeminal nerves were frequently involved. The motor system was substantially preserved. These somatic sensory and motor symptoms did not differ between ISAN and SS-SAN, but autonomic nervous system signs were more frequent in SS-SAN. Polyclonal elevations of serum IgG and/or IgA were seen in 8 patients. One autopsied case with ISAN combined with previous reports suggested that systemic T- and B-cell infiltration into the nervous tissues, as well as a wide variety of the visceral organs, may be a common finding in ISAN and SS-SAN, and could participate in the cause of this neuropathy and polyclonal hypergammaglobulinaemia. | |
| 1497555 | Recently characterised autoantibodies and their clinical significance. | 1992 Jun | Multisystem autoimmune diseases such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), scleroderma and polymyositis are characterised by the presence of antinuclear antibodies (ANAs). Immunoblotting and cDNA cloning studies reveal that the autoantigens of the multisystem autoimmune diseases are important proteins involved in nucleic acid metabolism, including tRNA charging, intron splicing, DNA uncoiling, and RNA polymerase co-factors. Each specific syndrome associates with a restricted variety of ANAs, e.g. anti-La with primary SS, anti-Sm with SLE, anti-synthetase enzymes with myositis, anti-topoisomerase 1 (Scl 70) with scleroderma, and anti-centromere with CREST. Precise characterisation of an ANA provides valuable diagnostic and prognostic information, and should be performed when an ANA is detected. | |
| 1371222 | Antinuclear antibodies: clinical correlations and biologic significance. | 1992 | Several trends become evident from the foregoing discussion. As the different ANA antigenic specificities have been identified, they have often been found to be highly conserved polypeptides that subserve very basic cellular functions that are carried out in the nucleus, nucleolus, and ribosomes. The reasons why only 30 or so basic cellular proteins become the targets of an autoimmune response in patients with connective tissue disease at the exclusions of the other 10,000 macromolecules that exist inside cells remain a mystery. However, some insight into this enigma might be provided by the mechanism of molecular mimicry (Table 9). The possibility that highly conserved immunogenic molecules that are expressed by infectious pathogens can trigger an immune response in a genetically predisposed human host that cross-reacts with cellular autoantigens is a well documented phenomenon in disorders such as rheumatic fever. This mechanism is now being mentioned with increasing frequency in discussions pertaining to the pathogenesis of autoimmune connective tissue diseases. Another trend relates to the increasing sensitivity of the newer assays that have been developed to detect ANA. When highly purified or recombinant autoantigens are used in versatile assays such as ELISA, radioimmunoassays, or immunoprecipitation, the frequency with which certain autoantibodies can be detected in patient subgroups can go up significantly. For example, with classical immunodiffusion, anti-Ro/SS-A antibodies can be detected in 25% of unselected patients with SLE, whereas with an ELISA based on affinity purified Ro/SS-A antigen, 50% of patients with SLE are found to have elevated levels of this autoantibody specificity. As is often the case, we pay for increased sensitivity in a laboratory test with decreased specificity. With immunodiffusion, virtually no normal individuals have anti-Ro/SS-A antibodies, but with the ELISA as many as 10% of normals have elevated anti-Ro/SS-A binding levels. Thus, the incremental diagnostic value of this newer anti-Ro/SS-A assay could be questioned. The true clinical value of this new laboratory technology will become more evident when these more sophisticated ANA assays are used together in a panel-like fashion to profile a given patient's autoimmune response at the very onset of his illness. Preliminary work has already begun in this area. This approach, if well standardized, could have significant diagnostic and prognostic value. Another benefit of this newer technology will be the ability to measure antibody binding levels to individual autoepitopes--limited portions of an autoantigen's amino acid sequence that represent single antibody binding sites. It is possible that certain patterns of clinical disease could be linked to autoantibody production against individual autoepitopes rather than whole autoantigenic molecules. This area is only now beginning to be explored. | |
| 8927595 | [Clonal B-cell reaction in Sjögren disease and Hashimoto autoimmune thyroiditis]. | 1996 Jul | Autoimmune diseases are defined as specific, adapted immune reactions against self-antigens. These antigens were attacked by activated, autoaggressive T-Cells in most cases. However, since introduction of the MALT concept it became clear, that particularly in the autoimmune diseases of the MALT specific subpopulations of B-cells play an important role. In this study, the B-cells in the thyroid gland of 40 patients suffering from Hashimoto's disease and 25 patients with Sjögrens syndrome and enlargement of the salivary glands were immunophenotyped and molecular-genetically investigated. The molecular-genetical investigation included PCR based amplification of immunoglobulin heavy chain CDR III region and the T-cell receptor gamma chain (TCR-gamma). By immunophenotyping, in the salivary glands monocytoid B-cells could be identified as intraepithelial effector cells in nearly all cases, whereas in the thyroid gland mostly marginal zone cells in the follicle epithelium were observed. In 13 biopsy specimen from salivary gland, clonal rearrangements of TCR-gamma, and in 9 cases of patients with Sjögren's syndrome JH rearrangements could be detected. Monoclonal TCR-gamma rearrangements were identified in 9/40 patients suffering from autoimmunethyroiditis Hashimoto. In 8/40 thyroid gland biopsies a monoclonal JH-rearrangement could be found. Within 11/25 patients with Sjögren's syndrome and in 23/40 patients with M. Hashimoto polyclonal rearrangements were observed. Within all biopsy specimen of patients with monoclonal rearrangements, lymphoepithelial lesions or lymphoepithelial destructions could be identified immunohistochemically. Additionally, in 2 biopsies from salivary gland and in one specimen from thyroid gland the transition from autoimmune disease into a secondary high grade lymphoma was observed. In 26/40 patients with M. Hashimoto and in 11/25 patients with Sjögren's syndrome the transition in a subsequent low grade B cell lymphoma of MALT-type was found. These results lead to the following conclusions: 1. clonal rearrangements of tumor forming B-cells in both autoimmune diseases investigated can be interpreted as facultative malignant. 2. Intraepithelial B-cells probably are the promotors of the autoimmune process and--in case of clonal evolution and immortalisation--can be regard as causative agent in the development of primary extranodal B-cell lymphoma. |