Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 1691758 | Dissociation of expression of two rheumatoid factor cross-reactive kappa L chain idiotopes | 1990 May 1 | mAb 6B6.6 and 17.109 recognize two distinct kappa III L chain cross-reactive idiotopes (CRI) present on approximately 2/3 of IgM kappa rheumatoid factor (RF) paraproteins. To determine the distribution of these two CRI and their relationship to each other among polyclonal RF, sera from 86 RA patients and 49 controls were analyzed for the presence of 6B6.6- and 17.019-bearing RF by using sensitive solid phase ELISA. Levels of CRI(+) RF were estimated by using 6B6.6(+) and 17.019(+) RF standards. Detectable levels (greater than or equal to 195 ng/ml) of CRI(+) RF were rarely present in the control sera (8% for 6B6.6; 0% for 17.109), whereas 59% of RA sera contained measurable CRI(+) RF (48% for 6B6.6; 35% for 17.109; 21% for both). Where detected, CRI(+) RF were present in low concentrations (6B6.6: 1.21 +/- 1.56 micrograms/ml; 17.109: 1.20 +/- 1.15 micrograms/ml) and constituted a small fraction of the total IgM RF in these sera (6B6.6: 0.9 +/- 2.2%; 17.109: 0.8 +/- 0.9%). There was no correlation between either RF CRI and levels of IgM RF (r less than 0.1, p greater than 0.5). Levels of 6B6.6(+) RF did not correlate with 17.109(+) RF (r = -0.11, p = 0.47). In selected sera that contained both RF CRI, it was possible to selectively absorb 6B6.6(+) RF. Taken together, these data indicate the mutual independence of these two RF CRI among polyclonal RF and suggest the presence of distinct regulatory mechanisms governing their expression. Moreover, that these two CRI constitute a small proportion of polyclonal RF, in contrast to their striking predominance among monoclonal RF paraproteins, argues for the importance of other germline VL genes contributing to polyclonal RF production or the presence of extensive somatic mutation among polyclonal RF in RA. | |
| 2736834 | Clinical serological correlations in the evaluation of Sjögren's syndrome. | 1989 Mar | Fifty-six subjects (46 females and 10 males) with signs of Sjögren's Syndrome (SS) have been evaluated for clinical and serological parameters. In 12 subjects such clinical signs were associated with a definite connective tissue disease (secondary SS): Rheumatoid Arthritis (2 cases), Systemic Lupus Erythematosus (4 cases), Progressive Systemic Sclerosis (4 cases), Essential Mixed Cryoglobulinemia (2 cases). All patients underwent a lip biopsy which was evaluated according to the Chisholm-Mason scale. Six out of 56 subjects (10.7%) had a normal salivary gland with few lymphocytes (class I); 5 (10%) had a scattered lymphoid infiltrate containing less than 1 focus/4 mm2 (class II); 36 (64.3%) had one focus/4 mm2 (class III) and, finally, 9 (16%) had more than 1 focus/4 mm2 (class IV). The great majority (91%) of the patients had some abnormalities at the ophthalmological examination (Schirmer test, Break up times, van Bijsterveld score): even those with a class I lip biopsy. Xerostomia was present in 69% of the patients, xerophthalmia in 78%, arthralgias in 78%, parotid swelling in 19%, Raynaud's phenomenon in 16%, recurrent abortion in 9 patients. The prevalence of autoantibodies in the group of primary SS was high: ANA 43.2%, anti-Ha 40%, anti-Ro 12%, anti-phospholipids 52.2%, rheumatoid factor (RF) 45.7%. A decrease of lysozyme concentration in tears and saliva has been demonstrated and a correlation between level of lysozyme and lip-biopsy has been observed.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 3548732 | A controlled study of concurrent therapy with a nonacetylated salicylate and naproxen in r | 1987 Feb | Previous studies of combinations of nonsteroidal drugs used in the treatment of rheumatoid arthritis (RA) have yielded conflicting results. We used standard methods to measure disease activity and high pressure liquid chromatography to measure plasma drug concentrations. We used doses of choline magnesium trisalicylate, adjusted to achieve therapeutic serum salicylate concentrations, and naproxen in a randomized, double-blind, placebo-controlled cross-over study of full dose trisalicylate (CMT), full dose naproxen (N), full dose of both (CMT-N), and half dose of both (cmt-n) to examine their relative efficacy and toxicity in treating RA. CMT-N was statistically superior to all other treatments in only 1 of 12 efficacy variables, but was equal to N and better than CMT or cmt-n for 7 variables. There were minimal differences among treatments for the other 4 efficacy variables. The mean percentage difference for the efficacy variables between CMT-N and N was 3%, between CMT-N and CMT was 10.6%, and between CMT-N and cmt-n was 10.5%. Thirteen percent of patients manifested toxic reactions during the initial open dose-adjustment salicylate run-in phase. During the double-blind phases of the study, CMT-N was more toxic than N, CMT, or cmt-n (7.5% versus 3.4%, 1.8%, and 3.7%, respectively). Tinnitus was more common when full-dose CMT was used; N (N or CMT-N) was associated with increased skin toxicity. Gastrointestinal complaints were equally common with all regimens. CMT-N, although sometimes statistically superior to CMT, N, or cmt-n, showed no clinically important additive or synergistic effect versus N or CMT alone. | |
| 2123476 | Retinoids inhibit phospholipase A2 in human synovial fluid and arachidonic acid release fr | 1990 Oct | Retinoids have demonstrated antiinflammatory activity in certain animal models and human disease states. The mechanism by which retinoids elicit this activity is unknown. Some retinoids are known to inhibit arachidonic acid (AA) release and metabolism in intact cells in vitro. Retinoids may exert their antiinflammatory effects by inhibiting phospholipase A2 (PLA2) and the resultant production of inflammatory AA metabolites. Retinoids were evaluated in vitro as inhibitors of the PLA2 activity in human synovial fluid (HSF-PLA2). Of the naturally occurring, nonaromatic retinoids tested, all-trans-retinal, all-trans-retinoic acid (all-trans-RA) and 13-cis-RA were the most potent inhibitors (IC50 S 6-15 microM), whereas all-trans-retinol was much less potent. Of the synthetic aromatic retinoids and arotinoids examined, the free carboxylic, sulfonic, and sulfinic acid forms were more than 15-fold more potent inhibitors of HSF-PLA2 than their corresponding ethyl esters. These retinoids also were evaluated as inhibitors of calcium ionophore A23187-induced AA release from rat peritoneal macrophages. All-trans-RA and 13-cis-RA were potent inhibitors of AA release from these cells (IC50 S 4 microM), while the other natural retinoids were inactive. Of the aromatic retinoids and arotinoids tested, the free acid forms (IC50 S 2-6 microM) were 5- to 21-fold more potent inhibitors of AA release from the macrophages than their corresponding ethyl esters. The potencies of the arotinoids as inhibitors of HSF-PLA2 appeared to correlate with their potencies as inhibitors of AA release from A23187-stimulated rat peritoneal macrophages. These data support the hypothesis that one possible mechanism for the known antiinflammatory activity of some retinoids may be by inhibition of phospholipase A2. | |
| 2186951 | A report of three multiclinic trials evaluating arbaprostil in arthritic patients with ASA | 1990 Jun | Three randomized, placebo-controlled multiclinic trials involving arbaprostil dosages of (a) 10 micrograms; (b) 25 micrograms; and (c) 10, 25, or 50 micrograms orally for 4 wk in patients older than 18 yr with rheumatoid arthritis or osteoarthritis who had endoscopically documented nonsteroidal antiinflammatory drug-associated gastric mucosal damage were conducted in the United States. All patients continued taking the nonsteroidal antiinflammatory drugs and were reendoscoped after 4 wk of therapy. Success at that time was defined as complete resolution of all gastric mucosal damage. Six hundred fifty-eight patients were enrolled in the three trials. Significantly more patients experienced healing in the arbaprostil treatment groups in all trials compared with those who received placebo. The healing rates in the various trials were 68% and 32% (10 micrograms vs. placebo; p = 0.007); 77% and 23% (25 micrograms vs. placebo; p less than 0.001); and 52%, 46%, 35%, and 16% (50, 25, and 10 micrograms vs. placebo; p less than 0.001, less than 0.001, and 0.002, respectively). Diarrhea, mostly of a mild nature, was the only arbaprostil-associated side effect and was found with the 25- and 50-microgram dosages (33% and 59%, respectively). No exacerbation of arthritis signs or symptoms was found. Arbaprostil at doses with varying effects on gastric acid secretion (25 and 50 micrograms) was documented in these trials to be an effective and safe agent for healing gastric mucosal damage associated with aspirin or other nonsteroidal antiinflammatory drugs in patients with either rheumatoid arthritis or osteoarthritis without adversely affecting joint symptomatology. | |
| 2441708 | Macrophage migration and maturation within rheumatoid nodules. | 1987 Jul | In long-established rheumatoid nodules, monocytes continue to be recruited and to migrate from the outer vascular zone toward the palisade and central necrotic area. Maturation of these cells is shown to take place during tissue migration. We found that the great majority of palisade cells express exclusive mononuclear phagocyte phenotypes. Among this mononuclear phagocyte population are many cells that bear the receptor for iC3b (CR3), but few that bear the receptor for C3b (CR1). HLA-D region molecule expression is intense and widespread. | |
| 2419964 | Dissection of the human antigammaglobulin idiotype system with monoclonal antibodies. | 1986 Feb | Murine monoclonal antibodies (MoAb) were prepared by immunizing mice with human monoclonal rheumatoid factors from patients with mixed cryoglobulinaemia. Indirect solid phase radioimmunoassay and haemagglutination inhibition were used to screen the MoAb. Reactivity patterns of MoAb were determined using (a) polyclonal and monoclonal IgM proteins, (b) monoclonal IgM proteins from patients with neuropathy, (c) monoclonal and polyclonal IgM antigammaglobulins, and (d) various isolated VkIIIb-positive immunoglobulins. Several patterns were obtained: MoAb reacting with private idiotypic determinants, with VkIIIb-related determinants, and with cross-reactive idiotypes (CRI). Two MoAb of the second type reacted with VkIIIb-positive immunoglobulins and light chains regardless of their antigenic activity. Another MoAb reacted with VkIII light chains only when in association with mu heavy chains. MoAb of the third type defined distinct CRI systems. One of these was restricted to antigammaglobulins and another also involved neuropathy-associated monoclonal IgM proteins. All MoAb clearly reacted with a minor population of normal polyclonal IgM, except for the MoAb detecting private idiotypic determinants. Studies using inhibition of binding by enzyme-linked immunosorbent assay showed that polyclonal IgM antigammaglobulins may carry a CRI determinant detected by one of the MoAb. This CRI system, defined by the MoAb Glo 86.3, was similar to but not identical with the previously described Wa CRI, which is widely prevalent among IgM antigammaglobulins of rheumatoid arthritis. | |
| 1696866 | Human IgG anti-F(ab')2 antibodies possess rheumatoid factor activity. | 1990 Aug | Individual preparations of affinity purified anti-F(ab')2 antibodies and anti-Fc antibodies isolated from the sera of patients with rheumatoid arthritis (RA), were examined for reactivity with the Fab and Fc fragments of human IgG. Western blot assays demonstrated specific interaction of affinity-purified anti-Fab antibodies with both Fab and Fc molecules. Approximately one-half of the anti-Fab antibody preparations studied contained IgG antibodies reactive with Fab and Fc fragments in ELISA, suggesting the existence of naturally occurring epibody-like autoantibodies in these patients. Thirteen of 14 affinity-purified anti-Fc antibody preparations contained IgG cross-reactive with Fab molecules in ELISA. Double-adsorption assays on affinity columns demonstrated that a minimum of 14%, and possibly as much as 50%, of the IgG anti-Fab antibodies reacted with the Fc of IgG. Conversely, a minimum of 12%, and possibly as much as 70%, of the IgG anti-Fc antibodies reacted with IgG Fab molecules. Anti-Fab antibodies isolated from non-RA individuals also exhibited anti-Fc reactivity in ELISA, demonstrating the presence of these dual-reactive antibodies in other autoimmune and normal individuals. These studies establish the presence of naturally occurring IgG autoantibodies reactive with both the Fab and Fc fragments of human IgG. Their existence emphasizes the potential of anti-immunoglobulin antibodies to recognize a multiplicity of antigens, possibly including other members of the immunoglobulin supergene family. | |
| 1932376 | Cytokine-mediated regulation of human leukocyte gelatinases and role in arthritis. | 1991 Aug | Gelatinases (type IV collagenases) produced by normal peripheral blood leukocytes were studied by the use of a substrate conversion assay. When monocytes were stimulated with IL-1 beta discrete amounts of a 85-kDa gelatinase were detected. This type of gelatinase comigrated with a phorbol ester-inducible metalloproteinase from human tumor cells. The levels of induction of the monocytic enzyme after stimulation with IL-1, double-stranded RNA, LPS, and mitogens paralleled those of the secondary cytokine IL-6. When peripheral blood neutrophils were stimulated with IL-8 or PMA significant amounts of a 91-kDa neutrophil gelatinase were released, whereas with IL-1 beta no effect was observed. Both neutrophil and monocyte gelatinases cross-reacted in immunoprecipitation experiments with tumor cell-derived gelatinases. Further evidence for structural similarity between the IL-1-inducible monocytic (85 kDa) and the IL-8-regulated neutrophilic (91 kDa) gelatinases was obtained after purification of the proteins to homogeneity: both gelatinases possessed an identical amino terminal amino acid sequence and appeared as truncated forms of gelatinase from tumor cells. Synovial fluids of arthritic joints contained extremely high concentrations of the 91-kDa gelatinase. The concentrations of this type of gelatinase were correlated with the titers of the marker cytokine IL-6. The controlled production and activity of leukocyte-derived gelatinase may play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. In the arthritis patient this enzyme might contribute to the pathogenesis of joint destruction and might constitute a useful marker of disease status. | |
| 3142593 | Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: cont | 1988 Oct 22 | OBJECTIVE: To evaluate the prophylactic effect of ranitidine 150 mg twice daily in patients requiring one of the following non-steroidal anti-inflammatory drugs: naproxen, piroxicam, diclofenac, and indomethacin. In addition, risk factors were studied in order to help in targeting of such treatment to specific groups of patients. DESIGN: Double blind, placebo controlled, randomised, parallel group with endoscopic assessments at 0, 4, and 8 weeks. SETTING: Multicentre outpatient study at secondary referral centres in five European countries. PATIENTS--297 patients with rheumatoid arthritis or osteoarthritis over the age of 18 without lesions in the stomach and duodenum at baseline endoscopy (after one week without taking non-steroidal anti-inflammatory drugs). Those taking other antirheumatic agents, concomitant ulcerogenic drugs, or treatment for peptic ulcers within the previous 30 days were excluded. Age, sex, arthritic disease, and type of non-steroidal anti-inflammatory drug used were comparable in the two treatment groups. In all, 263 patients completed the trial. INTERVENTIONS: Ranitidine 150 mg twice daily or placebo (plus the selected non-steroidal anti-inflammatory drug) was prescribed within five days after the baseline endoscopy for two consecutive periods of four weeks. Paracetamol was permitted during the study, but not antacids. Patients were withdrawn if the most severe grade of damage (including ulceration) was found at the four week endoscopy or when indicated, or with lesser damage at the investigator's discretion. END POINT: Frequency of gastric and duodenal ulceration or lesions, or both. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of peptic ulceration by eight weeks was 10.3% (27/263); 2 out of 135 (1.5%) developed duodenal ulceration in the ranitidine group, compared with 10 out of 126 (8%) taking placebo. The frequency of gastric ulceration was the same (6%) for the two groups at eight weeks. Though significantly fewer gastric lesions developed in the ranitidine group by eight weeks. The frequency of non-ulcerative lesions in the duodenum did not differ greatly for the two groups at either time point. Twelve out of 75 (16%) patients taking piroxicam developed peptic ulceration, of whom two thirds had duodenal ulceration. Patients with a history of peptic ulcer were particularly susceptible to recurrent ulceration, against which ranitidine offered some protection. CONCLUSIONS: Ranitidine 150 mg twice daily significantly reduced the incidence of duodenal ulceration but not gastric ulceration when prescribed concomitantly with one of four commonly used non-steroidal anti-inflammatory drugs. | |
| 1708314 | Monoclonal antibodies against human anti-F(ab')2 antibodies react with light chain epitope | 1991 Apr | Anti-F(ab')2 antibodies affinity isolated from sera of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or normal SLE relatives were used to produce monoclonal antibodies (mAbs) in Balb/c and NZB mice. Four of five mAbs showed only primary light chain specificity. Only one mAb produced in an NZB mouse against anti-F(ab')2 from a single SLE patient showed anti-mu-chain specificity. Parallel identical control immunizations with IgG or a single human IgG kappa myeloma produced mAbs with a predominant gamma-chain/Fc fragment specificity. Anti-light chain specificity of mAbs was demonstrated to involve epitopes requiring tertiary structure of the entire light chain instead of antigens confined to Ckappa/lambda or Vkappa/lambda fragments. Anti-kappa specificity of three mAbs was extremely similar but not identical to that defined by anti-Km1 allotyping systems. No evidence was obtained with any of the mAbs produced for antigens unique to SLE or RA anti-F(ab')2 antibodies. The light chain antigenic prominence of many anti-F(ab')2 antibodies may reflect structural features shared by this group of immunoglobulins somehow important for their biologic function. | |
| 2152497 | Dendritic cells in human blood and synovial exudates. | 1990 | Dendritic cells from human blood and synovial exudates are distinct from other leukocytes and are homogeneous by several criteria. Morphologically, their most prominent feature is numerous veils. Phenotypically, dendritic cells lack the surface antigens that identify monocytes, T cells, B cells, and NK cells. Human dendritic cells strongly express class I and class II MHC products, and have a distinct array of integrin and adhesin molecules. In many systems, dendritic cells are potent stimulators of T cell function. In the allogeneic mixed leukocyte reaction, for example, dendritic cells are 30-100 times more efficient than other cells in presenting transplantation antigens, for the induction of DNA synthesis, cytokine release, and generation of cytotoxic T cells. In addition, dendritic cells can induce the long-term clonal growth of T lymphocytes. Although dendritic cells are a minor subpopulation in human blood, new isolation protocols are available that permit efficient isolation and enrichment to > 90%. | |
| 2250079 | An association between long-term non-steroidal anti-inflammatory drug therapy and the seve | 1990 Oct | The present study was undertaken to compare the periodontal status of a group of 50 patients on long-term non-steroidal anti-inflammatory drug (NSAID) therapy with that of an age and sex-matched group of 42 controls. The mean duration of drug therapy in the study group was 9 years (range 2-30 years). The clinical parameters investigated were plaque index (PI), gingival index (GI), pocket probing depth (PPD), loss of attachment (LOA), gingival recession (GR) and gingival fluid flow (GFF). Long cone periapical radiographs were also taken to score the amount of alveolar bone resorption. Examinations were carried out on 6 Ramfjord teeth in each subject. The results showed that there were no significant differences between the groups for PI, GI, PPD, LOA, GR or alveolar bone resorption. However, a highly significant difference was seen between the gingival fluid flow in the study (16.74 +/- 10.61) and control (37.72 +/- 28.63) groups (p less than 0.001). It is suggested that this may be associated with the specific effects of NSAIDs in reducing the vascularity and permeability of small blood vessels. | |
| 2464001 | Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifes | 1989 Feb | Synovial inflammation is often associated with systemic changes, such as increased levels of acute phase proteins and hypergammaglobulinemia, which cannot be explained by the cytokines described in synovial fluids and synoviocyte secretions. Interleukin 6 (IL-6) has recently been characterized as a mediator of multiple inflammatory responses. This cytokine promotes T and B lymphocyte growth and differentiation, and acute phase protein synthesis. We therefore examined IL-6 production by human synoviocytes and its presence in synovial fluids. In vitro, synoviocytes spontaneously released IL-6, which was increased by IL-1 and tumor necrosis factor-alpha. Synoviocyte-derived IL-6 activity was able to induce hybridoma-plasmacytoma proliferation, and immunoglobulin and acute-phase protein synthesis. The synovial fluids from patients with diverse arthropathies contained IL-6 activity, but higher levels were present in inflammatory arthropathies than in osteoarthritis. These results demonstrate that synoviocytes are a potent source of IL-6, which can contribute to important manifestations of inflammatory arthropathies. | |
| 2199097 | Identification of protein components reactive with anti-PM/Scl autoantibodies. | 1990 Jul | The PM/Scl antigen from mammalian cells has been characterized as a nucleolar and nucleoplasmic molecular complex containing at least 16 polypeptides ranging in molecular weight from 110 to 20 kD. Of these polypeptides, we have found those of 68, 39 and 20 kD to be in a phosphorilated form. Whereas the entire complex was precipitated by all the anti-PM/Scl sera tested, in immunoblots the antibodies specifically recognized determinants on the 110-kD protein. This protein was immunoprecipitated more preferentially from nucleoli extracts than from total cell extracts. Moreover, this protein disappeared from the immunoprecipitates when treated with DNAse. Likewise, the immunoblot reaction of the specific antibodies with the 110-kD protein was abolished by treatment of the extracts with DNAse and trypsin, and was resistant when extracts were treated with RNAse. Affinity-purified antibodies from this protein selectively stained the nucleoli and the nucleoplasm of the mammalian cells. Moreover, when the cultured cells used in immunofluorescence were treated with DNAse, the affinity purified antibodies from the 110-kD protein gave negative fluorescence. However, when whole anti-PM/Scl sera were used, a nucleolar and nucleoplasmic staining was found. We conclude that the 110-kD protein has at least one of the autoimmunogenic epitopes of the PM/Scl antigen, recognized by all anti-PM/Scl sera tested. Other epitopes differing in their DNAse sensitivity may also be present in the PM/Scl antigen. | |
| 2016540 | Epitopes of group A streptococcal M protein shared with antigens of articular cartilage an | 1991 May 1 | Rabbit antisera evoked by purified pepsin-extracted group A streptococcal M proteins were screened for the presence of joint cross-reactive antibodies by indirect immunofluorescence using thin sections of mouse knee joints. Pep M1, M5, and M18 antisera contained antibodies that cross-reacted with chondrocytes, cartilage, and synovium. Immunofluorescence inhibition assays showed that some of the joint cross-reactive epitopes were shared among the three heterologous serotypes of M protein. The pep M5 joint cross-reactive epitopes were localized to three different synthetic peptides of the C-terminal region of pep M5. Immunoblot analyses showed that the M5 joint cross-reactive antibodies recognized two proteins of human synovium and cartilage of molecular mass 56 and 58 kDa. The cross-reactive antibodies binding to the 56-kDa protein were inhibited by purified vimentin in immunoblot inhibition experiments. M protein-specific antibodies from patients with acute rheumatic fever were also shown to cross-react with joint tissue in a pattern similar to the rabbit antisera. Rabbit and human M protein-specific antibodies that were bound to articular cartilage activated significant levels of complement when compared to control serum, suggesting that M protein joint cross-reactive antibodies could potentially be involved in the pathogenesis of ARF and arthritis. | |
| 2351304 | Major histocompatibility complex class II antigen (HLA-DR) expression by ileal epithelial | 1990 May | Major histocompatibility complex molecules act as non-specific receptors for antigenic proteins and present them to T-cells. Presented antigen together with class II molecules activates antigen specific T-helper cells and may trigger a cellular immune response. The expression of HLA-DR antigens by epithelial cells was examined with an indirect peroxidase technique in ileal biopsies from 38 patients with seronegative spondylarthropathy and features of acute or chronic gut inflammation on biopsy, 14 patients with chronic inflammatory bowel disease, 10 rheumatic and 10 non-rheumatic controls. In acute ileitis, there was more HLA-DR expression in villous and crypt epithelial cells than in non-inflamed controls (p less than 0.01). In chronic inflammation and in chronic inflammatory bowel disease, class II antigens were more expressed in villus (p less than 0.02) and crypt epithelium (p less than 0.01). Strong HLA-DR expression in crypt epithelial cells was connected with active inflammation (p less than 0.02). These findings suggest binding of unknown enterobacterial or nutritional luminal antigens to HLA-DR antigens normally present in enterocytes. The enterocytes act as antigen presenting cells causing a local increase of targets for activated T-cells and trigger the gut inflammation responsible for the clinical symptoms of the seronegative spondylarthropathy. | |
| 1718287 | Predominant role of neutrophils in the inactivation of alpha 2-macroglobulin in arthritic | 1991 Sep | We studied the state of alpha 2-macroglobulin (alpha 2M), an important inhibitor of cartilage-degrading proteinases, in relation to activation of neutrophils in 82 patients with several types of arthritis, including 52 with rheumatoid arthritis and 11 with osteoarthritis. Levels of total inactive alpha 2M (i alpha 2M), which comprises alpha 2M complexed to proteinases and alpha 2M inactivated by oxidation or hydrolysis, were measured with a monoclonal antibody specific for i alpha 2M. In addition, levels of alpha 2M complexed to proteinases were quantitated with specific assays. Neutrophil activation was assessed by measuring elastase-alpha 1-antitrypsin complexes and lactoferrin. In 83% of the 82 patients tested, the synovial fluid (SF) to plasma ratio of i alpha 2M exceeded 1, indicating an intraarticular generation. Levels of i alpha 2M significantly correlated with neutrophil numbers (P less than 0.0005) and with levels of elastase-alpha 1-antitrypsin complexes and of lactoferrin (P less than 0.00001 for both). Moreover, part of i alpha 2M consisted of alpha 2M complexed to elastase-like and chymotrypsin-like proteinases, presumably, neutrophil elastase and cathepsin G, respectively. However, the amount of i alpha 2M was approximately 10-fold larger than the amount complexed to these proteinases. In vitro inactivation of alpha 2M by activated neutrophils was only partly inhibitable by eglin C, a specific inhibitor of both elastase and cathepsin G. Release of reactive oxygen species was presumably responsible for the additional inactivation of alpha 2M, because eglin C completely abolished the inactivation of alpha 2M by cell-free supernatant of activated neutrophils. Thus, our results suggest a predominant role of neutrophils in the inactivation of alpha 2M in the SF of patients with inflammatory joint diseases. However, this inactivation could be explained only in part by the release of neutrophilic proteinases. We propose that the inactivation of alpha 2M in SF was due to the concerted action of both reactive oxygen species and lysosomal proteinases. | |
| 2470748 | Interaction of human rheumatoid synovial collagenase (matrix metalloproteinase 1) and stro | 1989 May 25 | The homologous proteinase inhibitors, human alpha 2-macroglobulin (alpha 2M) and chicken ovostatin, have been compared with respect to their "bait" region sequences and interactions with two human matrix metalloproteinases, collagenase and stromelysin. A stretch of 34 amino acid residues of the ovostatin bait region sequence was determined and the matrix metalloproteinase cleavage sites identified. Collagenase cleaved a X-Leu bond where X was unidentified, whereas the major cleavage site by stromelysin was at the Gly-Phe bond, 4 residues on the COOH-terminal side of the collagenase cleavage site. Collagenase cleaved the alpha 2M bait region at the Gly679-Leu680 bond, and stromelysin at Gly679-Leu680 and Phe684-Tyr685 bonds. Sequence similarity in the bait region of members of the alpha-macroglobulin family is strikingly low. The kinetic studies indicate that alpha 2M is a 150-fold better substrate for collagenase than type I collagen. Structural predictions based on the bait region sequences suggest that a collagen-like triple helical structure is not a prerequisite for the efficient binding of tissue collagenase to a substrate. The binding of stromelysin to alpha 2M is slower than that of collagenase. Stromelysin reacts with ovostatin even more slowly. Despite the preference of chicken ovostatin for metalloproteinases, human alpha 2M, a far less selective inhibitor, reacts more rapidly with collagenase and stromelysin. These results suggest that alpha 2M may play an important role in regulating the activities of matrix metalloproteinases in the extracellular space. | |
| 1978220 | T cell recognition of stress proteins. A link between infectious and autoimmune disease. | 1990 Aug | Exposure of any living cell to a change in environmental conditions such as increased growth temperature results in the induction of stress, or "heat shock", proteins. Proteins identified in such experiments have subsequently been shown to be ubiquitous components of all cells and to perform essential functions during normal cell growth in addition to their role during stress. It has recently been recognized that members of stress protein families play an important role in the immune response to a wide variety of infections, and the highly conserved nature of such proteins has led to the suggestion that they may also be immune targets in autoreactive responses. In this article we review the role of stress proteins in the immune response to infection and discuss the evidence which suggests that lymphocytes recognizing conserved determinants on such antigens may be associated with autoimmune diseases. |