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ID PMID Title PublicationDate abstract
1411091 Scanning electron microscopic evaluation of the arthritis in MRL/lpr mice. 1992 The articular surfaces of disarticulated knee joints from MRL/lpr and MRL/n mice, aged 4-33 weeks were examined by light microscopy (LM) and scanning electron microscopy (SEM). Light microscopy did not reliably predict SEM findings. Most of the abnormalities detected by SEM were related to surface disruption of articular cartilage. However, areas of articular cartilage covered by tightly adherent non-confluent monolayers of stellate-shaped cells with intertwining cytoplasmic processes were observed. In these areas the integrity of the underlying cartilage matrix was disrupted, with exposure of collagen fibers. These findings suggested that outgrowth of proliferating synovial cells in the joints of arthritic MRL/lpr mice may lead to cartilage destruction.
7696049 Insulin-like growth factor I accelerates recovery of articular cartilage proteoglycan synt 1994 Interleukin 1 (IL-1) is a cytokine which induces cartilage proteoglycan (PG) depletion by inhibiting PG synthesis and increasing PG breakdown. Insulin-like growth factor I (IGF-I), in contrast, is known to promote matrix formation. We examined the effects of both mediators in a bovine tissue culture model. IL-1 dose-dependently inhibited PG formation of articular cartilage [half-maximal effect (EC50) at 4 ng/ml], while PG synthesis was increased by IGF-I (EC50 = 15 ng/ml). After inhibition of PG formation with IL-1 for 2 days and subsequent removal of free IL-1, addition of IGF-I dose-dependently accelerated restoration of the original rate of synthesis with a half-maximal effect at 20 ng/ml and a maximal effect at 50 ng/ml. The IGF-I concentration required to elicit a half-maximal effect on cartilage PG synthesis remained constant in the absence or presence of IL-1. We therefore conclude that inhibition of cartilage PG synthesis by IL-1 is not effected by damage to the IGF receptor. Synovial fluid (SF) of 40 patients with rheumatoid arthritis (RA) was found to contain 64 +/- 6 ng IGF-I/ml (mean +/- SEM). The reported effects of IGF-I in vitro therefore occurred at concentrations comparable to those present in joints in vivo. IL-1 beta was detectable (> 0.5 pg/ml) in 38 of 40 RA-SF samples (mean 28 +/- 6 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
8080738 Serum metalloproteinases and their inhibitors: markers for malignant potential. 1994 Sep Death from cancer results from the development of metastases or local progression of tumour. Metastasis and local progression may result from the inappropriate activity of metalloproteinases released by tumour cells or of their regulatory peptides. We have developed quantitative assays for interstitial collagenase, stromelysin 1 and tissue inhibitors of metalloproteinase (TIMP) 1 and 2, which have allowed the study of serum levels of these proteins. Sera from 40 patients with prostatic cancer, stored prior to and after 6 and 12 months' treatment with a gonadotrophin-releasing hormone agonist and an anti-androgen were analysed. Levels were compared with two control groups, comprising 21 patients with active rheumatoid arthritis and 56 age-matched hospital attenders without arthritis or cancer. Contrasting levels have been found in patients with prostatic cancer as compared with hospital controls without cancer and patients with rheumatoid arthritis. Patients with prostatic cancer had higher levels of TIMP-1 and collagenase (P = 0.0001) and lower levels of TIMP-2 (P = 0.003) than controls. Patients with metastatic cancer had significantly higher levels of collagenase than those without metastases (P = 0.02). Patients with rheumatoid arthritis had significantly higher levels of stromelysin than either controls (P = 0.002) or patients with cancer (P = 0.008). Serum tissue inhibitor of metalloproteinase 1 in combination with collagenase levels was as sensitive as prostate-specific antigen as a marker of metastatic disease. These findings provide a basis for the investigation of the role of metalloproteinases and their inhibitors in other malignancies.
8480273 A new approach to the treatment of nonsteroidal anti-inflammatory drugs induced gastric bl 1993 May The effect of the free radical scavengers allopurinol (50 milligrams) and dimethyl sulfoxide (DMSO) (500 milligrams), taken orally four times a day, on the clinical outcome of hematemesis resulting from nonsteroidal anti-inflammatory drugs (NSAID) induced erosive gastritis was examined in a prospective randomized double-blinded controlled trial. In 180 fully evaluable patients with osteoarthritis or rheumatoid arthritis, administration of allopurinol (n = 63) or DMSO (n = 58) enabled significantly (p < 0.01) larger numbers of patients to remain hemodynamically stable with no rebleed relative to those in the control group (n = 59). The results of endoscopic examination 48 hours after admission demonstrated that gastric erosions were still present in significantly more patients in the control group (p < 0.01; n = 20; 50 percent) than in the allopurinol (n = 5; 9 percent) or DMSO (n = 4; 7 percent) groups. The radical scavengers also reduced the number of patients requiring blood transfusion because of a rebleed or continued bleeding and emergency operation relative to control values. It is, thus, construed that oxygen derived free radicals mediate the mechanism of NSAID induced erosive gastritis. Scavenging these radicals impairs the gastritis, stimulates healing and protects against the complications of its hemorrhagic episodes.
7513025 In vitro IgM rheumatoid factor production by peripheral blood mononuclear cells from patie 1993 Sep OBJECTIVE: We investigated whether mononuclear cells (MNC) from patients with seronegative rheumatoid arthritis (SNRA) are able to produce rheumatoid factor (RF) in response to lectin stimulation, Staphylococcus aureus Cowan I (SAC) or pokeweed mitogen (PWM), and also we investigated the role of CD5+ B cells in the pathogenesis of in vitro IgM RF production. METHODS: IgM RF production was measured by enzyme linked immunosorbent assay and CD5+ B cells by flow cytometry. Also, the effects of monocyte depletion and the inhibition of prostaglandin (PG) were compared in SNRA, seropositive RA (SPRA) and healthy controls. RESULTS: Peripheral blood MNC of patients with SNRA were able to produce the same amount of IgM RF as patients with SPRA following stimulation and SAC. CD5+ B cells also increased in patients with SNRA as well as patients with SPRA compared to healthy controls. However, a definite contribution of the CD5+ B cells to SAC-induced IgM RF production could not be demonstrated. The role of macrophage and PG on in vitro IgM RF synthesis were insignificant. CONCLUSION: MNC of patients with SNRA were able to produce IgM and IgG RF in response to SAC stimulation as well as that of the healthy controls. However, we could not find a significant role of CD5+ B cells and monocytes on in vitro IgM RF synthesis by MNC of patients with SNRA.
8189107 [Induction of arthritis in the ankles of rat immunized by intraperitoneally-injected lipop 1994 Apr The histological changes in the ankle joints were investigated in Sprague Dawley (SD) rat immunized through intraperitoneal injection of 10 micrograms or 100 micrograms of lipopolysaccharide(LPS; extracted from Escherichia coli), or Lipid A, for 10 or 15 weeks (short term) or for 30 weeks (long term). The serum anti-IgM rheumatoid factor-like substance (RFLS) was detected by enzyme-linked immunosorbent assay (ELISA). The macroscopic arthritic changes in the rat ankles, showing redness or swelling, were observed in 17 of 64 rats immunized by LPS and in 9 of 62 rats immunized by Lipid A. Rats immunized by 10 micrograms of LPS in the long term developed synovial lining cell hyperplasia in 12 of 28 ankles (12/28), lymphoid cell infiltration in 8/28, and pannus formation in 2/28. Rats immunized by 100 micrograms of Lipid A in the long term developed synovial lining cell hyperplasia in 8/18, lymphoid cell infiltration in 7/18, and pannus formation in 2/18. SD rats immunized by LPS or Lipid A developed a significantly higher incidence rate of hyperplasia in the synovial lining cells, than controls. In each case of immunization by LPS or Lipid A, the serum RFLS levels at sacrifice were significantly higher than before immunization (p < 0.01). These findings suggest that LPS and Lipid A played important roles as trigger substances causing arthritis with RFLS elevation in rats immunized with E. coli.
8918567 The chemoattractant activity of rheumatoid synovial fluid for human lymphocytes is due to 1996 Nov The majority of synovial fluids from 29 rheumatoid arthritis patients were strongly attractive for normal blood lymphocytes judged by assays of polarization and collagen gel invasion. While rheumatoid synovial fluids contained IL-15, IL-8, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) at levels sufficient to attract lymphocytes, inhibition of the activity of any single cytokine using specific antibody did not abolish the activity of the fluid. However combinations of anti-cytokine antibodies used together (anti-IL-15+anti-MCP-1; anti-IL-8+anti-MCP-1 or +anti-MIP-1 alpha) inhibited most of the activity, suggesting that attraction of lymphocytes by the fluids is due to a combination of attractants. Blood lymphocytes required activation by overnight culture to respond optimally, while rheumatoid synovial tissue lymphocytes responded to synovial fluids without a requirement for a period of culture. Lymphocytes derived from rheumatoid synovial fluids were poorly responsive to locomotor stimulants. Most of the responding cells from blood mononuclear cell fractions were T lymphocytes of the CD45RO isotype. Incubation in the presence of cyclosporin A or corticosteroids inhibited the response of lymphocytes to the fluids, but the presence of non-steroidal anti-inflammatory drugs (NSAIDs) and other agents used in therapy of the patients from whom the fluids were taken had no inhibitory effect.
8016581 Serum IgA anti-Klebsiella antibodies in ankylosing spondylitis patients from Catalonia. 1994 IgA antibodies against Klebsiella pneumoniae were measured by immunofluorescence in 84 Catalan patients with ankylosing spondylitis (AS), 41 patients with non-inflammatory arthropathies (NIA) and 22 patients with rheumatoid arthritis (RA). Patients with AS showed higher levels of anti-klebsiella IgA antibodies (IgA-Kp) than NIA and RA patients (4.7 +/- 1.6 U vs 3.7 +/- 1.5 U and 3.1 +/- 1.4 U respectively, p = 0.001). In AS patients a significant correlation between IgA-Kp and levels of C-reactive protein was observed. Although no clear correlation was found between IgA anti-klebsiella and total serum IgA levels, a significant correlation between IgA anti-klebsiella and serum levels of secretory IgA was detected (r: 0.43, p = 0.003). In conclusion, some patients with AS disclosed raised levels of Klebsiella antibodies in sera and this is related to an increase of secretory IgA level. Analysis about the relationship between response to klebsiella and the presence of gut inflammation in AS patients could be of interest.
8350330 Immunosuppression by the disease modifying antirheumatic drug bucillamine: inhibition of h 1993 Jun OBJECTIVE: Bucillamine: N-(2-mercapto-2-methyl-propanoyl)-L-cysteine has recently been suggested to be effective in the treatment of rheumatoid arthritis (RA). The molecular structure of this compound is similar to that of D-penicillamine, except that bucillamine has 2 free sulfhydryl groups in its structure whereas D-penicillamine has only one. The goal of our studies was to determine whether bucillamine exerted immunosuppressive effects in vitro. METHODS: The effect of bucillamine and its metabolites on mitogen induced proliferation and IL-2 production by human T cells was examined. RESULTS: Bucillamine, and its metabolites SA 679, and SA 981 inhibited mitogen induced T cell responses. The inhibitory effect of bucillamine and SA 679, in which one sulfhydryl group is S-methylated, was markedly augmented in the presence of CuSO4, and the effect was completely prevented by the addition of catalase. The capacity of SA 981, the internal disulfide of bucillamine, to inhibit T lymphocyte responses was not dependent on the presence of CuSO4. SA 672, in which both sulfhydryl groups are S-methylated, did not inhibit T cell proliferation. CONCLUSION: Our results suggest that bucillamine has 2 distinct inhibitory effects on T cell function. One is the ability to generate H2O2 in the presence of CuSO4 and is attributable to its free thiol groups. The other is related to a separate inhibitory mechanism, that is not dependent on CuSO4 or the reduced thiol groups. These 2 immunosuppressive effects may account for the potency of bucillamine in suppressing rheumatoid inflammation.
8154934 Lymphocyte responses to DR1/4 restricted peptides in rheumatoid arthritis. 1994 Mar OBJECTIVE: To determine whether analog and unrelated DR1/4 binding peptides alter DR1/4 restricted responses of peripheral blood lymphocytes (PBL) from patients with rheumatoid arthritis (RA). METHODS: PBL from 25 patients with RA and 12 healthy controls were cultured with DR1/4 restricted peptides of the influenza haemagglutinin, amino acids 307-319 (HA) and matrix proteins, amino acids 17-29 (IM). Responses were determined by 3H-thymidine uptake proliferation assays and limiting dilution analysis. Competitor peptides were analogs HA-R312 and HA-K313 differing from HA by one amino acid at the 312 or 313 position respectively or unrelated peptides which bind to DR1/4. RESULTS: The responses of eight patients with RA to the two stimulatory influenza peptides did not differ significantly from controls and this was confirmed by the frequency estimate of T cells in PBL which responded to HA (mean frequency: 1 in 9.0 x 10(4), n = 5, in DR1/4+ RA patients, 1 in 7.6 x 10(4), n = 5, in DR1/4+ healthy controls). DR1/4 binding analogs of the HA peptide inhibited HA specific peptide responses of PBL from patients with RA and controls. Inhibition was also detected with unrelated peptides which bind to DR1/4 but to which the individual did not respond. CONCLUSION: Similar responses to two DR1/4 restricted peptides were observed in patients with RA and controls. Both antigen analog- and unrelated peptide-major histocompatibility complexes (MHC) can result in the inhibition of antigen specific responses in multi-clonal human lymphocyte populations. However, an analog peptide may be stimulatory in some individuals. These results provide some initial data for the development of a rational approach to MHC-specific immunomodulation in rheumatoid arthritis.
8817672 Tissue IGFBP-3 proteolysis: contrasting pathophysiology to that in the circulation. 1995 Endogenous IGFBP-3 has been examined in the circulation and in four different extravascular fluids in normal healthy adults and in patients with psoriasis or arthritis. In all of these cases there was no apparent increase of IGFBP-3 protease activity in the circulation. In contrast, endogenous IGFBP-3 from normal skin interstititial fluid and synovial fluid from healthy adults was found to be predominantly in the 29 kDa proteolytically modified form. This indicated that in these extravascular fluids in normal healthy adults a protease was active which was similar, if not identical, to that found in the circulation in pregnancy and other conditions. This was confirmed by the fragmentation of recombinant IGFBP-3 when incubated with these fluids. When the skin interstitial fluid or synovial fluid were taken from abnormal tissues (psoriasis in the former and osteoarthritis or rheumatoid arthritis in the latter) there was a considerable reduction in the amount of endogenous IGFBP-3 in the 'clipped' form and a reduction in the protease activity. In psoriatic lesions, this reduction in IGFBP-3 protease activity was shown to be due to the presence of an inhibitor in the interstitial fluid but not in the circulation. In both peritoneal and follicular fluid, the ratio of intact to fragmented IGFBP-3 appeared to relate to the oestrogen status. In peritoneal fluid there was a decrease in intact IGFBP-3 during the late proliferative/early secretory phase of the endometrial cycle. In the ovary there was an increase in the amount of fragmented IGFBP-3 in the follicular fluid from the dominant follicle in comparison with atretic follicles from the same ovary. There is normally little proteo-lysis of IGFBP-3 in the circulation but this increases in many conditions where there is increased metabolic activity. The same enzyme(s) appear to be active in many extravascular fluids but under very different regulation. The activity in these extravascular fluids is normally high but can be decreased with local tissue inflammation; this decrease appears to be mediated by the induction of a local inhibitor.
7512421 Inhibitor regulation of tissue kallikrein activity in the synovial fluid of patients with 1994 Mar Tissue kallikrein (TK) and alpha 1-antitrypsin (AT)/TK complexes can be detected in SF from patients with RA if components of the fluids which interfere with the detection of TK are removed. alpha 2-Macroglobulin (alpha 2-M) in SF was demonstrated to contain trapped proteases which were still active in amidase assays. Removal of alpha 2-M from RA SF reduced their amidase activity. However, at least some of the remaining activity was due to TK because it was soya bean trypsin inhibitor resistant and trasylol sensitive and was partly removed by affinity chromatography on anti-TK sepharose. Removal of RF from the fluids reduced the values obtained for TK levels by ELISA. Addition of SF to human urinary kallikrein (HUK) considerably reduced the levels of TK detected suggesting the presence of a TK ELISA inhibitor in the fluids. Removal of components of > 300 kDa from SF markedly reduced the TK ELISA inhibitory activity and increased the values for both the TK and alpha 1-AT/TK levels in fluids as measured by ELISA. It is considered this novel inhibitor does not bind to the active site of TK but rather binds to the site reactive with anti-TK antibodies.
8624637 In vitro effects of methotrexate on human articular cartilage and bone-derived osteoblasts 1996 Apr Conflicting data have been published on whether low-dose methotrexate (MTX) treatment of rheumatoid arthritis (RA) is able to slow down radiological joint damage, i.e. retard the destruction of articular cartilage and (subchondral) bone. We studied the effects of MTX on proteoglycan (PG) turnover and interleukin-1 (IL-1)- and RA mononuclear cell (RA-MNC)-induced cartilage damage in human articular cartilage tissue cultures, and the effects of MTX on basal and RA-MNC-influenced proliferation and differentiation of osteoblasts in cultures of human bone-derived osteoblasts. MTX exerted no direct effect on cartilage nor did MTX influence IL-1- or RA-MNC-induced cartilage damage, despite strong suppression of basal as well as mitogen- and antigen-induced RA-MNC proliferation. MTX induced strong inhibition of osteoblast proliferation, but did not significantly interfere with osteoblast differentiation (i.e. alkaline phosphatase activity). RA-MNC-enhanced proliferation and differentiation of osteoblasts were abolished by MTX. These results suggest that if MTX is able to induce retardation of radiological progression in RA, this is not based on an initial direct effect of MTX on cartilage as measured by PG turnover, nor on an initial inhibition of IL-1- or RA-MNC-induced cartilage damage. However, longstanding MTX-induced inhibition of RA-MNC proliferation may lead to reduction of the catabolic activity involved in cartilage destruction. On the other hand, long-term inhibition of osteoblast proliferation may eventually lead to decreased bone formation and osteopenia. Whether this will turn out to be a problem of clinical importance in the treatment of RA has to be established.
1333967 Correlation between density of beta 2-adrenergic receptors on peripheral blood mononuclear 1992 Oct In order to study the influence of the autonomic nervous system on the immune response, we evaluated the density and the equilibrium dissociation constants (KD) of beta 2-adrenergic receptors (beta 2R) on peripheral blood mononuclear cells (PBMC) in patients with rheumatoid arthritis (RA), Crohn's disease (CD), and in controls. Results were correlated with the serum concentrations of soluble interleukin-2 receptors (sIL-2R) as a marker for T-cell activation in vivo. The density of beta 2R was significantly decreased in patients with RA (P < 0.05) and CD (P < 0.05) as compared with controls. The number of beta 2R in patients with RA was significantly lower than in CD patients (P < 0.05). KD values of beta 2R were markedly but not significantly decreased in both patient groups as compared with control values. Serum concentrations of sIL-2R were significantly elevated in RA patients as compared with those in CD patients (P < 0.05) and controls (P < 0.05), while there was no difference between the latter two groups. In patients with RA, a significant negative correlation between beta 2R density and serum IL-2R levels (r = -0.66, P < 0.02) was observed. These results demonstrate the close correlation between the modulation of beta 2R on PBMC and the activation of the immune response. However, the role of beta 2R stimulation in the pathogenesis of immunologically mediated diseases remains to be clarified.
7915850 Lymphocyte activation status, expression of adhesion molecules and adhesion to human endot 1994 Feb The synovial tissue of patients with rheumatoid arthritis (RA) is characterized by infiltration with inflammatory cells, mainly memory helper cells (CD4+CD29+). An important initiating step in tissue infiltration is the adhesion of peripheral blood lymphocytes to the vascular endothelium. Therefore, we studied lymphocyte-endothelium adhesion in 40 RA patients and in 19 controls by a sensitive fluorimetric assay, using human umbilical vascular endothelial cells. Furthermore, expression of adhesion molecules VLA (CD29) and LFA-1 (CD11a) on CD4+ and CD8+ T cells was determined. In order to evaluate the activation state of lymphocytes, the soluble interleukin-2 receptor (sIL2R) was measured. The relationship to disease activity was evaluated using the Ritchie articular index. RA patients had a higher percentage of CD4+ cells (p < 0.005) and a lower percentage of CD8+ cells (p < 0.001) than controls did. The CD4+CD29+/CD4+CD29- ratio and the CD8+CD29+/CD8+CD29- ratio were increased in patients with active RA (p < 0.01 and p < 0.05, respectively) and in patients with inactive disease (p = 0.09 and p < 0.005, respectively) compared with controls. LFA-1 (CD11a) was present on almost all T lymphocytes and its density did not differ between patients and controls. Serum levels of sIL2R were significantly higher in both patient groups compared with controls (p < 0.0005); patients with active disease showed significantly higher levels than patients with inactive disease (p < 0.05). Lymphocyte-endothelium adhesion was not increased in patients, although the expression of the adhesion molecule CD29 on T lymphocytes of RA patients was higher.(ABSTRACT TRUNCATED AT 250 WORDS)
8864317 Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: phar 1996 Aug 1. The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite > 6 months of SASP treatment. 2. SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two-compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t-test or signed rank test were applied in the statistical analysis. 3. Pharmacokinetics of MTX without vs with SASP, means +/- s.d. were follows: AUC: 673 +/- 179 vs 628 +/- 210 (95% confidence interval [CI] of the difference was -71 to 159) ng ml-1, MRT: 5.2 +/- 1.3 vs 5.2 +/- 1.1 (95% CI -0.4 to 0.4) h, t1/2,z: 4.3 +/- 1.1 vs 4.2 +/- 1.1 (95% CI -0.3 to 0.5) h, V/F: 59.3 +/- 29.3 vs 65.5 +/- 25.3 (95% -23.8 to 11.4) 1, CL/F: 12.3 +/- 5.0 vs 13.5 +/- 4.8 (95% CI -4.5 to 2.3) 1 h-1. CLR/F: 6.2 +/- 1.3 vs 6.3 +/- 2.1 (95% CI -1.3 to 1.1) l h-1. All P values were > or = 0.3. 4. A weak correlation existed between the change of ESR and the MRT, the t1/2,z and the V/F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05 < P < 0.1). 5. There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables on MTX.
11048623 IGF and IGF-binding protein system in the synovial fluid of osteoarthritic and rheumatoid 1996 Dec Various arthritic disorders result from a disruption of the equilibrium between the synthesis and degradation of tissue matrix macromolecules. Growth factors, particularly insulin-like growth factor-I (IGF-I), are believed to play an important role in maintaining this equilibrium. In this study, we determined the levels of IGF-I, IGF-II, and characterized and measured the amount of IGF-binding proteins (IGFBPs) in the synovial fluid (SF) of osteoarthritis (OA), rheumatoid arthritis (RA) patients and normal individuals. Furthermore, we characterized the IGFBP found in these SFs. The levels of IGF-I, IGF-II and IGFBP-3 were determined by specific radioimmunoassays (RIAs). IGFBP identification and measurement were carried out using the Western ligand blot (WLB) technique, and characterization performed by Western immunoblot. IGFBP-3 proteolysis was analyzed by autoradiography after incubation of SF with radiolabeled IGFBP-3. Results showed a statistically significant increase (P < 0.001) in the IGF-I level in arthritic SF vs normal controls; 75 +/- 11 ng/ml and 82 +/- 11 ng/ml were recorded for RA (N = 8) and OA (N = 10), respectively, whilst normal controls (N = 9) were at 19 +/- 7 ng/ml. No difference in the level of IGF-II was recorded between the three groups studied. Human SF demonstrated the presence of IGFBP-1, -2, -3 and -4, but not that of IGFBP-5 and -6. The level of IGFBP-3 tested either by WLB or RIA was significantly higher (P < 0.001) in RA and OA patients. Moreover, a statistical and positive correlation between the levels of IGF-I and IGFBP-3 was noted. WLB analysis indicated that the amount of IGFBP-1 did not vary among the groups. The levels of IGFBP-2 and -4 were significantly increased (P < 0.02) solely in the RA SF. Further experiments demonstrated that a limited IGFBP-3 proteolysis occurred in human SF. Moreover, the ratio of total IGF over total bioactive IGFBPs was lower in RA (P < 0.05), and to a lesser extent in OA than normal specimens. This study showed the presence of four IGFBPs (1 4) in human SF for which the IGFBP-2, -3 and -4 were enhanced in arthritic fluid. Importantly, although proteolysis occurred in the SF, an increased amount of bioactive IGFBPs were present in arthritic SF, which may affect the bioavailability of IGF-I within the articular tissues.
7531440 Synovial tissue response to treatment with Campath-1H. 1995 Feb OBJECTIVE: Therapeutic trials in rheumatoid arthritis with the monoclonal antibody Campath-1H have demonstrated recurrent clinical synovitis in some patients, despite profound depletion of circulating lymphocytes. This study was undertaken to examine the cellular infiltrates in synovial tissue at a time of persistent peripheral lymphopenia. METHODS: Immunohistochemical staining of synovial tissue and peripheral blood lymphocyte phenotyping. RESULTS: Synovial tissues from 2 patients with recurrent synovitis after Campath-1H therapy contained significant T lymphocytic infiltrates at a time when circulating T lymphocytes were markedly depleted. CONCLUSION: These results demonstrate that peripheral blood analysis may not accurately reflect the synovial tissue response to monoclonal antibody therapy.
7633938 Immunoprinting: various genes are associated with increased risk to develop rheumatoid art 1995 Jan To identify genes that contribute to the manifestation of rheumatoid arthritis we performed association studies via microsatellite analyses of immunorelevant loci (HLA-DRB, 5 T cell receptor loci, TNFa IL1, IL2, IL5R and CD40L). A total of 183 patients and 275 healthy controls were typed in terms of HLA and grouped according to the known predisposing HLA-DRB1 genes (DRB1*04; relative risk approx. 5; DRB1*01, relative risk approx. 2; a third group carried neither allele). Microsatellite polymorphisms characterizing the TCRBV6S3, CD3D, IL1A, IL2, and IL5R genes did not show significant associations with rheumatoid arthritis, whereas TCRBV6S1, TCRBV6S7, TNFa, and CD40L genes may influence relative protection or risk in certain groups of patients. Analysis of a microsatellite marker adjacent to the transcription element alpha (TEA) in the T cell receptor alpha delta complex indicates that in the cohort carrying neither the DRB1*04 nor the DRB1*01 allele the relative risk to acquire rheumatoid arthritis is increased (> 13) or decreased (< 0.07), depending on the inherited microsatellite allele adjacent to the TEA locus. Sequence analysis of the closely linked TEA region from patients and controls revealed a novel dimorphism. Only the newly identified TEA allele leads to binding of a nuclear protein that may be involved in the regulated expression of the TCRDA genes. Subsequent typing of rheumatoid arthritis patients and controls revealed, however, that the association of the microsatellite marker is largely independent of the TEA allele, confirming incomplete linkage in the 2 kb region of the TCRDA locus. These results are discussed in the context of hot spots of recombination in this genomic region and other linked candidate sequences that predispose to develop rheumatoid arthritis.
7923385 Mediators and autopathogenic effector cells in proteoglycan-induced arthritic and clinical 1994 Oct 15 Proteoglycan (aggrecan)-induced arthritis is an autoimmune inflammatory animal model produced in genetically susceptible BALB/c mice. This animal model shows many similarities to human rheumatoid arthritis as indicated by clinical assessments, histopathological studies, and immunological parameters. The systemic immunization of mice with a select group of cartilage proteoglycans provokes immune responses to the immunizing antigen and then the production of cross-reactive antibodies to self proteoglycans. This is followed by an explosive proliferation of autoreactive T cells, especially in joint draining lymph nodes, accompanied by local (joint) inflammatory events. In the current experiments we found that lymphocytes from arthritic, or potentially arthritic but yet clinically asymptomatic animals, produced more IL-2 than those T cells obtained from animals immunized with nonarthritogenic PGs. In addition, synoviocytes isolated from prearthritic or arthritic animals produced several-fold more interleukin-1 beta (IL-1 beta) than cells from normal animals. Flow cytometric analysis indicated an autoantigen (mouse PG)-specific selective proliferation of surface Ig+/CD45R+ cells in prearthritic stages followed by the proliferation of predominantly T helper (CD4+) cells during and after the development of arthritis.