Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. This paper describes the purification and characterization of collagenolytic property of renal cathepsin L isolated from kidney of rats rendered adjuvant arthritis. The enzyme was isolated by acid extraction, ammonium sulfate fractionation, Sephadex gel filtration, CM-Sephadex chromatography and Sephacryl S-300 chromatography. 2. The enzyme preparation was found to be homogeneous by gel filtration and SDS-polyacrylamide gel electrophoresis. The molecular weight of the enzyme was estimated to be 29,000. 3. Incubation of rat tail tendon collagen with purified cathepsin L resulted a conversion of cross-linked beta-chain dimers into uncross-linked alpha-chain monomers. The pH optimum for collagen degradation by purified cathepsin L was found to be 3.5. This optimal pH is shifted to 4.5 when haemoglobin was used as a substrate for the enzyme. 4. Various activators and inhibitors were tested for their influence on the activity of cathepsin L. The purified enzyme showed a maximal activity in the presence of EDTA. Cysteine was also found to increase the activity of cathepsin L. This enzyme was strongly inhibited by iodoacetate, p-chloromercurobenzoate, mercuric chloride but not inhibited by pepstatin or PMSF. E-64 and leupeptin were also found to be strong inhibitors for cathepsin L. The degradation of rat tail tendon collagen by cathepsin L was completely inhibited by E-64. 5. The results presented in this investigation suggest that cathepsin L play a crucial role in the pathogenesis of adjuvant arthritis.
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PMID:Purification and characterization of collagenolytic property of renal cathepsin L from arthritic rat. 142 27

To determine whether native bovine type XI collagen (BXI) is arthritogenic, five strains of inbred mice were immunized with BXI/CFA. Arthritis was not observed in any of these strains, though it was prevalent in DBA/1 and B10.RIII controls immunized with bovine type II collagen (BII). Antisera from BXI-immunized mice reacted with mouse type XI collagen (MsXI), weakly with the alpha-chains of BXI, and minimally with mouse type II collagen (MsII). However, antisera to BII reacted with MsII and MsXI, indicating antibodies to conformation-independent epitopes shared by alpha 1(II) and alpha 3(XI). Mice immunized with BXI containing a small amount of BII developed arthritis much like those immunized with BII; sera from these mice reacted with MsXI and MsII. Delayed-type hypersensitivity responses differed from IgG responses, i.e., BXI elicited responses to alpha 1(XI), alpha 2(XI), alpha 3(XI), and alpha 1(II); BII, to alpha 3(XI) and alpha 1(II) exclusively. To determine whether alpha 1(XI), alpha 2(XI), alpha 3(XI), and alpha 1(II) are arthritogenic, DBA/1J mice were immunized with each alpha-chain. Arthritis was seen in mice injected with alpha 3(XI) or alpha 1(II). Sera to both alpha-chains reacted similarly with MsII and peptide fragment alpha 1(II)-CB11. Epitope mapping using polyclonal and mAb to type II collagen revealed that all polyclonal and 11 of 14 mAb reacted with alpha 3(XI) and alpha 1(II), whereas three mAb reacted only with alpha 1(II). In conclusion, BXI is immunogenic but not arthritogenic in five strains of mice, whereas alpha 3(XI) and alpha 1(II) are arthritogenic and immunogenic in DBA/1 mice and share greater than or equal to 11 epitopes recognized by autoantibody.
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PMID:Immunity to type XI collagen in mice. Evidence that the alpha 3(XI) chain of type XI collagen and the alpha 1(II) chain of type II collagen share arthritogenic determinants and induce arthritis in DBA/1 mice. 171 Feb 40

Eight HLA B27-restricted influenza A virus nucleoprotein 383-391-specific cytotoxic T lymphocyte (CTL) clones were obtained from three unrelated donors following natural infection. T cell receptor (TcR) usage was studied using the "anchored" polymerase chain reaction. TcR alpha-chain usage was restricted with three predominant V alpha (V alpha 12.1, 14.1, 22) and two predominant J alpha segments. beta-chain variable-region usage was also conserved, with V beta 7 being used by five clones despite contributing less than 2% of peripheral blood lymphocyte V beta sequences of one individual studied. The TcR beta-chain junctional region was highly conserved even between CTL clones from unrelated individuals, with a negatively charged amino acid, contributed to by N-region addition, encoded at position 97 in all but two clones. This study shows that peptide-specific HLA B27-restricted CTL following influenza virus infection use very similar TcR and, when considered with previous studies, suggests a pattern of TcR conservation for major histocompatibility complex class I-restricted responses. No difference in TcR usage was detected between one healthy donor and two with HLA B27-associated arthritis.
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PMID:Conservation of T cell receptor usage by HLA B27-restricted influenza-specific cytotoxic T lymphocytes suggests a general pattern for antigen-specific major histocompatibility complex class I-restricted responses. 839 85

Synovial tissue is rarely available from patients with early synovitis, with the exception of synovial biopsies. However, T cell populations early in the development of synovitis may be enriched in antigen-specific cells and critical to disease pathogenesis. To investigate the T cell repertoire in early synovitis, we utilized a PCR protocol for detection of T cell receptor (TCR) transcripts present in small amounts of synovial tissue. To expand the substrate for PCR, preamplification of cDNA was performed with a 3' constant region primer plus either a mixture of variable region primers or random hexanucleotides. Utilizing this method improved the sensitivity of detection. This technique is applied here to the analysis of TCR transcripts in synovial biopsies from individuals with early rheumatoid arthritis (RA) and non-RA synovitis. TCR alpha-chain transcripts were detectable in 5/5 RA and 4/4 non-RA specimens evaluated, with beta-chain transcripts detected in 4/5 early RA and 4/4 non-RA specimens evaluated. Confirmation of transcripts by sequencing of cloned PCR products verified the specificity of amplification. The most frequently expressed TCR V region families in early RA synovitis were V alpha 11, V alpha 14, V alpha 28, V beta 7, V beta 9 and V beta 17. Several of these V regions have previously been implicated in studies of chronic RA synovitis. J alpha and J beta region usage was similar to that seen in chronic RA, and conserved N region motifs were apparent. We conclude that it is possible to detect TCR transcripts in small synovial biopsies from individuals with early arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Detection of T cell receptors in early rheumatoid arthritis synovial tissue. 855 98

A series of 101 peptides each 20 amino acids in length (10-residue overlap) spanning the helical portion of the mature alpha-chain of human type II collagen (CII) was synthesized. DBA/1 (H-2q) mice were immunized with individual peptides, and draining lymph node cells were challenged in vitro. Strong responses were measured to three peptides: peptide I (residues 74-93), peptide 14 (residues 254-273), and peptide 81 (residues 924-943). B10.Q (H-2q) mice were responsive to peptides I and 81 but not to peptide 14. B10.RIII (H-2r) mice, which are resistant to arthritis induction following immunization with human CII, were unresponsive to peptides I, 14, and 81. Using single amino acid truncated peptides, we determined minimal immunostimulatory lengths for peptides I and 81. Residues critical to antigenicity were identified by introducing alanine and glycine substitutions into minimal length immunostimulatory peptides. The determinants within peptides I and 81 are 100% homologous to mouse CII and are autoantigens. Peptide 81 has homology to viral proteins. Peptide 14 is 90% homologous to mouse CII and has homology to heat shock proteins.
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PMID:Characterization of the antigenic structure of human type II collagen. 860 94

Regulation of experimental autoimmune encephalomyelitis (EAE) can be induced by anti-idiotype immunity against T cell receptor (TCR) fragments associated with major histocompatibility complex (MHC) molecules. However, we have recently found that preimmunization with an alpha-chain TCR CDR3 peptide (LYFCAARSNYQL) derived from myelin basic protein (MBP)-specific clones did not suppress but rather augmented the severity of EAE induced by MBP-specific T cells in SJL/J mice. To test whether CDR3 vaccination could control only a highly restricted T cell population, we studied the effect of the peptide against EAE induced by T cells specific for different Ag/MHC ligands and autoimmune diseases affecting non-neural tissues. In contrast to expectations, the peptide was found to augment not only EAE induced by MBP-specific T cells, but also proteolipid protein (PLP)-specific T cell- or PLP peptide-induced EAE in SJL/J mice, and MBP-induced EAE and adjuvant arthritis (AA) in rats. The CDR3 peptide was neither inhibitory nor supportive for Ag-induced activation of an encephalitogenic clone in vitro. In addition, the peptide treatment neither inhibited the induction of Ag-specific T cells nor altered the APC function of spleen cells. These findings, on the one hand, confirm previous results showing TCR peptide-induced enhancement of the disease and, on the other hand, indicate that the TCR CDR3 peptide may control T cells with broader Ag/MHC specificities than could be expected. Structural similarity among TCR idiotypes of autoimmune T cells may partly account for these results.
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PMID:An alpha-chain TCR CDR3 peptide can enhance EAE induced by myelin basic protein or proteolipid protein. 889 82

This study describes a novel method of inhibiting T-cell function by the use of peptides rationally designed from the T-cell antigen receptor (TCR) alpha-chain transmembrane sequence involved with TCR receptor assembly. The most effective peptide (core peptide, CP) modulating in vitro and in vivo T-cell function contained nine amino acids two of which, lysine and arginine, were hydrophilic and separated by four hydrophobic amino acids. CP without chemical modification or conjugation was able to enter non-T and T cells. Conjugation of CP at the carboxyl terminus with palmitic acid resulted in a greater inhibition of T-cell interleukin-2 (IL-2) production in vitro than peptide alone. When examined for effects in vivo, CP reduced clinical signs of inflammation in three T cell-mediated disease models including adjuvant-induced arthritis, experimental allergic neuritis, and cyclophosphamide-induced diabetes in NOD/Lt(F) mice. This peptide or its analogues has potential as a therapeutic agent in human inflammatory and autoimmune disorders.
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PMID:T-cell antigen receptor transmembrane peptides modulate T-cell function and T cell-mediated disease. 898 47

Matrix metalloproteinases (MMPs) participate in physiological remodeling of the extracellular matrix. Recently we determined that both fibrinogen (Fg) and cross-linked fibrin (XL-Fb) are substrates for selected MMPs. Specifically, XL-Fb clots were solubilized by MMP-3 (stromelysin 1) by cleavage at gamma Gly 404-Ala 405, resulting in a D-like monomer fragment. Similarly, MMP-7 (matrilysin) and MT1-MMP (membrane type 1 matrix metalloproteinase) solubilized XL-Fb clots. However, the molecular mass of fragment D-dimer, obtained after MMP-7 and MT1-MMP degradation of XL-Fb, is similar to that of fragment D-dimer from plasmin degradation ( approximately 186 kDa). In contrast, fragment D-like monomer, from MMP-3 degradation of both fibrinogen (Fg) and XL-Fb, is similar to fragment D from plasmin degradation of Fg ( approximately 94 kDa). Reduced chains from MMP-3, MMP-7, and MT1-MMP digests of Fg and XL-Fb were subjected to direct sequence analyses and D/D-dimer alpha-chain showed cleavage at both alpha Asp 97-Phe 98 and alpha Asn 102-Asn 103. Degradation of the beta-chain resulted in microheterogeneity of cleavage sites at beta Asp 123-Leu 124, beta Asn 137-Val 138, and beta Glu 141-Tyr 142, whereas all three enzymes cleaved the gamma-chain at gamma Thr 83-Leu 84. In both Fg and XL-Fb, several cleavage sites obtained by proteolysis with MMP-3, MMP-7, and MT1-MMP were found to be in very close proximity to those obtained by plasmin on these same substrates. That does not occur with other MMPs such as MMP-1, -2, and -9 and MT2-MMP. The degradation of XL-Fb by MMPs suggests both plasmin-dependent and independent mechanisms of fibrinolysis that might be relevant in inflammation, angiogenesis, arthritis, and atherosclerosis.
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PMID:Characterization of stromelysin 1 (MMP-3), matrilysin (MMP-7), and membrane type 1 matrix metalloproteinase (MT1-MMP) derived fibrin(ogen) fragments D-dimer and D-like monomer: NH2-terminal sequences of late-stage digest fragments. 1052 39

Antigen-presenting cells degrade endocytosed antigens, e.g. collagen type II, into peptides that are bound and presented to arthritogenic CD4(+) helper T cells by major histocompatibility complex (MHC) class II molecules. Efficient loading of many MHC class II alleles with peptides requires the assistance of H2-M (HLA-DM in humans), a heterodimeric MHC class II-like molecule that facilitates CLIP removal from MHC class II molecules and aids to shape the peptide repertoire presented by MHC class II to CD4(+) T cells. In contrast to the HLA-DM region in humans, the beta-chain locus is duplicated in mice, with the H2-Mb1 beta-chain distal to H2-Mb2 and the H2-Ma alpha-chain gene. H2-M alleles appear to be associated with the development of autoimmune diseases. Recent data showed that Mbeta1 and Mbeta2 isoforms are differentially expressed in isolated macrophages and B cells, respectively. The tissue expression and functional role of these heterodimers in promoting CLIP removal and peptide selection have not been addressed. We utilized the human T2 cell line, which lacks part of chromosome 6 encompassing the MHC class II and DM genes, to construct transgenic cell lines expressing the MHC class II heterodimer I-A(q) alone or in the presence of H2-Malphabeta1 or H2-Malphabeta2 heterodimers. Both H2-M isoforms facilitate the exchange of CLIP for cognate peptides on I-A(q) molecules from arthritis-susceptible DBA/1 mice and induce a conformational change in I-A(q) molecules. Moreover, I-A(q) cell-surface expression is not absolutely dependent on H2-M molecules. These data suggest that I-A(q) exhibits a high affinity for CLIP since virtually all I-A(q) molecules on T2 cells were found to be associated with CLIP in the absence of both H2-M isoforms.
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PMID:H2-Mbeta 1 and H2-Mbeta 2 heterodimers equally promote clip removal in I-A(q) molecules from autoimmune-prone DBA/1 mice. 1114 2

Prodigiosin (PDG) was previously reported to be a T cell-specific immunosuppressant. Here we describe the mechanism of action of PDG in T cells and the effect of PDG on autoimmune diseases. PDG selectively suppresses concanavalin A (Con A)-induced T cell proliferation, but has little effect on lipopolysaccharide-induced proliferation of B cells and nitric oxide production of macrophages. Although PDG does not block interleukin (IL)-2 production, it efficiently inhibits interleukin-2 receptor alpha-chain (IL-2Ralpha) expression, and this results in a disruption of the IL-2/IL-2R signaling pathway, on which a great part of the regulation of T cell activation depends. PDG blocks T cell differentiation into effector helper T cells secreting interferon-gamma and IL-4 as well as into effector cytotoxic T lymphocytes expressing perforin, which is at least in part resulting from inhibition of the IL-2/IL-2R signaling. PDG indirectly blocks signal transducer and activator of transcription activation by inhibiting cytokine signalings in Con A-activated T cells, although it does not inhibit the activation of nuclear factor-kappaB, nuclear factor of activated T cells, and activator protein-1. As direct evidence of immunosuppression in vivo, we show that PDG markedly reduced blood glucose levels and cellular infiltration into the pancreatic islets in nonobese diabetic mice, and that it also delays the onset of collagen-induced arthritis in DBA/1 mice. In conclusion, our results demonstrate that PDG has a unique mode of action, namely, that it blocks T cell activation by inhibiting primarily IL-2Ralpha expression in the IL-2/IL-2R signaling, and show that this compound represents a promising immunosuppressant candidate for the treatment of autoimmune diseases.
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PMID:Prodigiosin blocks T cell activation by inhibiting interleukin-2Ralpha expression and delays progression of autoimmune diabetes and collagen-induced arthritis. 1160 50


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