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)

The T cell recognition of type-II collagen (CII) in H-2q mice, susceptible to CII-induced arthritis, was analyzed. With the use of T cell hybridomas derived from rat CII-immunized mice, a peptide corresponding to amino acids 245-270 on chick CII was found to harbor a T cell epitope which is present on heterologous CII (chick, rat, human, and bovine CII) but not on autologous CII. It was shown that this epitope was located within amino acids 260-270, although flanking regions in either direction were necessary for proper recognition. A peptide corresponding to human CII (256-270) was used for further studies. A single amino acid difference at position 266 between mouse CII (aspartic acid) and heterologous CII (glutamic acid) strongly influenced recognition of this peptide. No response towards the mouse peptide was seen with any of the T cell hybridomas. Inhibition studies revealed that the mouse peptide did not bind as well to major histocompatibility complex as the corresponding heterologous peptide. Both peptides gave rise to a T cell response after immunization. However, immunization with the heterologous peptide resulted in a response strictly directed to rat CII and the immunogen while immunization with the autologous peptide elicited T cells which reacted in a heteroclitic fashion, with a stronger response to the heterologous peptide than to the autologous peptide, and did respond to rat CII but not to mouse CII. We suggest that aspartic acid in position 266 results in a cryptic determinant in mouse CII which is neither recognized after CII immunization nor capable of tolerance induction. A glutamic acid at position 266, however, gives rise to an immunodominant epitope which is recognized by a large proportion of the T cells activated after immunization with heterologous CII.
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PMID:Identification of an immunodominant type-II collagen peptide recognized by T cells in H-2q mice: self tolerance at the level of determinant selection. 137 19

The effect of warfarin sodium on excretion of calcium, phosphorus, and 4-carboxy-L-glutamic acid (Gla) was studied in 5 patients with ectopic calcification (2 with scleroderma, 1 with dermatomyositis, and 2 with myositis ossificans progressiva). Warfarin reduced urinary excretion of Gla in all patients, but no changes in calcium and phosphorus excretion or in objective parameters of calcinosis were observed during 6-36 months of treatment. Two patients experienced hemorrhagic complications during therapy, emphasizing a hazard of long-term anticoagulation treatment. Since ectopic calcium deposits contain Gla-rich protein, suppression of Gla synthesis by warfarin sodium over a longer period may prevent deposition and allow removal of existing calcinosis deposits.
Arthritis Rheum 1986 Mar
PMID:Effect of warfarin sodium therapy on excretion of 4-carboxy-L-glutamic acid in scleroderma, dermatomyositis, and myositis ossificans progressiva. 300 64

Peptidoglycan (PG)-polysaccharide (PS) polymers derived from group A streptococcal cell walls were solubilized by M-1 mutanolysin (endo-N-acetylmuramidase) and phage-associated lysin (N-acetylmuramyl-l-alanine amidase). Fragments were isolated by ultrafiltration and a series of gel filtrations and were injected intravenously into Sprague-Dawley rats. No fragments with a molecular weight of less than 5 x 10(6) were able to induce arthritis by systemic injection. However, the enzyme-derived fragments displayed a new biological activity. High-molecular-weight PG-PS fragments ( congruent with500,000) derived from mutanolysin digests induced a severe edematous reaction in the front and hind limbs. The response started 5 to 10 min postinjection, reached maximum intensity in approximately 30 min, and disappeared by 10 h. The smallest dose capable of eliciting the response was 0.31 mug/g of body weight. Low-molecular-weight PG-PS ( congruent with30,000) derived from the mutanolysin digests and the PG-PS fragments isolated from phage-associated lysin digests also induced edema; however, a higher dose was required to elicit the same response as that produced by high-molecular-weight PG-PS fragments. The active fragments contained rhamnose, glucosamine, muramic acid, alanine, glutamic acid, and lysine in various molar ratios. PG-PS fragments obtained by sonic degradation of cell walls (molecular weight >/=5.3 x 10(6)), as well as enzyme-treated PG preparations and muramyl dipeptide, failed to elicit the response. These findings indicate that PG-PS fragments of sizes too small to be arthritogenic can affect the vascular endothelium to induce a rapidly developing edema. Fragments with this biological property could have a key role in the pathogenesis of experimental arthritis by influencing the tissue distribution of arthritogenic PG-PS.
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PMID:Soluble peptidoglycan-polysaccharide fragments of the bacterial cell wall induce acute inflammation. 675 2

The folic acid antagonist, 4-aminopteroyl glutamic acid ("aminopterin"), is a potent inhibitor of growth and of connective tissue proliferation. The present study indicates that the suppressive effects of "aminopterin" on epithelial structures are more striking than on connective tissue, as revealed by observation of interference with wound healing and epithelization, atrophy and ulceration of mucosa, alopecia, and prompt suppressive effects in such dermatologic disorders as psoriasis and chronic indurative dermatoses. "Aminopterin" was administered orally in daily doses of 1.5 to 2.0 mg. to thirteen patients with psoriasis (of whom six had associated arthritis) and to five patients with chronic indurative dermatoses. The latter included one patient with chronic atopic eczematoid dermatitis with associated asthma, one with chronic eczematoid seborrheic dermatitis, one with chronic discoid lupus erythematosus involving the face, and two with scleroderma. In all patients there were remissions in cutaneous lesions, which appeared most commonly between the 5th and 10th day of "aminopterin" therapy. Treatment was interrupted in most patients after an initial course of 14 to 28 mg. because of the regular occurrence of shallow ulceration of the buccal mucosa and frequent development of abdominal cramps. Remissions persisted for periods ranging from two weeks to several months, after which lesions returned which responded to further courses of "aminopterin." The therapeutic response was more complete in the seven patients with psoriatic arthritis than in in six subjects with uncomplicated psoriasis. In four patients with psoriatic arthritis in whom the responses to "aminopterin" and cortisone were compared, arthritic manifestations were considerably more relieved by cortisone, but improvement in psoriasis was consistently more complete and more sustained with "aminopterin." No evidence of a summative effect of cortisone and "aminopterin" on psoriasis was observed when the two were employed concomitantly, although amelioration of arthritic symptoms was more complete than when cortisone was given alone. Topical application of "aminopterin" in a 1% ointment was found to be ineffective. "Aminopterin" is a toxic drug, and its administration must be carefully supervised. The citrovorum factor has proved useful in overcoming "aminopterin" toxicity but interferes with its therapeutic effects. It is suggested that "aminopterin" may prove useful in other dermatologic disorders and in cutaneous manifestations of some systemic diseases which, in certain instances, have been temporarily benefited by cortisone.
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PMID:Effect of "aminopterin" on epithelial tissues. 685 92

Amino asid metabolism was studied by thin layer chromatography in 25 Pasteurella multocida strains isolated from various manifestations of the disease chicken septicemia. Six amino acids were used: DL-ornithin, L-cystein, L-asparagin, DL-serin, L-arginin and Acidum glutaminicum. The Pasteurella strains studied include in their metabolism the amino acid asparagin, but serin and cystein are excluded. The strains isolated from birds suffering from acute and atypical septicemia do not metabolize ornithin, while these isolated from birds having wattles oedema or from calves suffering from arthritis metabolize it. The reaction of Pasteurellae to arginin and glutamic acid varies and no regularity in this respect is observed. Strains isolated from calves suffering from bronchopneumonia do not include in their metabolism any one of the named amino acids. As a result of the test applied a correlation between the Pasteurella multocida biotypes assessed by the authors and the amino acid metabolism was established. This is one proof more that the isolated pasteurellae can be groupped in two big biotypes by the tests for virulence in birds and including in their metabolism the amino acid ornithin.
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PMID:[Amino acid metabolism in Pasteurella multocida studied using thin-layer chromatography]. 741 30

An immune response directed against type II collagen (CII) has been reported in several autoimmune diseases including the animal models of collagen-induced arthritis (CIA) and collagen-induced autoimmune ear disease (CIAED). In this communication, we have found that T cells from type II collagen-immunized DBA/1-lac could transfer auricular chondritis to naive mice. The T cells from type II collagen-immunized H-2r and H-2q mice recognize different epitopes from the CB11 peptide of CII. The CII-specific T cells from H-2q background mice recognize peptide residues p121-147 (P1) but do not respond to residues p211-247 (P2). The T cells of H-2r mice immunized with CII respond better to P2 rather than P1. By altering certain amino acids within these epitopes, the response of CII-specific TCR to antigen has been increased or abolished. Our results suggest that the lysine residues at positions 129, 141, and 147 in P1, the arginine residue at position 227, and glutamic acid at position 230 in P2 might play an important role in the trimolecular interaction. Ten clonally distinct T cell hybridomas specific for CII have been established from H-2r B10.RIII mice and the beta chains of their TCR have been analyzed. Three subfamilies, V beta 1, V beta 6, and V beta 8, were utilized with dominant expression of V beta 8 (60%). This is quite similar to the pattern found in type II collagen-induced arthritis in H-2q mice. This preferential use of V beta 8 in CIAED implies that an immunotherapy may make it possible to control this autoimmune disease, even in a MHC-diverse situation.
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PMID:Epitope specificity and T cell receptor usage in type II collagen induced autoimmune ear disease. 751 52

T cells play a critical role in the development of collagen-induced arthritis (CIA). Immunization with heterologous (chick) type II collagen (cII) results in chronic inflammation with progressive damage to the joints. The expression of specific MHC Class II alpha beta dimers, including IAq, is critical to induction of disease. The alpha chains of IAq and IAp are identical in sequence. The IAq and IAp beta chains differ by only four amino acid residues: 85, 86, 88, and 89. However, mice of the H-2p haplotype are not susceptible to CIA. To examine the impact of these structural differences in IA molecules on T cell Ag recognition, we studied presentation of cII peptides and denatured cII by APCs obtained from H-2q and H-2p mice. We also assessed presentation of ovalbumin, myelin basic protein (MBP), and MBP peptides by these APC populations. H-2q APCs presented both peptides and proteins to our T cell hybrids. In contrast, APCs obtained from H-2p mice presented peptides, but were defective in the processing and/or presentation of protein Ags. We then altered pairs of the residues in IAq to those found in IAp using site-directed mutagenesis and transfected these constructs into M 12.C3 B cells. All transfectants were able to present peptides, but those expressing IAp were unable to present protein Ags. The use of transfectants expressing hybrid molecules (residues 85 and 86 from IAp, 88 and 89 from IAq, or vice versa) allowed us to localize the region responsible for this defect to residues 85 and 86 of the beta chain. The presence of IAp residues (glu and thr versus gly and val in IAq) at these sites severely compromised the capacity for protein presentation. Resistance to CIA in H-2p haplotype mice may be a reflection of the limited repertoire of epitopes to which these mice can respond relative to susceptible H-2q mice.
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PMID:Polymorphism in the beta chain of IAq versus IAp influences presentation of protein but not peptide antigens. 755 84

Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H-1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro. Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.
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PMID:Antirheumatic agents: novel methotrexate derivatives bearing a benzoxazine or benzothiazine moiety. 901 34

The Aq major histocompatibility complex (MHC) class II molecule is associated with susceptibility to murine collagen-induced arthritis (CIA), whereas the closely related H-2Ap molecule is not. To understand the molecular basis for this difference, we have analyzed the ability of H-2Aq and H-2Ap molecules (referred to as Aq and Ap) to bind and present collagen type II (CII)-derived glycosylated and non-glycosylated peptides. T cell clones specific for the immunodominant CII 256-270 peptide and restricted to both Aq and Ap molecules were identified. When these clones were incubated with CII protein and either Aq- or Ap-expressing antigen-presenting cells (APC), only Aq-expressing APC were able to induce stimulation. With the use of A(beta) transgenic mice this could be shown to be solely dependent on the MHC class II molecule itself and to be independent of other MHC- or non-MHC genes. Peptide binding studies were performed using affinity-purified MHC class II molecules. The CII 256-270 peptide bound with lower affinity to the Ap molecule than to the Aq molecule. Using a set of alanine-substituted CII 256-270 peptides, MHC class II and T cell receptor (TCR) contacts were identified. Mainly the side chains of isoleucine 260 and phenylalanine 263 were used for binding both the Aq and Ap molecule, i.e. the peptide was orientated similarly in the binding clefts. The major TCR contact amino acids were lysine 264, which can be posttranslationally modified, and glutamic acid 266, which is the only amino acid in the heterologous peptide which differs from the mouse sequence. Glycosylation at positions 264 and 270 of the CII 256-270 peptide did not change the anchor positions used for binding to the Aq or Ap molecules. The autologous form of the peptide (with aspartic acid at position 266) bound with lower affinity to the Aq molecule as compared with the heterologous peptide. The variable affinity displayed by the immunodominant CII 256-270 peptide for different MHC class II molecules, the identification of MHC and TCR contacts and the significance of glycosylation of these have important implications for the understanding of the molecular basis for inherited MHC class II-associated susceptibility to CIA and in turn, for development of novel treatment strategies in this disease.
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PMID:The structural basis of MHC control of collagen-induced arthritis; binding of the immunodominant type II collagen 256-270 glycopeptide to H-2Aq and H-2Ap molecules. 952 Oct 85

We purified, cloned, and expressed aggrecanase, a protease that is thought to be responsible for the degradation of cartilage aggrecan in arthritic diseases. Aggrecanase-1 [a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4)] is a member of the ADAMTS protein family that cleaves aggrecan at the glutamic acid-373-alanine-374 bond. The identification of this protease provides a specific target for the development of therapeutics to prevent cartilage degradation in arthritis.
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PMID:Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. 1038 32


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