Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.1 (chymotrypsin)
 10,938 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patient A.F. is a 28-year-old polytransfused woman with an inherited bleeding disorder, Glanzmann's thrombasthenia. An abnormal platelet function is linked to severe decreases in the platelet content of the integrins GP IIb and GP IIIa. In 1987 the patient gave birth to a child with severe anemia and thrombocytopenia. Serological tests revealed the presence of anti-platelet antibody together with an anti-Rhesus D. Western blotting identified a major antibody that reacted with a protein of 90-95 kDa present in platelets and endothelial cells. This was identified as the beta 3 integrin subunit (GP IIIa). Antibody-binding required intact disulfides, while controlled digestion with proteases showed the determinant(s) to be retained within chymotrypsin- (50, 63 kDa) and Staphylococcus aureus V8 protease-derived (25-38 kDa) fragments of GP IIIa. Direct binding assays performed in the presence of monoclonal antibodies specific for different epitopes on GP IIb-IIIa complexes confirmed that the epitope was exposed on intact platelets and revealed a specific inhibition of A.F. IgG binding by the monoclonal antibody, AP-3. Other tests confirmed that the antibody reacted independently of the PlA or Pen polymorphisms carried by GP IIIa. IgG purified from A.F. plasma by adsorption and elution from paraformaldehyde-fixed normal platelets or electrophoretically separated GP IIIa was an inhibitor of ADP-induced platelet aggregation. Unexpectedly, Western blotting showed trace amounts of abnormally migrating GP IIIa in A.F. platelets, which retained an ability to react with her antibody. This suggests that the patient has formed an autoantibody reactive with an active site of the beta 3 integrin subunit and linked to the development of neonatal thrombocytopenia.
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PMID:Characterization of an antibody to the integrin beta 3 subunit (GP IIIa) from a patient with neonatal thrombocytopenia and an inherited deficiency of GP IIb-IIIa complexes in platelets (Glanzmann's thrombasthenia). 163 70

Glanzmann's thrombasthenia is an inherited bleeding disorder that results from a deficit of glycoprotein (GP) IIb-IIIa complexes in platelets. Patient (EBV) is an adult male with GP IIb-IIIa levels < 5% of normal values and a history of blood transfusions. Western-blot analysis revealed a strong IgG antibody to GP IIIa in his plasma. The determinants were localized to the minimum-sized fragment of GP IIIa (50 kDa) retained on chymotrypsin-treated platelets and were lost on reduction of disulphides. A female patient (AF), previously described by us [Jallu, V., Pico, M., Chevaleyre, J., Vezon, G., Kunicki, T.J. & Nurden, A.T. (1992) Hum. Antibod. Hybridomas 3, 93-106] developed her anti-GP-IIIa antibody during pregnancy. This antibody was poorly reactive with the 50-kDa proteolytic fragment, yet bound to 115-kDa and 60-kDa hydrolytic products of GP IIIa. Antibodies from both patients recognized the GP-IIIa-like protein of endothelial cells, thus confirming that they were directed against the integrin beta 3-subunit. The (EBV) antibody reacted strongly with GP IIb-IIIa in an antigen capture assay performed with each of a panel of four murine monoclonal antibodies (mAbs) recognizing different epitopes on GP IIb-IIIa. In contrast, that from (AF) was specifically inhibited by AP-3, a murine mAb whose epitope is thought to be localized between amino acids 324-422 of GP IIIa. The residual GP IIb and GP IIIa contents of platelets from each patient were assessed in Western blotting using chemiluminescence detection. SZ-22, a murine mAb to the GP IIb heavy chain (140 kDa), located small amounts of a 130-kDa protein in (EBV) platelets. The anti-GP IIIa mAbs XII F9, P 37 and P 97 revealed trace amounts of protein with a relative mobility identical to that of GP IIIa in both (AF) and (EBV) platelets. This residual GP IIIa represented less than 0.5% of the amount in normal platelets. When, for each patient, plasma was tested in Western blotting against their own platelets, autoantibody activity to the residual GP IIIa was detected in both cases. Thus, patients (AF) and (EBV) have developed anti-GP-IIIa antibodies with restricted and distinct epitopes but recognizing self antigens.
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PMID:Two human antibodies reacting with different epitopes on integrin beta 3 of platelets and endothelial cells. 751 65