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At least 469 records · Page 26Linked to original sources
PubMed2003

Complement activation by direct C4 binding to thyroperoxidase in Hashimoto's thyroiditis.

Biosynthesis of thyroid hormones is an oxidative process that generates reactive oxygen species (ROS) and involves thyroperoxidase (TPO) that is one of the main autoantigens involved in autoimmune thyroid diseases. The ectodomain of TPO consists of a large N-terminal myeloperoxidase-like module followed by a complement control protein (CCP)-like module and an epidermal growth factor-like module. The presence of these two additional gene modules suggests that they may play some crucial, hitherto unsuspected role associated with thyroid function. Because the CCP module is a constituent of the molecules involved in the activation of C4 complement component, we investigated the possibility that C4 may bind to TPO and activate the complement pathway in autoimmune conditions. We showed that TPO via its CCP module directly activated complement without any mediation by Ig. We suggested that this additional complement pathway requires the production of ROS and specially hydroxyl radicals that aggregate TPO and oxidize methionines of C4. Moreover, we found, in patients with Hashimoto's thyroiditis, that thyrocytes overexpress C4 and all the downstream components of the complement pathway. These results indicate that TPO has some as yet unknown function, which may contribute along with other mechanisms to the massive cell destruction observed in Hashimoto's thyroiditis. Investigating this complement pathway, therefore, would provide an excellent means of reaching a better understanding of the etiology of other degenerative diseases.

Acute Disease↗
PubMed1992

Regulation of glycoprotein IIb-IIIa receptor function studied with platelets permeabilized by the pore-forming complement proteins C5b-9.

Recent evidence suggests that the cytoplasmic domains of platelet glycoprotein (GP) IIb-IIIa are involved in the agonist-initiated transformation of this integrin into a receptor for fibrinogen. To identify intracellular reactions that regulate the receptor function of GP IIb-IIIa, membrane-impermeable agonists and antagonists were introduced into the platelet by permeabilizing the plasma membrane with the pore-forming complement proteins C5b-9. Platelet responses were then analyzed by flow cytometry. Non-lytic concentrations of C5b-9 caused permeabilization of the platelet plasma membrane, as determined by uptake of a water-soluble fluorescent tracer dye. The complement pores were large enough to permit the entry of fluorescein isothiocyanate (FITC)-labeled oligopeptides in a size-dependent manner. Under conditions of low external Ca2+, C5b-9 treatment per se did not activate GP IIb-IIIa, as measured by binding of the activation-dependent antibody FITC-PAC1. However, FITC-PAC1 binding to C5b-9-permeabilized platelets was stimulated by a thrombin receptor agonist acting at the cell surface and by guanosine 5'-O-(thiotriphosphate), a membrane-impermeable activator of G proteins. Permeabilization also permitted the entry of cyclic AMP and the peptide, RFARKGALRQKNV, a pseudo-substrate inhibitor of protein kinase C. Each of these inhibited agonist-induced FITC-PAC1 binding to permeabilized platelets but not to intact platelets. Agonist-induced GP IIb-IIIa activation in permeabilized platelets was also inhibited by tyrphostin-23, a protein tyrosine kinase inhibitor. Thus, C5b-9 can be used to permeabilize the plasma membrane to permit the selective entry of small peptides and other bioactive compounds into permeabilized platelets. Results obtained with these platelets indicate that GP IIb-IIIa receptor function is regulated by a network of signaling reactions involving G proteins, serine/threonine kinases, and tyrosine kinases.

Amino Acid Sequence↗
PubMed1991

[Perifascicular necrosis and regeneration in a case of adult polymyositis].

We report a case of adult polymyositis with peculiar muscular pathology of innumerable muscle fiber necrosis and regeneration accentuated in the perifascicular area. A 51-year-old woman developed generalized weakness of the extremities, trunk and bulbar muscles subacutely for two months. Anterior tibial muscle biopsy showed numerous tube-like necrotic/regenerative muscle fibers predominantly in the perifascicular area. The diameters of the muscle fibers were smaller in the periphery of the fascicles. Small arteries at the center of the fascicles occasionally showed marked perivascular cuffing, although complement component C9 was negative in the vessel wall. The gradient of the diameters of necrosis/regeneration fibers was thought to have been caused by ischemia of the muscles, which persisted at the perifascicular area leading to recurrent necrosis and regeneration and gradually invaded towards the center of the fascicles. We designated this muscular pathology as perifascicular necrosis and regeneration, and regarded it was an acute severe form of the perifascicular ischemic lesions of myositis.

Female↗
PubMed1989

Reversible injury of cultured rat oligodendrocytes by complement.

Rat oligodendrocytes are lysed on exposure to normal homologous serum as a result of classical pathway complement activation and attack in the absence of anti-myelin antibodies. The effect of non-lethal complement attack on oligodendrocytes in vitro was studied by exposing dissociated neonatal rat optic nerve cell cultures to low concentrations of complement alone and also in the presence of oligodendrocyte-specific monoclonal antibodies. Regardless of the mode of complement activation, non-lethal complement attack led to reversible cell injury, recovery following a transient rise in intracellular calcium and fall in ATP in the absence of membrane permeabilization to propidium iodide. A single episode of non-lethal injury had no effect on the ability of oligodendrocytes subsequently to express cell-specific antigens, but repeated episodes had a cumulative effect and ultimately resulted in cell death. Reversible and/or lytic complement-mediated oligodendrocyte injury has implications for the pathogenesis of human and experimental demyelinating diseases.

Adenosine Triphosphate↗
PubMed1986

Functional C8 associated with human platelets.

Haemolytic assay for C8 revealed its association in functionally active form with washed human platelets. Platelet-bound C8 haemolytic activity was inhibited by F(ab')2 anti-C8 and was undetectable in the platelet suspension obtained from three C8 deficient patients. Incubation of platelets from C8 deficient individuals in normal plasma did not restore C8 haemolytic activity, indicating that platelets do not absorb C8 from plasma in vitro during platelet preparation. Thrombin, a mediator of the platelet release reaction, did not induce the release of C8 from normal platelets. Conversely, lysis of EAC1-7.9 by platelet bound C8 was not accompanied by release of beta-thromboglobulin or serotonin from the platelets. C8 was detected in a homogenate prepared from platelets as well as in the supernatant collected after high speed centrifugation of the homogenate. The association of C8 with platelets as an individual component rather than as part of the C5b-9 membrane-attack complex was supported by the following evidence: platelet bound C8 eluted from a Sephacryl S-200 column at the same volume as C8 from normal human serum; F(ab')2 anti-C8, but not F(ab')2 anti-C5, inhibited platelet C8 activity; the platelet homogenate, which lysed EAC1-7.9, had no effect on EAC43 which are susceptible to the lytic activity of the C5b-9 complex.

Blood Platelets↗