Analysis of signaling by human FcgammaRIIA and of its potential role in autoimmune diseases.
Item
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Title
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Analysis of signaling by human FcgammaRIIA and of its potential role in autoimmune diseases.
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Identifier
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AAI9218255
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identifier
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9218255
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Creator
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Odin, Joseph Alan.
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Contributor
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Adviser: Jay Unkeless
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Date
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1992
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Immunology | Chemistry, Biochemistry
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Abstract
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The activation mechanism of macrophages following the binding of IgG complexes to Fc receptors (Fc{dollar}\sb{lcub}\gamma{rcub}{dollar}R) is a complex and poorly understood process. Cross-linking of Fc{dollar}\sb{lcub}\gamma{rcub}{dollar}Rs results in multiple cellular responses that are important for cell-mediated immunity, including phagocytosis and the release of oxidative metabolites. The analysis of a series of truncations of human Fc{dollar}\sb{lcub}\gamma{rcub}{dollar}RIIA, which were expressed in a mouse macrophage-like cell line, presented here indicates that separate cytoplasmic regions are required for internalization of antibody-FcR complexes versus internalization of opsonized erythrocytes and an increase in (Ca{dollar}\sp{lcub}2+{rcub}\rbrack\sb{lcub}\rm i{rcub}.{dollar} The cytoplasmic region required for antibody-FcR internalization extended from Arg{dollar}\sp{lcub}234{rcub}{dollar} to Asp{dollar}\sp{lcub}264{rcub}{dollar}, whereas internalization of opsonized erythrocytes and the increase in (Ca{dollar}\sp{lcub}2+{rcub}\rbrack\sb{lcub}\rm i{rcub}{dollar} were dependent on the final 17 COOH-terminal amino acids, Lys{dollar}\sp{lcub}265{rcub}{dollar} to Asn{dollar}\sp{lcub}281{rcub}{dollar}. The internalization of opsonized erythrocytes was dependent on the increase in calcium levels. The internalization of antibody-FcR complexes was dependent on protein kinase C and tyrosine kinase activity, and all functional responses required factors found in macrophages but not in fibroblasts. These results suggest a signal transduction model in which huFc{dollar}\sb{lcub}\gamma{rcub}{dollar}RIIA cross-linked by immune complexes couple directly to multiple effector systems, each of which initiates a distinct biological response.;Recently, high levels of anti-Fc{dollar}\sb\gamma{dollar}R antibodies were identified in the sera of patients with autoimmune diseases and in several mouse autoimmune strains by using a recombinant, soluble murine Fc{dollar}\sb\gamma{dollar}RII to screen the sera (1). To enhance the screening of sera from human patients, large quantities ({dollar}>{dollar}1 mg/L) of a recombinant, soluble huFc{dollar}\sb\gamma{dollar}RIIA were expressed and purified from transfected CHO cells. An initial screening of autoimmune sera showed some positive reactivity with this soluble huFc{dollar}\sb\gamma{dollar}RIIA.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
