Mary LaBue

Abstract

Autoimmune diseases are a world-wide health concern and are an intense area of investigation. However, one area of research has been largely ignored. This involves the contribution of the target tissue to the disease process. We hypothesized that cell-cell communication is disrupted by lymphocytic infiltration and advancing fibrosis and this disruption results in altered target cell responses to immune components produced at the site of inflammation, including Tumor Necrosis Factor-alpha (TNF- α).

We have used thyroiditis as our model of autoimmunity and have documented the development of spontaneous thyroiditis in MRL-lpr/lpr mice. We have found aberrant connexin expression in thyroid tissue from these mice. The abnormal gap junction assembly persisted when the cells were removed from the inflammation site and cultured in vitro. Primary thyrocyte cultures from these mice were also functionally uncoupled, as indicated by decreased Lucifer Yellow dye transfer. This indicated that mechanisms other than physical disruption were influencing intercellular communication in diseased thyrocytes.

Protein kinase C (pKC) decreases connexin 43-mediated communication and regulates numerous cellular properties. We found increased pKC activity in diseased thyrocytes. This enhanced pKC activity was found to be responsible for their decreased cell-cell communication. Furthermore, pKC also decreased T4 release from murine thyrocytes and this decrease was partially mediated through the effect of pKC on intercellular communication.

TNF- α did not cause cytotoxic damage to the diseased thyrocytes. We did find, however, that the enhanced pKC activity in the diseased thyrocytes caused an increase in soluble TNF- α receptor production. The production of soluble TNF- α receptors was not the result of proteolytic cleavage of the cell-surface receptor. Instead, the diseased thyrocytes may be secreting soluble receptors. We are the first to report this mode of production for soluble TNF- α receptors.

LLU Discipline

Microbiology and Molecular Genetics

Department

Microbiology, Molecular Biology and Biochemistry

School

Graduate School

First Advisor

Lora M. Green

Second Advisor

James D. Kettering

Third Advisor

Daila S. Gridley

Fourth Advisor

John E. Lewis

Fifth Advisor

Kenneth Dorshkind

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

1996

Date (Title Page)

12-1996

Language

English

Library of Congress/MESH Subject Headings

Autoimmune Diseases -- physiopathology; Thyroiditis, Autoimmune -- etiology; Protein Kinase C; Receptors, Cell Surface; Cell Communication.

Type

Dissertation

Page Count

xvii; 244

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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