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IMMUNOREGULATION IN THE LACRIMAL GLANDS OF MICE.
IDENTIFICATION OF AUTOANTIGENS
by
Rasheeda Michelle Hawk
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHYSIOLOGY AND BIOPHYSICS)
May 2007
Copyright 2007 Rasheeda Michelle Hawk
Object Description
| Title | Immunoregulation in the lacrimal glands of mice: identification of autoantigens |
| Author | Hawk, Rasheeda Michelle |
| Author email | rhawk@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Physiology & Biophysics |
| School | Keck School of Medicine |
| Date defended/completed | 2006-12-07 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-05-18 |
| Advisor (committee chair) | Mircheff, Austin K. |
| Advisor (committee member) |
Trousdale, Melvin D. Samuchyin[?] Duncan, Roger F. Hamm-Alvarez, Sarah F. |
| Abstract | We detected serum autoantibodies in healthy and diseased NOD mice targeted against membrane-bound proteins found in the lacrimal glands of mice, rat, and rabbits. As disease in the NOD mouse model progressed with age, we observed an increase in autoantibody titer as well as a shift in IgG isotypes from non-complement-fixing (IgG1, IgG3) to complement-fixing (IgG2A, IgG2B) isotypes. This shift appeared to be age and gender dependent: female NOD mice had higher titers of the complement-fixing immunoglobulins, IgG2A and IgG2B. It is regularly reported that male NOD mice develop more severe dacryoadenitis than females, whereas female mice develop more severe disease in other organs.; Flow cytometry showed that the ratios of CD4+ T cells to CD8+ T cells were 2:1 in the lacrimal glands of both male and female animals with disease. However, within the CD4+ cell populations, the female mice appeared to have a larger subpopulation of CD4+CD25+ FoxP3 expressing cells. These results suggest that immunoregulatory mechanisms operate in the lacrimal glands of female NOD mice and prevent them from acquiring autoimmune dacryoadenitis with the same severity as the males.; Knowing that autoantibody production is antigen-driven and T cell-dependent, we used MALDI-TOF spectrometry to identify novel autoantigens in rat lacrimal gland. We used the TEPITOPE algorithm to predict peptides that would most likely fit in the major grooves of twenty-five HLA class II haplotypes. The predicted T cell epitopes for three confirmed autoantigens where conserved amongst mice, rat, rabbit, and human. By analyzing Western blots of density gradient fractions of rabbit lacrimal gland probed with either antibodies to identified autoantigens or NOD mouse sera, we were able to associate autoantigen proteolytic products and predicted T cell epitopes with endomembrane compartments where activated cysteine proteases and cathepsins are found to accumulate when cells are chronically stimulated with the muscarinic cholinergic agonist, carbachol (CCh). These data support our hypothesis that novel proteolytic products of autoantigens are generated within lacrimal epithelial cells when membrane traffic is altered by chronic stimulation. We now propose that depending on hormonal environment, these proteolytic products initiate activation of either autoimmune effector cells or regulatory T cells. |
| Keyword | lacrimal autoantigens; density gradients; complement fixing IgG |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m492 |
| Contributing entity | University of Southern California |
| Rights | Hawk, Rasheeda Michelle |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Hawk-20070518 |
| Archival file | uscthesesreloadpub_Volume35/etd-Hawk-20070518.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | IMMUNOREGULATION IN THE LACRIMAL GLANDS OF MICE. IDENTIFICATION OF AUTOANTIGENS by Rasheeda Michelle Hawk A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHYSIOLOGY AND BIOPHYSICS) May 2007 Copyright 2007 Rasheeda Michelle Hawk |
