T cell diversity in the induction of systemic autoimmunity / Brian W. Busser.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Busser, Brian W.

Contributor:

Laufer, Terri M., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Allergy and Immunology.

Academic Dissertations as Topic.

Medical Subjects:

Allergy and Immunology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Physical Description:

ix, 115 pages : illustrations (some color) ; 29 cm

Production:

2003.

Summary:

CD4+ helper T cells are required for the production of the anti-nuclear autoantibodies (ANAs) that characterize systemic lupus erythematosus. We asked if the T cell help which promotes ANA production is derived from a diverse repertoire of autoreactive T cells or from a select number of T cells of limited specificity. We utilized the chronic graft-versus-host-disease model to define the diversity of the CD4+ T cell repertoire required to induce ANAs. By transferring clonally-limited versus clonally-diverse populations of MHC class II-reactive CD4+ T cells, we show that polyclonal B cell activation is insufficient for the production of isotype-switched IgG ANAs. In fact, non-cognate interactions driven by activated bystander T cell help is sufficient to promote polyclonal B cell activation and the production of IgM ANAs. Interestingly, we found that CD4+ T cell diversity was necessary to promote CD4+ T cell trafficking into the follicle and for the generation of isotype-switched IgG ANAs. Finally, we show that the presence of a lupus-prone B cell compartment lessens the demanding T cell requirements for the production of IgG ANAs. However, even in this autoimmune setting, T cell receptor diversity is still necessary for the production of pathologic anti-dsDNA antibodies. Therefore, B cell epitope spreading is promoted by T cell antigen-receptor diversity. In summary, these results led us to propose a new model of autoantibody production in which polyclonal B cell activation is followed by antigen-driven selection. We argue that the production of IgM ANAs induced by bystander T cell help reflects the necessity to balance tolerance and immunity in the adaptive immune system. In addition, we contend that the help provided by follicular T cells aids the antigen-driven selection of high affinity, isotype-switched ANAs. Finally, we suggest that B cell tolerance is normally tightly regulated and propose an important role for the selection and activation of a diverse repertoire of autoreactive T cells to sustain a pathologic B cell-mediated systemic autoimmune response.

Notes:

Supervisor: Terri M. Laufer.

Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 2003.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3095863.

OCLC:

244973649