The regulation of anti-double-stranded DNA B cells in healthy and aged mice / Ashlyn Eaton Bassiri.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Bassiri, Ashlyn Eaton.

Contributor:

Erikson, Jan, 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:

xi, 172 pages : illustrations ; 29 cm

Production:

2002.

Summary:

The immune system generates a diverse repertoire of B cells that recognize foreign antigens (Ags) to which it is exposed. Inherent in this generation is the production of B cells specific for self-Ags. Early studies defining the mechanism(s) regulating autoreactive B cells come from studies using immunoglobulin (Ig) transgenic (Tg) models to neo-self Ags. Whether these rules applied to B cells with disease-associated specificities, such as double-stranded (ds) DNA, was not clear. The absence of anti-dsDNA Abs from the serum of non-autoimmune individuals suggests that anti-DNA B cells are normally regulated. In this dissertation, the processes by which anti-dsDNA B cells are regulated in healthy environments and what factors contribute to autoantibody production in specific autoimmune settings were examined.

Previously it was shown that B cells expressing heavy (H) and light- (L) chain VH3H9/Vkappa4 anti-dsDNA B cell Tgs edited away DNA-reactivity by expressing multiple L-chains. To further investigate factors governing the regulation of anti-DNA B cells, mice containing the VH3H9 H-chain only Tg were studied. This Tg pairs with endogenous L-chains to create both anti-DNA and non-DNA B cells. Splenic hybridomas were generated from VH3H9 mice to determine the range of anti-dsDNA B cells that persist in VH3H9 mice and whether the recovered anti-DNA B cells were expressing multiple H- and L-chains (Chapter 3). Additional experiments were designed to determine if anti-dsDNA B cells were also present in the LNs and whether the splenic and LN populations were similarly regulated (Chapter 4). Finally, whether aging alters the established mechanisms of anti-DNA B cell regulation was investigated (Chapter 5). In these studies, it was found that both Iglambda1 and Igkappa anti-dsDNA B cells persist in VH3H9 mice without expressing multiple endogenous receptors. Iglambda1 anti-dsDNA B cells are present in the LN with a distinct phenotype and localization from those in the spleen. Aged mice display a loss of regulation of anti-dsDNA B cells, and specific factors that could contribute to the age-associated loss of tolerance were defined. In the final chapter, the consequences of the persistence of anti-dsDNA B cells and potential mechanisms contributing to their survival and/or rescue are discussed.

Notes:

Supervisor: Jan Erikson.

Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 2002.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3043849.

OCLC:

244972016