Dissertation/Thesis Abstract

Dendritic cell and macrophage-mediated tolerance in lupus-prone mice
by Gilbert, Mileka Richelle, Ph.D., The University of North Carolina at Chapel Hill, 2007, 149; 3272567
Abstract (Summary)

During infection, immune cells respond to polyclonal activators, like bacterial and viral antigens, through innate immune responses. Therefore, mechanisms to regulate the activation of autoreactive B cells during polyclonal activation are necessary to prevent autoimmunity. Previous studies into the mechanisms of B cell tolerance have focused on B cell Receptor (BCR)-mediated regulation of autoreactive or chronically antigen-experienced B cells. However, the regulation of chronically antigen-experienced B cells during polyclonal activation is less understood. We recently identified a novel mechanism of tolerance wherein DCs and MΦs repress Ig secretion by autoreactive B cells. Polyclonal activators through Toll-like Receptors (TLRs) induce DCs and MΦs to secrete soluble factors (IL-6, sCD40L, and TNFα) that differentially regulate naïve and chronically antigen-experienced B cells. IL-6, sCD40L, and TNFα selectively repress chronically stimulated autoreactive B cells while having no effect on naïve B cells. Thus, we have identified a mechanism that prevents autoimmunity while allowing naïve B cells to respond during innate immune responses. Significantly, TLR-activated DCs and MΦs from lupus-prone mice are defective in repressing autoreactive B cells, coincident with defects in IL-6, sCD40L, and TNFα secretion. This could allow autoreactive B cells to secrete autoantibodies during innate immune responses, promoting autoimmune disease in lupus-prone mice. Determining the TLR defect in DCs and MΦs from lupus-prone mice could identify a genetic signature for individuals susceptible to lupus disease.

Indexing (document details)
Advisor: Vilen, Barbara
Commitee: Clarke, Stephen, Frelinger, Jeffrey, Matsushima, Glenn, Ting, Jenny
School: The University of North Carolina at Chapel Hill
Department: Microbiology & Immunology
School Location: United States -- North Carolina
Source: DAI-B 68/06, Dissertation Abstracts International
Subjects: Immunology
Keywords: Dendritic cell, Macrophages, Systemic lupus erythematosus
Publication Number: 3272567
ISBN: 9780549122388
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