Date of Award

1-1-2012

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xvi, 167 pages) : illustrations (some color)

Dissertation/Thesis Chair

Gary M Winslow

Committee Members

William Lee, Nicholas Mantis, Joseph Wade, Timothy Sellati

Keywords

Antibody, B cells, Bacterial Infection, Ehrlichiosis, Immunoglobulin M, Immunoglobulins

Subject Categories

Immunology of Infectious Disease

Abstract

Historically, the role for antibodies in mediating protective immunity against intracellular pathogens was thought to be minimal. However, our previous studies demonstrated that antibodies were both necessary and sufficient to establish protective immunity against Ehrlichia muris, a tick-transmitted intracellular bacterium. The identification of a unique population of CD11c-expressing IgM-secreting plasmablasts in the spleen during early infection of mice led to the appreciation that IgM was a critical component of the humoral immune response, and that IgM was required for control of acute ehrlichial infection. Here, we addressed the generation of the IgM-secreting cells, as well as the properties of the antibodies produced. We identified the splenic CD11c-expressing cells as the sole producers of IgM during infection; however, protective antibody was still generated in mice lacking a spleen or secondary lymphoid organs. We identified the omentum as the source of the compensatory IgM response, and the cells secreting antibody also expressed CD11c. To address the generation of CD11c-expressing IgM-secreting plasmablasts, we neutralized BAFF, a factor typically required for B cell survival. Although the generation of these cells was BAFF-independent, IgM production by these cells was diminished. Gene expression characteristic of antibody-secreting cells was unaffected by BAFF neutralization, and these cells contained intracellular IgM. Addition of BAFF to plasmablasts rescued IgM secretion, indicating that BAFF regulates IgM secretion in B cells. In addition, the IgM produced by these cells was highly polyreactive, and bound both self and foreign antigens. Polyreactivity was antigen-driven, and was highly correlated with specificity for an immunodominant ehrlichial antigen. Polyreactive IgM was also detected in human ehrlichiosis patients. We also addressed the functional consequences of the generation of self and foreign-reactive antibodies. Polyreactive IgM was associated with a reduction of disease in a murine model of autoimmunity, and provided protection upon challenge infection with influenza virus, suggesting a protective role for broadly reactive antibodies. These studies identify compensatory features that allow the generation of protective antibody-mediated immune responses, the novel requirements for efficient IgM production, and the functional attributes of the antibody produced, and underscore the importance of the humoral immune response during intracellular bacterial infection.

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