Publication Date

2016-08-11

Availability

Embargoed

Embargo Period

2017-08-11

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2016-07-19

First Committee Member

Wasif N. Khan

Second Committee Member

Kurt R. Schesser

Third Committee Member

Robert B. Levy

Fourth Committee Member

Maria T. Abreu

Fifth Committee Member

Robert W. Keane

Sixth Committee Member

Laurence M. Morel

Abstract

T-cell independent (TI) antibodies may be critical in closing the gap between early innate and late adaptive immune responses against bacterial pathogens. In the mouse, innate marginal zone (MZ) B cells rapidly produce these antibodies. In humans, the characterization of a MZ B cell equivalent to that of mice is controversial because of phenotypic differences between the two species. Studies suggest that TLR activation upregulate BAFF receptors, TACI and BR3 in mouse splenic B. Upregulation of BAFF receptors is important because the ligands for these receptors, BAFF and APRIL, are critical in the regulation of humoral immune responses and immunoglobulin (Ig) isotype class switching in the context of TI antigens. By comparison of human splenic MZ B cells (MZ) with their well characterized mouse counterparts we investigated a role for innate TLRs and BAFF receptors (BR3 and TACI) in TI antibody responses. I show in this dissertation that among splenic B cells, the bulk of TI antibodies are produced by MZ B cells relative to follicular I and II B cells (FOBI and FOBII) both in human and mouse. Although MZ B cells were most responsive to TLR stimulation in both species, they differed qualitatively in the regulation of BAFF receptors. Human MZ B cells increased TACI, but not BR3. Once the TACI was increased, human MZ B cells produced more IgM and switched to IgA and to a lesser extent to IgG1 in the presence of BAFF or APRIL. Bruton’s tyrosine kinase (Btk) was found to be required to mediate TLR signaling that enhanced expression of antibody regulators, TACI and an atypical IκB, NF-κBid. Together these results suggest that like mouse, human splenic MZ B cells are the major responders to TLR ligand containing TI antigens and require Btk signaling for these TLR driven TI antibody responses.

Keywords

B cell; Marginal zone; T-cell independent; Btk; TLR; Human

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