Date on Master's Thesis/Doctoral Dissertation

12-2018

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Yan, Jun

Committee Co-Chair (if applicable)

Kosiewicz, Michel

Committee Member

Kosiewicz, Michel

Committee Member

Alard, Pascale

Committee Member

Jala, Venkatakrishna

Committee Member

Powell, David

Author's Keywords

B cell; systemic lupus erythematosus; CD11b; B cell receptor

Abstract

Loss of function mutation in CD11b has been associated with incidence of systemic lupus erythematosus (SLE), a disease driven by B cell production of pathogenic autoimmune antibody. Our previous work has revealed the ability of CD11b to regulate B cell receptor (BCR) signaling and control autoimmune disease in mice. However, how CD11b regulates the immune response under normal conditions remains unknown. Through the use of a CD11b knockout model, we demonstrated that CD11b-deficient mice have an elevated antigen-specific humoral response in a Th2 type immunization. Deletion of CD11b resulted in elevated serum IgM and IgG antibody, increases in antigen-specific germinal center (GC) B cells and plasma cells (PCs), and increased expression of survival and regulatory factors Bcl-XL and Blimp1 within these subsets. Subsequent experiments using a tissue-specific CD11b deletion model revealed this effect to be B cell intrinsic, and not altered by myeloid cell CD11b expression. Examination of BCR signaling in GC B cells of CD11b knockouts revealed defects in association of negative regulators SHP-1 and pLyn with the BCR following stimulation, as well as alterations in nuclear iv localization of GC regulators cMyc and FOXO1. Through the use of a CD11b-reporter mouse model, we identified multiple novel CD11b-expressing B cell subsets that are dynamically altered during immunization and autoimmune conditions. Lastly, we investigated the incidence of CD11b mutation rs1143679 in SLE patients and examined its effect on the clinical outcome of disease and impact on B cell function. These studies describe a novel role for CD11b in regulation of the healthy humoral response at the GC stage and reveal previously unknown populations of CD11b expressing B cell subsets, suggesting a complex function for CD11b in B cells during development and maturation.

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