All ETDs from UAB

Advisory Committee Chair

Randall S Davis

Advisory Committee Members

John Kearney

Allan Zajac

Troy Randall

Mark Walter

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

At homeostasis and during the initial phases of primary responses to pathogens, humoral host defense is chiefly coordinated by specialized B cells known as splenic marginal zone (MZ) and body cavity-derived B-1 B cells. These front line immune mediators are termed “innate like” due to their ability to secrete broadly-reactive natural antibodies and respond rapidly to antigens in a T cell-independent manner. The production of natural antibodies possessing specificities for self-antigens allows clearance of cellular debris, maintenance of homeostasis and protection from infections that can also predispose the host to immunological disease. However, how the functions of these specialized cells are regulated remains unclear. Over a decade ago an extended family of Fc receptor-like (FCRL1-6) molecules was identified opening a new area of study in B cell regulation. FCRL molecules have homology to the classical Fc receptors (FCR) for IgG and IgE, but differ given their more complex extracellular Ig-like domain composition, cytoplasmic tyrosine-based signaling capacity, and preferential B cell expression. The importance of this family of receptors is highlighted by their increasing associations with a variety of immunologically-based diseases. Interestingly, human FCRL3 has emerged as a risk factor in autoimmunity, but the mechanistic basis of its function in B cells remains un-known. To investigate FCRL3’s role in normal B cell functions, we have focused on its mouse ortholog termed mouse FCRL5. FCRL3 and FCRL5 share homologous extracellular domains, binary tyrosine-based signaling, and innate-like B cell expression. Here we characterize the first in vivo model of FCRL function by examining Fcrl5 deficient mice. Our findings demonstrate that at homeostasis Fcrl5 deficient mice have normal total B cell numbers and frequencies, but enhanced natural antibody production. By contrast, Fcrl5 deficiency was found to impair humoral responses to T cell-independent antigens, but T cell-dependent responses remained intact. Changes in antibody levels correlated with impaired differentiation to antibody secreting cells. While impairment of in vivo antibody responses appears to be B cell intrinsic. These data indicate a critical role for mFCRL5 in regulating innate-like B cell function at the interface of host defense and tolerance.

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