Distinguished Professor of Microbiology
|Address:||Shelby Building, room 410
Birmingham, AL 35294-2182
|Members of the Laboratory|
Ph.D. (Immunology), University of Melbourne, Australia
Postdoctoral Studies, University of Alabama at Birmingham (with Drs. Cooper and Lawton)
The overall research plans of our laboratory are aimed at discovering fundamental cellular and molecular mechanisms involved in the development of T and B lymphocytes. Particular attention is focused on the factors involved in the establishment of a diverse B cell repertoire and the identification of novel B cell subsets and B cell progenitors. The development and establishment of the B cell repertoire is the net result of both genetic and environmental forces. The primary event at the genetic level is immunoglobulin gene rearrangement resulting in numerous possible combinations of germline encoded genes, which are further modified by somatic events such as N segment addition and nibbling during the rearrangement process. Somatic mutation, later in response to antigen, leads to further diversity. Environmental forces in the form of self and exogenous antigens also shape the repertoire by positively or negatively selecting B cells according to the specificity of their Ig receptors. These are dynamic processes beginning with the earliest expression of immunoglobulins in fetal life and continuing throughout life. These studies analyze the early repertoires in mice with a goal of determining genetic and selective mechanisms responsible for differences in the early immune system compared to that of the adult.
Mechanisms responsible for the self-reactivity, polyreactivity and connectivity, which characterize the fetal and neonatal repertoire, are determined in B cells. Immunoglobulin transgenic and knockout mice models are used to define the antigens involved in the selection process, to determine the phenotypes of B cells at different states of differentiation and selection, and to seek out the fetal and adult anatomical sites where positive and negative selection of B cells occurs. The impact of terminal deoxynucleotidyl transferase activity (Tdt) expression on the diversity of immunoglobulin CDR3 regions and the subsequent effects on fetal perinatal and adult B cells, is being addressed by the use of transgenic mice in which N region additions have been introduced during stages of B cell development when such additions are normally absent or minimal. The molecular and cellular differences between B cell subsets are compared in studies on precursor/progeny relationships using newly developed monoclonal antibodies as cellular markers, and the use of a variety of transgenic and knockout mice.
The overall goal of these studies is to understand the differentiative events during early development that mold the B cell repertoire. What will be determined is whether a restricted perinatal B cell repertoire is important for the development of a healthy immune system with a highly diversified adult B cell repertoire. The experiments outlined in this area of research will aid in our understanding of the role that fetal and neonatal B cells play in establishment and maintenance of the normal immune system and will provide insight into their roles in autoimmune diseases, B cell neoplasia, immunodeficiency diseases and the development of more efficient vaccines.
Road biking and gardening.