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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. |
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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.
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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. |
Based
on these basic studies of B cell development, we have recently embarked
on studies on the novel role of B cells and antibodies in allergic
asthma and type 1 diabetes.
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Publications