The immune system is the body's major protective mechanism
against infection with pathogenic organisms, called antigens.
Specific immunity is provided by the stimulation of T and
B lymphocytes in response to antigen. B cells make immunoglobulin
(Ig) or antibody, which recognizes and binds to antigen.
An antigen-specific interaction between T and B cells is
critical because it sends signals to the B cells to differentiate
to secrete antibody, as well as to proliferate, mutate,
and generate memory cells.
We study B cell development, in particular the events that
influence the expression of the Ig gene repertoire and that
generate immunological memory. A characteristic feature
of antibody production is its diversity. This usually reflects
the activation of B cells expressing different germline
Ig genes as well as somatic mutation of these genes. However,
we have observed - in both neonatal and adult mice - that
the primary antibody response to a particular multi-determinant
antigen is restricted both in epitope recognition and in
the germline Ig gene combinations used. In contrast, after
a second antigenic stimulus, the memory (recall) response
is heterogeneous with respect to both parameters. Since
both primary and memory antibody responses are important
for protective immunity, a major focus of our lab is to
understand the mechanisms that determine whether an activated
B cell enters the effector (antibody secretion) or memory
pathway.
The model we published for the epitope-specific repertoire
shift proposes that the intracellular signaling pathways
for antibody secretion vs memory cell formation are distinct,
and that the nature of the signals B cells receive during
their priming event determines which pathway is taken. The
B cell receptor affinity for ligand is likely a key factor.
To test this hypothesis, we have produced genetically engineered
mice whose B cell populations are monoclonal: they all express
the same heavy and light chain gene rearangements. To make
these mice, the rearranged VDJ portion of a selected Ig
heavy chain gene was placed into the germline locus of the
mouse by homologous recombination. The immune responses
of these "VDJ knockin" mice were analyzed by a variety of
cellular and molecular techniques. The data obtained were
consistent with the predictions of our model. Higher affinity
B cells produced more primary antibody than lower affinity
B cells, but lower affinity B cells could be activated to
enter the memory cell pool. We have also produced "VJ" knockin"
mice, whose light chains are the partners of and pair with
the "VDJ knockin" heavy chains. We are crossing these mice
to generate B cells whose affinity, specificity, and B cell
receptor composition are known. The molecular and cellular
outcomes of activating these lower and higher affinity B
cells can then be studied.
Selected Publications:
Press JL. (2000). Neonatal immunity and somatic mutation.
Int Rev Immunol. 19:265-87. [abstract]
C. A. Giorgetti and J. L. Press. (1998). Somatic mutation
in the neonatal mouse. J. Immunol. 161:6093-6104.
[abstract]
Mainville, C. A., K. M. Sheehan, L. D. Klaman, C. A. Giorgetti,
J. L. Press, and P. H. Brodeur. (1996). Deletional mapping
of fifteen mouse VH gene families reveals a common organization
for three Igh haplotypes. J. Immunol. 156:1038.
[abstract]
C. A. Giorgetti and J. L. Press. (1994). A peptide sequence
mimics the epitope on the multideterminant antigen (Tyr,Glu)-Ala--Lys
that induces the dominant H10/VK1+
primary antibody response. J. Immunol. 152:136.
[abstract]
Press, J. L. and C. A. Giorgetti. (1993). Molecular and
kinetic analysis of an epitope-specific shift in the B cell
memory response to a multideterminant antigen. J. Immunol.
151:1998-2013. [abstract]
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