Project 2: Division of Labor in Different Subsets of B Cells
Once
the newly formed B cell
exits the generative sites in fetal liver or adult bone marrow it goes
through selection events which may involve interactions with self or
external
antigens. These selective events can influence the fate of individual B
cells with respect to their phenotype and functional characteristics.
These
B cell receptor-mediated events also influence the characteristic sites
of localization in lymphoid organs for follicular (B-2 cells) and
marginal
zone B cells in the spleen, as well as another set (B-1 cells) in the
peritoneal
and pleural cavities.
Compartmentalization of Lymphocytes in the Spleen
The
spleen is a very important large
lymphoid organ consisting of the so-called red pulp which contains
macrophages
and other cellular elements and is richly bathed in blood entering from
a network of sinuses. The white pulp is follicular in nature as shown
in
a cross section of a mouse spleen in figure 3 and does not contain as
many
red blood cells hence the name white pulp. These follicles are
compartmentalized
and various sets of cells reside in special areas in these structures.
In the higher power view of one of these (Fig. 4) it can be seen that T
cells are found around the arterioles and form the periarteriolar
lymphocyte
sheath (PALS) (reddish-brown). Adjacent to the T cells are B cell
follicles
in which B-2 cells reside (green).
Specialized
Macrophages in the Marginal
Zone
There
are then two concentric rings
of specialized macrophages Metallophilic macrophages (blue) and
marginal
sinus macrophages (red). These macrophages are in juxta-position to the
open ended marginal sinuses through which blood enters into the
parenchyma
of the spleen. They are strategically situated therefore to contact and
clear foreign particles such as bacteria from the blood the blood. In
figure
5 fluorescent bacteria can be seen trapped by these macrophages 30
minutes
after their intravenous injection.
Why Are B Cells Different?
We are particularly interested in the subset of MZ B cells that reside in this area. We have shown that they have special properties that enable them to respond very rapidly to introduced bacteria by mobilization and differentiation into large clusters of antibody forming plasma cells (Fig. 6).
We propose that
the compartmentalized
distribution of MZ versus FO B cells reflects the different functions
associated
with each subset. These include the types of antigens recognized by
each
subset and their roles as antibody producers and antigen presenters.
Chronic
stimulation by intrinsic or
extrinsic antigens induces an "activated" state of MZ and B1 cells. The
special properties of these activated B cells and their involvement in
the maintenance of the adult B cell repertoire makes them especially
susceptible
to transformation into chronic lymphocytic leukemia (CLL)-like cells
and/or
marginal zone and MALT lymphomas.
References
Martin, F., Oliver, A.M., and Kearney, J.F. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14:617-629, 2001.
Martin, F. and Kearney, J.F. Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 12(1):39-49, 2000.
Martin, F. and Kearney, J.F. B1 cells: Similarities and differences with other B cell subsets. Curr. Opin. Immunol. 13:195-201, 2001.
Oliver, A. M., Martin, F., Gartland, G. L., Carter, R.H., and Kearney, J. F. Marginal zone B cells exhibit unique activation, proliferation, and immunoglobulin secretory responses. Eur. J. Immunol. 27:2366-2374, 1997.
Oliver,
A. M., Martin, F. and Kearney,
J. F. IgMhighCD21high
lymphocytes enriched in
the splenic marginal zone generate effector cells more rapidly than the
bulk of follicular B cells. J Immunol. 162:7198-207, 1999.
In the Future
We
will determine the relative
roles of auto-reactivity, positive and negative selection, in the
establishment
of fetal and adult B cell repertoires and B cell subsets. By deriving
our
transgenic mice onto a germ free background we will determine the role
of extrinsic antigens on the development of B cell subsets. We will use
monoclonal antibodies and molecular techniques to analyze the
functional
differences between the different B cell subsets in their responses to
T-dependent and bacterial T-independent antigens and their roles as
antigen
presenting cells. Similarly, we will use various cloning strategies to
isolate the genes responsible for these functional differences. We will
then be in a position to determine if overexpression or dysregulated
expression
of any of these genes are involved in mechanisms leading to the
development
of B cell neoplasia within the defined B cell subsets.
Significance of Our Studies
These
studies are a continuation
of our long-standing goals over the last 25 years to understand the
cellular
and molecular events during fetal and neonatal B cell differentiation
that
give rise to the adult B cell repertoire. This repertoire includes
long-lived
clones of B cells protective against environmental pathogens. These
studies
will also help us determine whether some of the restricted perinatal B
cell repertoire are retained in the more highly diversified adult
repertoire.
We hope to define the mechanisms that distinguish development of fetal
and neonatal B cells from that of their adult counterparts. Of central
importance is the role that these self-reactive B cells play in the
establishment
and maintenance of the normal immune system as well as in B cell
neoplasia,
autoimmune diseases, and immunodeficiencies. A particular interest is
to
understand the developmental origins and functions of the B cells and
auxiliary
cells that participate in the antibody response to bacterial
determinants.