Download Lymphocytes

B-lymphocyte maturation and differentiation
Part 1.
Dr Laila Hamed Damanhouri
2nd year medical technology
Objective.
The student should be learning about:1. B-cell generation, maturation and differentiation.
2. Student should know different stage of B-cell maturation in bone marrow,
including Immunoglubulin gene rearrangement and B-cell selection.
3. Student should understand the mechanism of interaction between mature Bcell and its specific antigen in secondary lymphoid organ.
4. Student should be known how the B-cell differentiates into plasma cell and
memory cell and the difference between them.
Introduction.
Lymphocytes are wholly responsible for the specific immune recognition of
pathogens, so they initiate adaptive immune response. They represent about
20% of the total white blood cells (leukocyte) present in the adult circulation.
Lymphocytes are comprised of three separate populations, T cells, B cells, and
NK cells, each of which express different phenotypic and functional properties.
Two major types, T and B cells, produce and express specific receptors for
antigens. Many of mature lymphoid cells are long-lived, and may persist as
memory cells for several years, and even for the life-time of the individual.
All lymphocytes are derived from bone marrow stem cells, but T lymphocytes
then develop in the thymus, while the B-cells continue their development and
maturation in bone marrow.
B-lymphocytes represent about 5-15% of the circulating lymphoid pool,
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B-lymphocytes are the cell that produce antibody. They express
immunoglobulin as antigen-specific receptors along with several other
important molecules. Morphologically they have a large nucleolus surrounded
by a small rim of cytoplasm. In addition to their important function in defense
against extracellular infections, they can act as antigen-presenting cell.
B-lymphocytes receptors.
The B lymphocytes defined by the presence of surface immunoglobulin. The
immunoglobulin molecules are inserted into the surface membrane of the Bcell where they act as specific antigen receptor. They are detected on the
surface of mature cells with immunofluorescent technique.
The majority of human B-cells in peripheral blood express two
immunoglobulin isotypes on their surface IgM & IgD on the same cell. Very
few cells in the circulation express IgG, IgA or IgE, although these are
present in larger numbers in specific locations. A number of other markers
are expressed by human B-cells. The majority of B-cells carry MHC class II
antigens which important for cooperative interaction with T-cells. CD19,
CD20 and CD22 are the main markers currently used to identify human B
cells (fig 1)
Figure (1); B-cell surface marker
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B -cell development and maturation:The B-cell lymphopoiesis in early stages, take place in lymphoid stem cells in
the haemopoietic tissue of the fetal liver. From 8-9 weeks of gestation in
human. Later the site of B-cell production move from the liver to the bone
marrow, where it is continued into adult life.
All B lymphocytes arise in the bone marrow from a pluripotential stem cell; this
cell can differentiate into different types of haematopoietic cells. In the
production of lymphocytes some of pluripotential stem cell become
lymphopoietic stem cells which give rise both T and B lymphocytes. T
lymphocytes then migrate from bone marrow to thymus gland to continue their
development and maturation, while the B-cells continue their development and
maturation in bone marrow (figure 2).
In bone marrow, the B-cell develops their receptors and undergoes gene
rearrangement process.
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In addition self-reactive B-cells may be deleted or anergized in bone marrow.
The deletion of B-cells in bone marrow involves the B-cell clones with a high
affinity for self and autoantigen during the phase of transient from pro-B to
mature B-cells.
B lymphocyte differentiation occurs in two stages:
A. Antigen independent: (in bone marrow)
▬ result in the formation of mature B-cell expressing
Immunoglobulin receptor specific for antigen.
▬ each step defined by several cell-surface molecules.
B- Antigen dependent: (In peripheral lymphoid organ)
▬ depend on the presence of a specific antigen and its
interaction with specific receptors on B cell.
▬ result in the proliferation of B-cell to memory B cell and
Plasma cell secreting antibody.
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Stages of B-cell development and differentiation.
A. Rearrangement of Immunoglobulin genes.
1. pro-B cell. The earliest identifiable cell committed to the B lineage
is the Pro-B Cell. During this stage, the rearrangement of IgM heavy
(H) chains takes place. The first rearrangement entails the joining of
the D segment to the J segment of Ig heavy chain gene (IgH).
These cells also express a surface molecule or receptor called CD19.
2. pre-B cells. At this stage, the rearrangement and the joining of V region to
the DJ portion take place. A productive rearrangement of the IgH gene must
occur before rearrangement of the Ig light chain. Cells that have successfully
completed both the D to J and V to DJ are allowed to continue their
development and are called pre-B cells.
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3. immature B-cell. the next stage of B cell development is the
rearrangement of light chain gene (IgL), which begin by the joining of the V
segment to the J segment forming of (IgL) chain that associates with Ig
heavy chain and the B lymphocyte will express IgM on its cell surface. At
the end of this stage complete IgM receptor is observe on the surface of the
B-cell. This cell now is known as immature B cells..
4. Mature B-cell. Finally B Cells will also express both IgD on their surface.
At this point the B cell has completed the antigen-independent stage of
maturation. This cells is called naïve or virgin B cells because its never
experienced with antigen.
Naïve B Cells are released to the peripheral lymphoid tissue such as tonsil,
spleen lymph node and others where they circulate through blood and
lymphoid tissues and wait to encounter the antigen for which their Ig is
specific.
In secondary lymphoid organ the B-cells are exposed to further
differentiation after their exposure to antigenic stimulation.
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When the mature B-cell encounter antigen in presence of appropriate T cell
help they will undergo antigen-dependent maturation and differentiate into
plasma cells or memory cells. Most B cells that do not encounter antigen
within a week of leaving the bone marrow die.
B. Self-tolerance and clonal deletion of B cells. The environment in the bone
marrow where B cells develop is usually sterile and devoid of foreign
antigens. Therefore the only antigen that developing B cells could encounter
is self-antigen. If immature B-cells, expressing IgM but not IgD on their
surface, recognize antigen through their IgM receptor they die by a
mechanism of apoptosis and this mechanism is called clonal deletion. over
75% of maturing B cells in the bone marrow do not reach the circulation,
but they undergo a process of programmed cell death or apoptosis.
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