BTC402_2c

Overview of
B cell development
Antigen independent phase
1. Progenitor B Cells Proliferate in Bone Marrow
• B-cell development begins as lymphoid stem cells differentiate into the earliest distinctive B-lineage cell—the progenitor B cell (pro-B
cell)—which expresses a transmembrane tyrosine phosphatase called CD45R (sometimes called B220 in mice).
• Pro-B cells proliferate within the bone marrow, filling the extravascular spaces between large sinusoids in the shaft of a bone.
• Proliferation and differentiation of pro-B cells into precursor B cells (pre-B cells) requires the microenvironment provided by the bone-
marrow stromal cells.
• If pro-B cells are removed from the bone marrow and cultured in vitro, they will not progress to more mature B-cell stages unless
stromal cells are present.
• The stromal cells play two important roles: they interact directly with pro-B and pre-B cells, and they secrete various cytokines,
notably IL-7, that support the developmental process.
2. Ig-Gene Rearrangment Produces Immature B Cells
IgD is not critical to the process
3. The Pre–B-Cell Receptor Is Essential for B-Cell Development
The membrane-bound complex of µ heavy chain and surrogate light chain appears on the pre-B cell associated with the Ig-
α/Ig-β heterodimer to form the pre–B-cell receptor.
Only pre-B cells that are able to express this are able to proceed along the maturation pathway.
The pre–B-cell receptor recognizes a not-yet-identified ligand on the stromal-cell membrane,

thereby transmitting a signal to the pre-B cell that prevents VH to DHJH rearrangement of the other heavy-chain allele, thus
leading to allelic exclusion.
Allelic exclusion
4. Cell-Surface Markers Identify Development Stages
5. Self-Reactive B Cells Are Selected Against in Bone Marrow
• It is estimated that in the mouse the bone marrow produces about 5 x 107 B cells/day but only 5x 106 (or
about 10%) are actually recruited into the recirculating B-cell pool. This means that 90% of the B cells
produced each day die without ever leaving the bone marrow.
• Some of this loss is attributable to negative selection and subsequent elimination (clonaldeletion) of
immature B cells that express auto-antibodies against self-antigens in the bone marrow.
6. Self-Reactive B Cells May Be Rescued by Editing of Light-Chain
Genes
• Negative selection of immature B cells does not always result in their immediate deletion.
Instead, maturation of the self-reactive cell is arrested while the B cell “edits” the light-chain gene
of its receptor.
B-Cell Activation and
Proliferation- Antigen
dependent phase
After export of B cells from the bone marrow,

activation, proliferation, and differentiation occur in
the periphery and require
antigen.
Antigen-driven activation and clonal selection
of naive B cells leads to generation of plasma cells
and memory B cells.
In the absence of antigen-induced activation,

naive B cells in the periphery have a short life span,
dying within a few weeks by apoptosis
Secondary lymphoid organ
A spleen and a lymph node
Spleen
• Largest mass of lymphoid tissue
• It (a) collects antigens from the blood and
also (b) collects and disposes of senescent
RBCs.
• Bulk of the spleen is composed of red pulp
which is the site of RBCs disposal
• The lymphocytes surround the arterioles
entering the organ, forming areas of white
pulp
• Surrounding the central arteriole is the area,
periarteriolar lymphatic sheath (PALS), that is
rich in T lymhocytes
• The secondary follicle (germinal center) consist
mainly of B lymphocytes
Thymus dependent and independent methods of activation
Depending on the nature of the antigen, B-cell activation proceeds by two different routes, one dependent upon T H
cells, the other not.
The B-cell response to thymus-dependent (TD) antigens requires direct contact with TH cells, not simply exposure
to TH-derived cytokines.Antigens that can activate B cells in the absence of this kind of direct participation by T H cells
are known as thymus-independent (TI) antigens
Two Types of Signals Drive B Cells into and through the Cell Cycle
Naive, or resting, B cells are nondividing cells in the G0 stage of the cell cycle. Activation drives the resting cell into the
cell cycle, progressing through G1 into the S phase, in which DNA is replicated. The transition from G1 to S is a critical
restriction point in the cell cycle. Once a cell has reached S, it completes the cell cycle, moving through G2 and into
mitosis (M).
Transduction of Activating Signals Involves Ig-α/Ig-β Heterodimers
Some signal transduction
pathways activated by B cells
Steps involved in activation: (Look for the similarity in both T and B cells)
1. Compartmentalization of function within receptor subunits
2. Activation by membrane-associated Src protein tyrosine kinases

The receptor-associated PTKs (Lck in T cells and Lyn, Blk, and Fyn in B cells) catalyze phosphorylations during the early
stages of signal transduction that are essential to the formation of a functional receptor signaling complex.
3. Assembly of a large signaling complex with protein tyrosine- kinase activity: The phosphorylated tyrosines in the ITAMs
of the BCR and TCR provide docking sites for the molecules that endow these receptors with PTK activity; ZAP-70 in T cells
and Syk in B cells.
4. Recruitment of other signal-transduction pathways: Signals from the BCR and TCR result in the production of the second
messengers IP3 and DAG. IP3 causes the release of Ca2+ from intracellular stores, and DAG activates PKC. A third
important set of signaling pathways are those governed by the small G proteins Ras and Rac that are also activated by
signals received through the TCR or BCR.
5. Changes in gene expression: One of the important outcomes of signal-transduction processes set in motion
with engagement of the BCR or the TCR is the generation or translocation to the nucleus of active transcription factors
that stimulate or inhibit the transcription of specific genes.
B cells have a co-receptor
X-Linked Agammaglobulinemia
The role of the T cells and the TD antigens
In Vivo Sites for Induction of Humoral Responses
When an antigen is introduced into the body, it becomes

concentrated in various peripheral lymphoid organs.
Bloodborne antigen is filtered by the spleen, whereas antigen

from tissue spaces drained by the lymphatic system is filtered
by regional lymph nodes or lymph nodules.
Antigen or antigen-antibody complexes enter the lymph nodes

either alone or associated with antigentransporting
cells (e.g., Langerhans cells or dendritic cells) and macrophages.
As antigen enters it will encounter one of three types of antigen-presenting cells:
1. interdigitating dendritic cells in the paracortex,
2. macrophages scattered throughout the node, or
3. specialized follicular dendritic cells in the follicles and germinal centers.
Once antigen-mediated B-cell activation takes place, small foci of proliferating B cells form at the edges of the T-cell–rich
zone. These B cells differentiate into plasma cells secreting IgM and IgG isotypes. Most of the antibody produced during
a primary response comes from plasma cells in these foci.
A few days after the formation of foci within lymph nodes, a few activated B cells, together with a few TH cells, are
thought to migrate from the foci to primary follicles. These follicles then develop into secondary follicles, which provide a
specialized microenvironment favorable for interactions between B cells, activated TH cells, and follicular dendritic
cells.
Activated B cells (together with some activated TH cells) may migrate towards the center of the secondary follicle, forming a
germinal center
Germinal centers arise within 7–10 days after initial exposure to a thymus-dependent antigen. During the first stage of
germinal-center formation, activated B cells undergo intense proliferation. These proliferating B cells, known as
centroblasts, appear in human germinal centers as a well-defined dark zone.
Centroblasts are distinguished by their large size, expanded cytoplasm, diffuse chromatin, and absence or near absence of
surface Ig.
Centroblasts eventually give rise to centrocytes, which are small, nondividing B cells that now express membrane Ig.
The centrocytes move from the dark zone into a region containing follicular dendritic cells called the light zone, where
some centrocytes make contact with antigen displayed as antigen-antibody complexes on the surface of follicular
dendritic cells
Three important B-cell differentiation events take place in germinal centers:

affinity maturation, class switching, and formation of plasma cells and memory B cells. In general, affinity maturation
and memory-cell formation require germinal centers.
Centroblasts
Centrocytes
Somatic hypermutation :
Because somatic mutation occurs randomly, it will generate a few cells with receptors of higher affinity and many cells
with receptors of unchanged or lower affinity for a particular antigen.
Therefore, selection is needed to derive a population of cells that has increased affinity. The germinal center is the
site of selection. B cells that have high-affinity receptors for the antigen are likely to be positively selected and leave the
germinal center; those with low affinity are likely to undergo negative selection and die in the germinal center.
Memory and plasma cell generation

Humoral response
Primary and Secondary Responses Differ Significantly
The kinetics and other characteristics of the

humoral response differ considerably
depending on whether the humoral response
results from activation of naive lymphocytes
(primary response) or memory lymphocytes
(secondary response).
In both cases, activation leads to production of

secreted antibodies of various isotypes, which
differ in their ability to mediate specific
effector functions
Comparison between primary and secondary response
• A major factor in the more rapid onset and greater magnitude of secondary responses is the fact that the population
of memory B cells specific for a given antigen is considerably larger than the population of corresponding naive B cells.
• Furthermore, memory cells are more easily activated than naive B cells. The processes of affinity maturation and class
switching are responsible for the higher affinity and different isotypes exhibited in a secondary response.
• The higher levels of antibody coupled with the overall higher affinity provide an effective host defense against
reinfection.
• The change in isotype provides antibodies whose effector functions are particularly suited to a given pathogen.
• The existence of long-lived memory B cells accounts for a phenomenon called “original antigenic sin,”
Tolerance
Upon encountering an antigen, the immune system can either develop an immune response or enter a state of
unresponsiveness called tolerance.
Death by neglect
Naïve:
A naive B cell is a B cell that has not been exposed to an antigen. Once exposed to an antigen, the naive B cell either becomes
a memory B cell or a plasma cell that secretes antibodies specific to the antigen that was originally bound.
Anergic:
Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, This phenomenon was first
described in B lymphocytes by Gustav Nossal and termed "clonal anergy." The clones of B lymphocytes in this case can still be
found alive in the circulation, but are ineffective at mounting immune responses.
B-cell anergy can be induced by exposure to soluble circulating antigen, and is often marked by a downregulation of
surface IgM expression and partial blockade of intracellular signaling pathways
Anergy may also be used to induce activated lymphocytes to

become unresponsive with autoimmune diseases like diabetes
mellitus, multiple sclerosis and rheumatoid arthritis.

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Overview of

The pre–B-cell receptor recognizes a not-yet-identified ligand on the stromal-cell membrane,

After export of B cells from the bone marrow,

In the absence of antigen-induced activation,

1. Compartmentalization of function within receptor subunits

2. Activation by membrane-associated Src protein tyrosine kinases

When an antigen is introduced into the body, it becomes

Bloodborne antigen is filtered by the spleen, whereas antigen

Antigen or antigen-antibody complexes enter the lymph nodes

Three important B-cell differentiation events take place in germinal centers:

Memory and plasma cell generation

The kinetics and other characteristics of the

In both cases, activation leads to production of

Anergy may also be used to induce activated lymphocytes to

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