Immunology I
B CELLS
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UIMLT
LEARNING OBJECTIVES
B cells
B cell receptors
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Development of B cells
Stages of development
Types of B cells
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LYMPHOCYTES
Lymphocytes can be broadly subdivided into
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three major populations on the basis of
functional and phenotypic differences:
B lymphocytes (B cells),
T lymphocytes (T cells), and
Natural killer (NK) cells.
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In humans, approximately a trillion (10¹²)
lymphocytes circulate continuously through
the blood and lymph and migrate into the
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tissue spaces and lymphoid organs.
Lymphocytes are relatively nondescript cells
that are very difficult to distinguish
morphologically.
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T and B cells, in particular, appear identical
under a microscope.
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We therefore rely heavily on the signature of
surface proteins they express to differentiate
among lymphocyte subpopulations
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Surface proteins expressed by immune cells
are often referred by the cluster of
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differentiation (CD or cluster of designation)
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CLUSTER OF
DIFFERENTIATION (CD)
CD Function B cell Th Tc
CD2 Adhesion molecule,signal transduction _ + +
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CD3 Signal transduction element of T-cell _ + +
receptor
CD4 Adhesion molecule that binds to class II _ + _
MHC molecules,signal transduction
CD8 Adhesion molecule that to class I MHC _ _ +
molecules,signal transduction
CD19 Signal transduction; CD21 co-receptor + _ _
CD28 Receptor for costimulatory B7 _ + +
molecule on antigen-presenting cells
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CD40 Signal transduction + _ _
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Inaddition to their CD surface signatures, each
B or T cell also expresses an antigen-specific
receptor (the B cell receptor (BCR)or the T cell
receptor (TCR), respectively) on its surface.
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Although the populations of B cells and T
cells express a remarkable diversity of
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antigen receptors (more than a billion), all
receptors on an individual cell’s surface have
identical structures and therefore have
identical specificities for antigen.
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If a given lymphocyte divides to form two
daughter cells, both daughters bear antigen
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receptors with antigen specificities identical
to each other and to the parental cell from
which they arose, and so will any
descendants they produce.
The resulting population of lymphocytes, all
arising from the same founding lymphocyte,
is a clone.
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At any given moment, a human or a mouse
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will contain tens of thousands, perhaps a
hundred thousand, distinct mature T- and B-
cell clones, each distinguished by its own
unique and identical cohort of antigen
receptors.
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Mature B cells and T cells are ready to
encounter antigen, but they are considered
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naïve until they do so.
Contact with antigen induces naïve
lymphocytes to proliferate and differentiate
into both effector cells and memory cells.
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Effector cells carry out specific functions to
combat the pathogen, while the memory cells
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persist in the host, and upon re challenge with
the same antigen mediate a response that is
both quicker and greater in magnitude.
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B LYMPHOCYTES
Millions of B lymphocytes are generated in the
bone marrow every day and exported to the
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periphery.
The rapid and unceasing generation of new B
cells occurs in a carefully regulated sequence of
events.
B-cell development from HSC to mature B cell
takes from 1 to 2 weeks
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B LYMPHOCYTES
The B lymphocyte (B cell) derived its letter
designation from its site of maturation, bone
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marrow.
Mature B cells are definitively distinguished
from other lymphocytes and all other cells by
their synthesis and display of the B-cell
receptor (BCR), a membrane-bound
immunoglobulin (antibody) molecule that
binds to antigen.
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Ultimately, activated B cells differentiate into
effector cells known as plasma cells.
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Plasma cells lose expression of surface
immunoglobulin and become highly
specialized for secretion of antibody. A single
cell is capable of secreting from a few
hundred to more than a thousand molecules
of antibody per second.
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Plasma cells do not divide and, although
some long-lived populations of plasma cells
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are found in bone marrow, many die within 1
or 2 weeks.
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DEVELOPMENT
B cells develop from hematopoietic stem
cells (HSCs) that originate from bone
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marrow. HSCs first differentiate
into multipotent progenitor (MPP) cells,
then common lymphoid progenitor (CLP)
cells. From here, their development into B
cells occurs in several stages, each marked by
various gene expression patterns.
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The stages of B-cell differentiation have been defined by
more than one group of scientists and, as a result, two
systems of nomenclature are in common use.
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The first, and most widely used, is the Basel
nomenclature developed by Melchers and colleagues is
given below.
Pre-pro B cell, pro B cell, pre B cell, immature B cell
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PRE-PRO-B-CELL
With the acquisition of the B-cell lineage-
specific marker B220 (CD45R), and the
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expression of increasing levels of the
transcription factor EBF1, the developing cell
enters the pre-pro-B-cell stage.
At the pre-pro-B-cell stage, EBF-1, along with
E2A, binds to the immunoglobulin gene,
promoting accessibility of the D-J H locus and
preparing the cells for the first step of Ig gene
recombination. 23
Pre-proB cells remain in contact with CXCL-
12-secreting stromal cells in the bone marrow.
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However, the onset of D to JH gene
recombination classifies the cell as an early pro-
B cell, and at this stage the developing cell
moves within the bone marrow, seeking contact
with IL-7 secreting stromal cells.
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PRO-B-CELL
In the early pro-B-cell stage, D to JH
recombination is completed and the cell begins
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to prepare for V to DJH joining.
However, this final recombination event awaits
the expression of the quintessential B-cell
transcription factor, PAX5.
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PAX5 promotes VH to D recombination by
contracting the IgH locus, thus bringing the
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distant VH gene segments closer to the D-JH
region.
By the late pro-B-cell stage, most cells have
initiated VH to DJH Ig gene segment
recombination, which is completed by the onset
of the large pre-B-cell stage
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During the pre-B-cell stage, the cell expresses a
pre-B-cell receptor composed of the rearranged
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heavy chain, complexed with the VpreB and
gamma-5 components of the surrogate light
chain.
The appearance of this pre-B-cell receptor
signals the entry of the developing B cell into the
large, or early pre-B-cell phase.
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Once a light-chain gene rearrangement has been success-
fully completed, the IgM receptor is expressed on the
cell surface, signaling entry into the immature B-cell
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stage.
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POSITIVE SELECTION
Positive selection occurs through antigen-
independent signaling involving both the pre-
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BCR and the BCR.
If these receptors do not bind to their ligand,
B cells do not receive the proper signals and
cease to develop.
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NEGATIVE SELECTION
Negative selection occurs through the binding of
self-antigen with the BCR; If the BCR can bind
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strongly to self-antigen, then the B cell undergoes
one of three fates: clonal deletion, receptor editing
or anergy.
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This negative selection process leads to a
state of central tolerance, in which the mature
B cells don't bind with self antigens present
in the bone marrow.
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To complete development, immature B cells
migrate from the bone marrow into the spleen
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as transitional B cells, passing through two
transitional stages: T1 and T2.
Throughout their migration to the spleen and
after spleen entry, they are considered T1 B
cells.
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Within the spleen, T1 B cells transition to T2
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B cells.
T2B cells differentiate into either follicular
(FO) B cells or marginal zone (MZ) B cells
depending on signals received through the
BCR and other receptors.
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Oncedifferentiated, they are now considered
mature B cells, or naive B cells.
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B-CELL RECEPTOR EXPRESSION
The expression of a receptor on the surface of a
B cell is the end result of a complex and tightly
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regulated series of events.
First, the cell must ensure that the various gene
recombination events culminate in productive
rearrangements of both the heavy- and light-
chain loci.
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Second, only one heavy-chain and one light-
chain allele must be expressed in each B cell.
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Finally, the receptor must be tested to ensure it
does not bind self antigens, in order to protect
the host against the generation of an autoimmune
response.
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The mechanism by which B cells ensure that
only one heavy- and one light-chain allele are
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transcribed and translated is referred to as allelic
exclusion.
The rearrangement of Ig genes occurs in an
ordered way, and begins with recombination at
one of the two homologous chromosomes
carrying the heavy-chain loci.
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The production of a complete heavy chain and
its expression on the B-cell surface in concert
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with a surrogate light chain, made up of two
proteins, VpreB and gamma-5, signals the end of
heavy-chain gene rearrangement and, thus, only
one antibody heavy chain is allowed to complete
the rearrangement process.
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