2. INTRODUCTION
Antigen stimulation of B cells results in a proliferative response
that is as rapid as any observed in vertebrate organisms;
An activated lymphocyte may divide once every 6 hours.
In further primary and memory response will arise.
In this we will see about the regulations B cell responses.
3. THE B CELL RECEPTOR (BCR) COMPLEX
Mature B cell contains IgM and IgD on surface.
They associate with 2 poly peptides Ig alpha & Ig beta –
transduce signals.
Required for T cell maturation and assembly and expression of
Ig’s- BCR
4. B CELL CO-RECEPTORS
Co-receptors, including CD21, CD32 and CD19 associate with the
BCR complex especially when both the BCR and one or more of
the co-receptors are linked through an antigen-
complement/antibody complex.
Depending on which molecules are ligated, signaling by the Ig-
Igα/Igβ complex is enhanced
or inhibited.
5. RECEPTOR–LIGAND INTERACTIONS
Lymphocytes need to be activated in order to carry out their
function.
Binding of the lymphocyte to an antigen via its antigen receptor,
signal 1, is necessary, but not sufficient to stimulate it and may
lead to anergy.
Accessory and co stimulatory molecules on the surface of B cells
are required for cell–cell interaction and the signal transduction
events leading to activation (signal 2).
6. SIGNALING BY CO-RECEPTORS
B cell signaling is initiated through the Igα/Igβ complex
associated with the BCR and results in phosphorylation of tyrosine
motifs (ITAMs).
This is followed by an ordered series of biochemical events
involving kinases and phosphatases.
These events are modulated by signals from co-receptors.
Second messengers lead to activation of transcription factors and
thus to activation of lymphocyte function
7. POSITIVE EFFECTS OF ANTIBODIES
Antibodies of the IgM class appear to be important in enhancing
humoral immunity.
In particular, antigen–IgM–complement complexes that bind to the
B cell antigen receptor stimulate the cell more efficiently than
antigen alone.
This is probably the result of simultaneous interaction of the C3b
component of complement with the CD21 molecule of the antigen
receptor complex, which then transduces a positive signal to the B
cell.
8. SELECTION AND ACTIVATION OF B CELLS
When antigen is introduced into an individual, B cells with receptors for
that antigen bind and internalize it into an endosomal compartment, and
process and present it on MHC class II molecules to helper T cells
(Topic E2).
These B cells are triggered to proliferate, giving rise to clones of large
numbers of daughter cells.
Some of the cells of these expanding clones serve as memory cells,
others differentiate and become plasma cells (Topic E2) that make and
secrete large quantities of specific antibody.
For example, on introduction of antigen 5 (Ag5) into a person (Fig. 1),
more than 10 B cells have the opportunity to interact with it. Only a very
few B cells (e.g. B5) have receptors specific
for this antigen.
9. Only a very few B cells (e.g. B5) have receptors specific for
this antigen.
B5 binds Ag5, internalizes, and processes and presents it on
MHC class II molecules on the surface of this B cell.
T helper cells with specific receptors for a peptide from Ag5
in MHC class II bind to this complex and stimulate this B cell
to clonally expand and differentiate into memory B cells and
plasma cells that produce soluble antibody to Ag5.
In addition, direct T cell interaction with the B cell induces
class switching, which depending on the type of helper cell
(Th1 vs Th2) and the cytokines it secretes, will result in
production of antibody of the IgG, IgA or IgE classes.
10. MULTICLONAL RESPONSES
Although antibodies produced by a single cell and its daughter cells are
identical (homogeneous or monoclonal), the response to a given antigen
involves many different clones of cells and thus, overall, is very
heterogeneous (multiclonal).
Considering the size of an antigenic determinant, the number of
determinants on a molecule, and the number of different molecules on a
microorganism, the total response to a microorganism results in a large
number of different antibodies .
Even antibodies against a single antigenic determinant are
heterogeneous, indicating that the immune system is capable of
producing many different antibodies, even to a single well-defined
antigenic determinant.
This heterogeneity is essential for many of the protective functions of
antibodies
11. CROSS-REACTIVE RESPONSES
Occasionally, a similar or identical antigenic determinant is found
in association with widely different molecules or cells. This is
termed cross-reactivity.
Thus, the presence in most individuals of antibodies directed
toward blood group carbohydrates other than their own is a result
of the presence on certain microorganisms of carbohydrate
antigens which are very similar, if not identical, to the blood group
antigens.
Infection with such an organism causes the production of
antibodies directed toward the antigenic determinants of the
microorganism including these carbohydrate antigens.
12. NEGATIVE FEEDBACK BY IGG
The interaction of IgG–antigen complexes with antigen-specific B
cells through the simultaneous binding of both the B cell antigen
receptor and the FcγRII molecule of the B cell receptor complex
can deliver a negative signal to the B cell.
Thus, IgG, which is produced later in the antibody response, could
interact with antigen (if present) forming a complex that, on
binding to antigenspecific B cells, may provide feedback
inhibition mediated via FcγRII, decreasing the amount of antigen-
specific antibody being produced.
13. Control mechanisms have therefore evolved to ensure that B-
cell proliferation is slowed down once sufficient specific B
cells have been generated and that most of the B cells enter
into an apoptotic program once the pathogen has been
eliminated.
In this section, we will address negative regulation of B-cell
activation that is mediated through two different molecules on
the B-cell surface.
14. CD22 SHUTSDOWN UNNECCESARY BCR
SIGNALLING
In addition to CD19/CD21 and CD81, the BCR of resting B cells
is also associated with an additional transmembrane molecule,
CD22.
CD22 bears an Immunoreceptor Tyrosinebased Inhibitory Motif
(ITIM), similar in structure to the ITAM motifs introduced in
Chapter 3, but mediating inhibitory, rather than activating
functions.
Activation of B cells results in phosphorylation of the ITIM, thus
allowing association of the SHP-1 tyrosine phosphatase with the
cytoplasmic tail of CD22.
SHP-1 can then strip activating phosphates from the tyrosine of
neighboring signaling complexes.
15. For as long as the BCR signaling pathway is being activated
by antigen engagement, phosphate groups are reattached to the
tyrosine residues of adapter molecules and other signaling
intermediates as fast as the phosphatases canstrip them off .
However, once antigen levels begin to decrease, receptor-
associated tyrosine kinase activity slows down, and signaling
through CD22 can then induce the removal of any residual
activating phosphates.
CD22 thus functions as a negative regulator of B-cell
activation, and its presence and activity ensure that signaling
from the BCR is shut down when antigen is no longer bound
to the BCR.
Consistent with this negative feedback role, levels of B-cell
activation are elevated in CD22 knockout mice, and aging
CD22 knockout animals have increased levels of
autoimmunity.
16. CD22 is a cell-surface receptor molecule that recognizes N-
glycolyl neuraminic acid residues on serum glycoproteins and
other cell surfaces and can thus double as an adhesion
molecule.
It is expressed in mature B cells that bear both mIgM and
mIgD Ig receptors.
17. FCΓRIIB RECEPTOR INHIBITS B CELL ACTIVATION
It has long been known that the presence of circulating, specifi c,
antigen-IgG complexes is inhibitory for further B-cell activation,
and this phenomenon has now been explained at the molecular level
by the characterization of the FcγRIIb receptor (also known as
CD32).
FcγRIIb recognizes immune complexes containing IgG and, like
CD22, bears a cytoplasmic ITIM domain. Co-ligation of the B cell’s
FcγRIIb receptor molecules with the BCR by a specific antigen-
antibody immune complex results in activation of the FcγRIIb
signaling cascade, and phosphorylation of FcγRIIb’s ITIM.
The phosphorylated ITIM serves as a docking site for the inositol
phosphatase SHIP, which binds to the ITIM via its SH2 domain.
SHIP then hydrolyzes PIP3 to PIP2, thus interfering with the
membrane localization of the important signaling molecules Btk and
PLC2 and causing the effective abrogation of B-cell signaling.
18. Signaling through FcγRIIb also results in decreased
phosphorylation of CD19 and reduced recruitment of PI3
kinase to the membrane.
SHIP then hydrolyzes PIP3 to PIP2, thus interfering with the
membrane localization of the important signaling molecules
Btk and PLC2 and causing the effective abrogation of B-cell
signaling.
Signaling through FcγRIIb also results in decreased
phosphorylation of CD19 and reduced recruitment of PI3
kinase to the membrane
Negative signaling through the FcRIIb receptor makes
intuitive sense, as the presence of immune complexes
containing the antigen for which a B cell is specific signals the
presence of high levels of antigen-specific antibody, and hence
a reduced need for further B-cell differentiation.
19. B-10 B CELLS- NEGATIVE REGULATORS
Recently, an unusual population of B cells has been discovered
that appears to be capable of negatively regulating potentially
infl ammatory immune responses by secreting the cytokine IL-
10 upon stimulation.
Working with two mouse autoimmune models, investigators
demonstrated that B cells capable of secreting the
immunoregulatory cytokine IL-10 could alleviate the symptoms
of a mouse suff ering from a form of the antibodymediated
autoimmune disease multiple sclerosis.
Recall from Chapter 11 that IL-10 is a cytokine normally
associated with regulatory T cells.
It has pleiotropic eff ects on other immune system cells, which
include the suppression of T-cell production of the cytokines
IL-2, IL-5, and TNF-α.
20. Furthermore, IL-10 interacts with antigen-presenting cells in
such a manner as to reduce the cell surface expression of MHC
antigens.
The finding that B cells could be capable of secreting this
immunoregulatory cytokine represents the first indication that
they, as distinct from T cells, might have the capacity to down-
regulate the function of other immune system cells.
A small population of splenic B cells appears to account for
almost all of the B-cell-derived IL-10.
However, at this point, we do not know whether this IL-10
secreting B-cell population truly represents a single
developmental B-cell lineage. For example, B cells producing
IL-10 have been identifi ed among both B-1 and B-2 B-cell
populations.
21. In addition, some, but not all B cells producing IL-10 bear
markers typical of the transitional T2 B-cell subset.
Importantly, all B-10 B cells appear to demonstrate the
capacity to secrete a diverse repertoire of antibodies, with
specificities for both foreign and auto-antigens.
It is thought that the function of these cells may be to limit and
control inflammation during the course of an ongoing immune
response.
A great deal of work is still required to tease out the lineage
relationships among these various IL-10-secreting and other
B-cell subpopulations.
22. CONCLUSION
Positive - for proliferation in order to enhance the
immunity.
Negative – for control of prolifertion.
Regulative mechanism is essential for the Homeostasis.
Over production may leads to auto immunuity.
