IMMUNOLOGY

12.Mar.2015

UNIT

III

T.N.JAYA GANESH

I-M.Sc BIOTECHNOLOGY

DEPT. OF BIOTECHNOLOGY

BHARATHIAR UNIVERSITY

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.

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

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.

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).

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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 FcγRIIbsignaling cascade, and phosphorylation of FcγRIIb’s ITIM.

The phosphorylated ITIM serves as a docking site for the inositolphosphatase 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.

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.

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 antibodymediatedautoimmune 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.

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.

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.

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.

REFERENCES

1.Immunology – J.Kuby- 6th Ed.,

2.Roitt’s Essential Immunology – 11th Ed.,

3.Instant Notes in Immunology- P.M. Lydyard – 2nd Ed.,