Introduction
The immune system serves essential functions in
protection from numerous pathogenic organisms
and, in general, is not harmful to the host.
The process by which the immune response is
restrained or controlled is termed
(Immunoregulation)
Introduction
Immune responses are essential in providing protection from infectious
organisms such as bacteria, viruses and parasites. The immune response
is finely tuned to respond rapidly and appropriately to these agents.
However, not only must the response be turned on quickly,
but, equally important, it must be turned off effectively to prevent the
harmful effects.
Immune response to exogenously antigens Must be controlled, Also the
immune response to self antigens also must be constrained or ‘turned
off’.
Macrophages
NK Cells
Complement
System
Lymphocytes
Antibodies
Non-Specific Immunity
Regulation
Cellular Components
Macrophages : Activation
Activation of macrophages in response to endogenous Ag in vesicles.
a)
Macrophages are involved in :
1) Initial defense against pathogens.
2) Ag presentation to T-Helper cells.
3) Various effector functions
(e.g., cytokine production, bactericidal and tumoricidal activities) .
Macrophages : Activation Cont.
b) Macrophage functions can only be performed by activated macrophages.
Macrophage activation can be defined as alterations in the expression of
various gene products that enable the activated macrophage to perform
some function that cannot be performed by the resting macrophage.
c) Macrophage activation is an important function of Th1 cells. When Th1 cells
get activated by an APC such as a macrophage, they release IFN-γ, which is
one of two signals required to activate a macrophage. Lipopolysaccharide
(LPS) from bacteria or TNF-α produced by macrophages exposed to bacterial
products deliver the second signal.
Macrophages : Activation Cont.
d) Macrophage activation by Th1 cells is very important in protection against
many different pathogens. For example, For example, Pneumocystis carinii,
an extracellular pathogen, is controlled in normal individuals by
activated macrophages; it is, however, a common cause of death in
AIDS patients because they are deficient in Th1 cells. Similarly
Mycobacterium tuberculosis, an intracellular pathogen is controlled in normal
individuals by activated macrophages; it is, however, a problem in AIDS patients
because they are deficient in Th1 cells.
Macrophages : Deactivation
Macrophage deactivation is an active process that switches off classically and
alternatively activated macrophages, resulting in decreased antigen
presentation and increased immunosuppression.
IL-10, glucocorticoids, and transforming growth factor-β are potent
stimulators of macrophage deactivation.
FIG.6. MACROPHAGES PLAY A CENTRAL ROLE IN THE IMMUNE SYSTEM.
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NK Cells
NK cells are generally non-specific, MHC-unrestricted cells involved primarily in
the elimination of neoplastic or tumor cells. there is some type of NKdeterminant expressed by the target cells that is recognized by an NK-receptor
on the NK cell surface. Once the target cell is recognized, killing occurs in a
manner similar to that produced by the CTL.
Humoral Components
Complement
Biological effects of complement
1) Cytolysis:
activated complement proteins polymerize on cell surfaces of bacteria or erythrocyte
to form pores in its membrane (killing by osmotic lysis)
2) Opsonization:
binding of complement proteins opsonin to surfaces of foreign organisms or
particles. Phagocytic cells express specific receptors for opsonins, so promote
phagocytosis.
3) Enhancement of antibody production:
- Binding of C3b to its receptors on activated B cells (CR2)
greatly enhances antibody production
- Patient who are deficient in C3b produce much less antibody than normal individuals and
more susceptible to pyogenic infection.
4) Inflammatory response :
Small fragments released during complement activation have several
inflammatory actions :
a) C5a is chemotactic and attract neutrophiles and macrophages.
b) C5a activate phagocytes and neutrophils
C) C3,C4 and C5 are anaphylatoxins cause degranulation of mast cells and
release of histamine and other inflammatory mediators.
Harmful effects:
- If complement activate systematically on a large scale (Gm –ve bacilli).
- If activated by an autoimmune response to host cells.
5) Immune complex clearance:
- C3b facilitate binding of immune complex to several
surfaces (erythrocytes) and enhance removal by liver
and spleen.
- binds erythrocytes to blood vessels , make them as
easy prey for phagocytosis.
Regulation Of The Complement Cascade
Because both the Classical (C1) and Alternate (C3) pathways depend upon C3b,
regulation of the complement cascade is mediated via 3 proteins that affect the
levels and activities of this component.
C1 Inhibitor inhibits the production of C3b.
Protein H inhibits the production of C3b.
Factor I inhibits the production of C3b.
Specific Immunity regulation
Types of T-Helper Cells
There are four subpopulations of Th cells, Th0, Th1, Th2, and Th17 cells.
When naïve Th0 cells encounters Ag, they are capable of differentiating into
inflammatory Th1 cells, helper Th2 cells, or pathogenic Th17 cells, which are
distinguished by the cytokines they produce .
Whether a Th0 cells becomes a Th1, Th2, or Th17 cell depends upon the
cytokines in the environment, which is influenced by Ag.
For example some antigens stimulate IL-4 production which favors the
generation of Th2 cells while other antigens stimulate IL-12 production, which
favors the generation of Th1 cells.
TH cells regulation
Th1, Th2, and Th17 cells affect different cells and influence the type of immune
response :
i)
Cytokines produced by Th1 cells activate macrophages and participate in the
generation of CTL cells, resulting in a cell-mediated immune response.
ii) In contrast cytokines produced by Th2 cells help to activate B cells,
resulting in antibody production. In addition, Th2 cytokines also activate
granulocytes.
iii) A relatively recent discovery, Th17 cells (designated as such by their
production of IL-17) differentiate in response to IL-1, IL-6, and IL-23.
It (IL-17) enhances the severity of some autoimmune diseases including :MS,
inflammatory bowel disease, and rheumatoid arthritis.
TH cells regulation Cont.
Equally important, each subpopulation can exert inhibitory influences on the
other.
IFN-γ produced by Th1 cells inhibits proliferation of Th2 and differentiation of
Th17 cells.
IL-10 produced by Th2 cells inhibits production of IFN-γ by Th1 cells.
In addition, although not shown, IL-4 inhibits production of Th1 and
differentiation of Th17 cells.
The immune response depends on the type of the pathogen encountered – cellmediated responses for intracellular pathogens or antibody responses for
extracellular pathogens.
MECHANISMS THAT REGULATE IMMUNE
RESPONSES:
(a) Foreign antigens are presented to T cells by antigen-presenting cells
(APCs) such as macrophages, B cells and dendritic cells.
T
cells recognize foreign antigen by virtue of their clonotypic T-cell
antigen receptors (TCRs).
Occupancy of the TCR initiates a series of biochemical events that lead
to activation of T cells; however, the T cells are not fully activated
unless they also receive signals from costimulatory molecules like CD28,
which binds to B7 molecules on APCs.

When fully activated, T cells produce cytokines, some of which
enhance inflammatory and immune responses whereas others inhibit.
Still others regulate the type of immune response, promoting allergic or
cell-mediated responses.

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CONT. MECHANISMS THAT REGULATE IMMUNE
RESPONSES:
(b) If T cells do not receive signals from CD28, and if they are unable
to produce and respond to cytokines, they may become anergic or
nonresponsive.
(c) In addition, after activation T cells upregulate another molecule,
cytotoxic T lymphocyte-associated antigen 4 (CTLA4) which also binds
B7 molecules, in contrast to CD28, CTLA4 transmits signals that inhibit
lymphocyte activation.
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CONT. MECHANISMS THAT REGULATE IMMUNE
RESPONSES:
(d) When activated, T cells also express the molecules Fas
and Fas ligand (FasL).

Interaction of these molecules causes lymphocytes to
undergo apoptotic cell death, thus constraining immune
responses.

Lymphocytes can also die because of the lack of cytokines;
this is termed cytokine withdrawal apoptosis.
13
FIG.2. MECHANISMS THAT REGULATE THE IMMUNE RESPONSE
14
Cell-cell interactions in cell-mediated immune response:
Generation of CTL in response to exogenous Ag
a)
Cytotoxic T lymphocytes are not fully mature when they exit the thymus. They
have a functional TCR that recognizes antigen, but they cannot lyse a target
cell. They must differentiate into fully functional CTL cells.
Cytotoxic cells differentiate from a "pre-CTL" in response to two signals:
- specific Ag in the context of MHC class I on a stimulator cell
- cytokines produced by Th1 cells (especially IL-2 and IFN-γ).
b) Features of CTL-mediated lysis- CTL killing is Ag-specific. To be killed by a CTL,
the target cell must bear the same class I MHC-associated Ag that triggered preCTL differentiation. CTL killing requires cell contact.
CTLs are not injured when they lyse target cells; therefore, each CTL is capable of
killing sequentially numerous target cells.
c) Mechanisms of CTL killing - CTLs utilize several mechanisms to kill target cells, some
of which require direct cell-cell contact and others that result from the production of
certain cytokines. In all cases death of the target cells is a result of apoptosis.
i) Fas- and TNF-mediated killing : Once generated CTLs express Fas ligand on their
surface, which binds to Fas receptors on target cells. In addition, TNF-α secreted
by CTLs can bind to TNF receptors on target cells. The Fas and TNF receptors are a
closely related family of receptors. These receptors also contain death domains in
the cytoplasmic portion of the receptor, which can activate caspases that induce
apoptosis in the target cell.
Fas- and TNF-mediated killing
ii) Granule-mediated killing : Fully differentiated CTLs have numerous
granules that contain perforin and granzymes. Upon contact with target
cells, perforin is released and it polymerizes to form channels in the target
cell membrane. Granzymes, which are serine proteases, enter the target cell
through the channels and activate caspases and nucleases in the target cell
resulting in apoptosis.
Granule-mediated killing
TC cells regulation
CTLA4 is found on the surface of T cells.
The T cell attack can be turned on by stimulating the
CD28 receptor on the T cell.
The T cell attack can be turned off by stimulating the CTLA4 receptor,
which acts as an "off" switch.
Cell-cell interactions in Ab responses to exogenous T-dependent Ag
Hapten-carrier model:
Hapten-carrier model
i)
Historically one of the major findings in immunology was that both T cells
and B cells were required for antibody production.
Studies with hapten-carrier conjugates established that:
1)
Th2 cells recognized the carrier determinants and B cells recognized haptenic
determinants
2) Interactions between hapten-specific B cells and carrier-specific Th cells was
self MHC restricted
3) B cells can function both in antigen recognition and in antigen presentation.
Hapten-carrier model Cont.
ii) B cells occupy a unique position in immune responses because they express
immunoglobulin (Ig) and class II MHC molecules on their cell surface.
In addition they can function as an antigen presenting cell. In terms of the hapten-carrier
conjugate model, the mechanism is thought to be the following: the hapten is recognized
by the Ig receptor, the hapten-carrier is brought into the B cell, processed, and peptide
fragments of the carrier protein are presented to a helper T cell .
Activation of the T cell results in the production of cytokines that enable the haptenspecific B cell to become activated to produce anti-hapten antibodies
iii) Note that there are multiple signals delivered to the B cells in this model of Th2
cell-B cell interaction. As was the case for activation of T cells where the signal
derived from the TCR recognition of a peptide-MHC molecule was by itself
insufficient for T cell activation, so too for the B cell. Binding of an antigen to the
immunoglobulin receptor delivers one signal to the B cell, but that is insufficient.
Second signals delivered by co-stimulatory molecules are required; the most
important of these is CD40L on the T cell that binds to CD40 on the B cell to initiate
delivery of a second signal.
Immunoglobulin ( Antibody) :
:Classes of immunoglobulins
IgG :
a75% - mures ni dna secaps ralucsav artxe ni gI rojam eht si GgI )of serum Ig is IgG
b) Placental transfer - IgG is the only class of Ig that crosses the placenta.
c) Fixes complement
d) Binding to cells. IgG is a good opsonin. Binding of IgG to Fc receptors on other
types of cells results in the activation of other functions.
IgM:
a) IgM is the third most common serum Ig.
b) IgM is the first Ig to be made by the fetus and the first Ig to be made by a virgin
B cells when it is stimulated by antigen.
c) As a consequence of its pentameric structure, IgM is a good complement fixing
Ig. Thus, IgM antibodies are very efficient in leading to the lysis of microorganisms.
d) As a consequence of its structure, IgM is also a good agglutinating Ig . Thus, IgM
antibodies are very good in clumping microorganisms for eventual elimination
from the body.
:IgA
.nd most common serum Ig2a) IgA is the
b) IgA is the major class of Ig in secretions - tears, saliva, colostrum, mucus. Since it is
.found in secretions secretory IgA is important in local )mucosal) immunity
.c) Normally IgA does not fix complement, unless aggregated
:IgD
.a) IgD is found in low levels in serum; its role in serum uncertain
b) IgD is primarily found on B cell surfaces where it functions as a receptor for antigen.
IgD on the surface of B cells has extra amino acids at C-terminal end for anchoring to the
.membrane. It also associates with the Ig-alpha and Ig-beta chains
.c) IgD does not bind complement
.d) IgA can binding to some cells - PMN's and some lymphocytes
:IgE
a) IgE is the least common serum Ig since it binds very tightly to Fc receptors on
.basophils and mast cells even before interacting with antigen
b) Involved in allergic reactions
.c) IgE also plays a role in parasitic helminth diseases
.d) IgE does not fix complement
The effector functions of antibodies
Humoral (Immunoglobulin) Regulation
Regulation of the immune response is possibly mediated in several ways. First, a
specific group of T-cells, suppressor T-cells, are thought to be involved in turning
down the immune response. Like helper T-cells, suppressor T-cells are stimulated
by antigen but instead of releasing lymphokines that activate B-cells (and other
cells), suppressor T-cells release factors that suppress the B-cell response.
While immunosuppression is not completely understood, it appears to be more
complicated than the activation pathway, possibly involving additional cells in the
overall pathway.
Humoral (Immunoglobulin) Regulatio Cont.
Other means of regulation involve interactions between antibody and B-cells.
One mechanism, "antigen blocking", occurs when high doses of antibody interact
with all of the antigen's epitopes, thereby inhibiting interactions with B-cell
receptors.
A second mechanism, "receptor cross linking", results when antibody, bound to
a B-cell via its Fc receptor, and the B-cell receptor both combine with antigen.
This "cross-linking" inhibits the B-cell from producing further antibody.
Humoral (Immunoglobulin) Regulatio Cont.
Another means of regulation that has been proposed is the idiotypic network
hypothesis. This theory suggests that the idiotypic determinants of antibody
molecules are so unique that they appear foreign to the immune system and are,
therefore, antigenic. Thus, production of antibody in response to antigen leads to
the production of anti-antibody in response, and anti-anti-antibody and so on.
Eventually, however, the level of [anti]n-antibody is not sufficient to induce
another round and the cascade ends.
The humoral response begins with the •
activation phase, when a cell of the immune
system engulfs an antigen. Here a
machrophage engulfs an antigen by
phagocytosis. Although not shown, the
antigen may be complexed to IgG antibodies
that facilitate phagocytosis. Inside the cell,
.the new vesicle is called a phagosome
The phagosome fuses with a lysosome, which contains digestive enzymes. The enzymes break •
.down the engulfed particle into fragments, in a phenomenon called antigen processing
Within the cell, the processed antigens combine with class II MHC proteins. The complex is
displayed on the macrophages plasma membrane. This display is known as antigen presentation,
.and macrophages are considered antigen presenting cells
Antibody response to protein antigen requires
.participation of both T cells and B cells
•
Those antigens which require participation of T cells
for immune response are called T-dependent and
those which do not require participation of T cells
.are called T-independent antigens
T lymphocytes stimulate B cells, they 4 Since the CD
.are called helper T cells
Antibody response to non-protein antigens, such as
polysaccharides and lipids do not need participation
of antigen-specific helper T cells, thus these antigens
.are said to be T-independent
•
•
Antigen recognition and B cell activation
The effector phase begins with a B cell. The IgD and monomeric IgM surface receptors of B
.cells binds to specific antigen and initiate the B cell activation
The B lymphocyte antigen receptor serves two roles in B cell activation
•
First, antigen-induced clustering of receptors delivers biochemical signals to the B cells
.that initiate the process of activation
•
Second, the receptor binds protein antigen and internalizes it into •
endosomal vesicles, which are processed and presented to helper T cells at
.the surface with MHC II molecules
RESPONSE TO T-DEPENDENT ANTIGENS
*Antibody responses to protein antigens require recognition of antigen by the
helper T cells and co-operation between the antigen-specific B cells and T
lymphocytes .
*The interaction between helper T cells and B cell sequentially involves antigen
presentation by B cells to differentiated T cells, activation of helper T cells and
expression of membrane and secreted molecules by the helper T cells that bind
to and activate the B cells .
*The net result is the stimulation of B cell clonal expansion, isotype switching,
affinity maturation and differentiation into memory cells .
T-dependent antibody responses to protein antigen occur in phases that are
.localized in different anatomical regions within peripheral lymphoid organs
The early phase that comprises B cell proliferation, initial antibody secretion
.and isotype switching occur in the T cell area and primary follicles
The late phase occurs in the germinal center within lymphoid follicles and
.result in affinity maturation and memory B cell production
*Activated B cells and T cells that recognize foreign protein antigen in the peripheral
lymphoid tissue come together to initiate humoral immune response. Within one or
two days of antigen administration, naïve CD detneserp negtina ezingocer sllec T +4
.snagro diohpmyl fo aera llec T eht ni sCPA lanoisseforp yb
* B lymphocytes that also recognize the antigen in the follicle get activated and move
out of the follicle into the T
cell area .
*The initial encounter between the antigen-activated T cell and B cell occur at the
interface of the follicles and T cell area .
*This event occurs approximately 7-3days after antigen exposure .
*Antigen-specific B cells bind to native antigen to surface Ig receptors, internalize
(receptor mediated endocytosis) and process it in endosomal vesicles .
*The peptide fragment of the antigen is then presented along with MHC class II proteins
on their surfaces .
*The antibodies that are subsequently formed are specific to conformational
determinants of the antigen .
*A single B cell may bind and endocytose a protein and present multiple different
peptides complexed with MHC class II proteins to different T cells, but the resultant
antibody response remains specific for the native protein .
*Activated helper T cell secretes cytokines that stimulate B cell proliferation. Cytokines
serve two principal functions in antibody responses :
-1They provide amplification mechanism by B cell proliferation and differentiation
-2They determine type of antibodies produced by promoting isotype switch
*All the stimuli that B cell receives activate transcription of immunoglobulin genes.
Some of the B cells that have proliferated differentiate into effector cells that actively
secrete antibodies. The secreted antibodies have same specificity to the surface Ig
receptor that captured the antigen, but vary in their carboxyl terminal .
RESPONSE TO T-INDEPENDENT ANTIGENS
*Many non-protein antigens such as polysaccharides and lipids stimulate
antibody production in the absence of helper T cells, and these antigens are
called T-independent antigens .
*Important TI antigens include polysaccharides, glycolipids, and nucleic
acids. These antigens are not processed and presented along with MHC
proteins and hence cannot be recognized by helper T cells.
*Most TI antigens are polyvalent, being composed of multiple identical
epitopes. Such polyvalent antigens may induce cross-linking of surface Ig
molecules on B cell. This leads to activation of B cell without the
requirement of helper T cell. TI antigens are classifies into two types, TI-2
antigens are polysaccharides, glycolipids, and nucleic acids where as TI-1 8
antigen is lipopolysaccharide (LPS)
*TI-1 antigens can directly stimulate B cells without requirement of any other
cell.
At low concentration gram negative bacterial LPS stimulates specific antibody
production, but at high levels it acts as a polyclonal B cell activator, stimulating
growth and differentiation of most B cells without binding to the membrane
receptors .
*LPS is a polyclonal activator in mice but not in humans. In addition, many
polysaccharides activate complement by alternate pathway and generate C3d,
which binds to the antigen and provide second signal for B cell activation .
*Responses to TI antigens consist largely of IgM antibodies of low affinity and do
not show significant heavy chain class switching, affinity maturation or memory.
However, certain non-protein antigens such as penumococcal capsular
polysaccharide can induce antibodies predominantly of IgG2 subclass.