Immunology

The immune system consists of an intricately linked network of cells,
proteins and lymphoid organs that are strategically placed to ensure
maximal protection against infection.
• The mechanisms of defense against microbes fall into two broad
categories:----
A. Innate immunity (also called natural, or native, immunity) refers
to the mechanisms that are ready to react to infections even before
they occur, and that have evolved to specifically recognize and
combat microbes.
B. Adaptive immunity (also called acquired, or specific, immunity)
consists of mechanisms that are stimulated by (“adapt to”)
microbes and are capable of recognizing microbial and
nonmicrobial substances.

Innate Immunity
Ancient immune recognition system of host cells bearing germline-
encoded pattern recognition receptors that recognize pathogens and
trigger a variety of mechanisms of pathogen elimination.
 Cells of the innate immune system include natural killer cell
lymphocytes, monocytes/macrophages, dendritic cells, neutrophils,
basophils, eosinophils, tissue mast cells, and epithelial cells.
Cells of the innate immune system, such as macrophages, dendritic cells,
and NK lymphocytes, recognize PAMPs that are highly conserved
among many microbes.
Pathogen-associated molecular patterns (PAMPs) are Invariant
molecular structures expressed by large groups of microorganisms that
are recognized by host cellular pattern recognition receptors in the
mediation of innate immunity.

Important components
of the recognition of microbes by the innate immune system
include
• Recognition by germline-encoded host molecules
• Recognition of key microbe virulence factors but not
recognition of self-molecules
• Nonrecognition of benign foreign molecules or microbes

Cellular Receptors for Microbes, Products of Damaged
Cells, and Foreign Substances
The cellular receptors that recognize the molecules known as pathogen-
associated molecular patterns and damage-associated molecular
patterns are often called pattern recognition receptors.
Pattern recognition receptors are located in all the cellular
compartments where microbes may be present:
plasma membrane receptors detect extracellular microbes,
endosomal receptors detect ingested microbes, and cytosolic
receptors detect microbes in the cytoplasm.
Major PRR families of proteins include transmembrane proteins,
such as the Toll-like receptors (TLRs) and C-type lectin receptors
(CLRs), and cytoplasmic proteins, such as the retinoic acid–inducible
gene (RIG)-1-like receptors (RLRs) and Nucleotide-oligomerisation
domain protein like receptors (NLRs)

 A major group of PRR, collagenous glycoproteins with C-type lectin
domains are termed collectins and include the serum protein mannose-
binding lectin (MBL).
 MBL and other collectins, as well as two other protein families—the
pentraxins (such as C-reactive protein and serum amyloid P) and
macrophage scavenger receptors—all have the property of opsonizing
(coating) bacteria for phagocytosis by macrophages and can also activate
the complement cascade to lyse bacteria.
Toll-Like Receptors—
 Toll-like receptors (TLRs), whose founding member, Toll, was discovered
in Drosophila.
 Proteins in the Toll family can be expressed on macrophages, dendritic
cells, and B cells as well as on a variety of nonhematopoietic cell types,
including respiratory epithelial cells.
 11 TLRs have been identified in humans, and 13 TLRs have been
identified in mice.

 The TLRs are present in the plasma membrane and endosomal vesicles
 All these receptors signal by a common pathway that culminates in the
activation of two sets of transcription factors:
o NF-κB, which stimulates the synthesis and secretion of cytokines and the
expression of adhesion molecules (Integrins ) both of which are critical for the
recruitment and activation of leukocytes .
o interferon regulatory factors (IRFs), which stimulate the production of the
antiviral cytokines, type I interferons.
NOD-Like Receptors and the Inflammasome:-
 They recognize a wide variety of substances, including products of necrotic
cells (e.g., uric acid and released ATP), ion disturbances (e.g., loss of K+), and
some microbial products.
 The intracellular microbial sensors, NLRs, after triggering, form large
cytoplasmic complexes termed inflammasomes, which are aggregates of
molecules including NOD-like receptor pyrin (NLRP) proteins that are
members of the NLR family and inflammasome link the sensing of microbial
products and cellular stress to the proteolytic activation of interleukin (IL)-1β
and IL-18 inflammatory cytokines.

 Activation of molecules in the inflammasome is a key step in the
response of the innate immune system for intracellular recognition of
microbial and other danger signals in both health and pathologic states.
Other Receptors for Microbial Products-
 C-type lectin receptors (CLRs) expressed on the plasma membrane of
macrophages and dendritic cells detect fungal glycans and elicit
inflammatory reactions to fungi.
 RIG-like receptors (RLRs) are located in the cytosol of most cell types
and detect nucleic acids of viruses that replicate in the cytoplasm of
infected cells. These receptors stimulate the production of antiviral
cytokines.
 G protein–coupled receptors on neutrophils, macrophages, and most
other types of leukocytes recognize short bacterial peptides containing
N-formylmethionyl residues. this receptor enables neutrophils to detect
bacterial proteins and stimulate chemotactic responses of the cells.
 Mannose receptors recognize microbial sugars (often contain terminal
mannose residues,) and induce phagocytosis of the microbes.

EFFECTOR CELLS OF INNATE IMMUNITY
Monocytes and macrophages
• Monocytes are the precursors of tissue macrophages. They are produced
in the bone marrow and constitute about 5% of leucocytes in the
circulation.
• Monocytes-macrophages are on the first line of defense associated with
innate immunity and ingest and destroy microorganisms through the
release of toxic products such as hydrogen peroxide (H2O2) and nitric
oxide (NO).
• Inflammatory mediators produced by macrophage include
prostaglandins; leukotrienes; platelet activating factor; cytokines such as
IL-1, TNF-α, IL-6, and IL-12; and chemokines.
• Activated macrophages can also mediate antigen-nonspecific lytic activity
and eliminate cell types such as tumor cells in the absence of antibody.
This activity is largely mediated by cytokines (i.e., TNF-α and IL-1).
• Monocytes-macrophages express lineage-specific molecules (e.g., the
cell-surface LPS receptor, CD14) as well as surface receptors for a
number of molecules, including the Fc region of IgG, activated
complement components, and various cytokines.

Dendritic Cells
• Dendritic cells are the most important antigen-presenting cells for
initiating T-cell responses against protein antigens.
• These cells have numerous fine cytoplasmic processes that resemble
dendrites, from which they derive their name.
• Human dendritic cells (DCs) contain several subsets, including
myeloid DCs and plasmacytoid DCs.
• Myeloid DCs can differentiate into either macrophages-monocytes or
tissue-specific DCs.
• Plasmacytoid DCs are inefficient APCs but are potent producers of
type I interferon (IFN) (e.g., IFN-α) in response to viral infections.
• When DCs come in contact with bacterial products, viral proteins, or
host proteins released as danger signals from distressed host cells,
infectious agent molecules bind to various TLRs and activate DCs to
release cytokines and chemokines that drive cells of the innate
immune system to become activated to respond to the invading
organism, and recruit T and B cells of the adaptive immune system to
respond.

• Several features of dendritic cells account for their key role in
antigen presentation-------
 These cells are located at the right place to capture antigens—under
epithelia, the common site of entry of microbes and foreign
antigens, and in the interstitia of all tissues, where antigens may be
produced. Immature dendritic cells within the epidermis are called
Langerhans cells.
 Dendritic cells express many receptors for capturing and responding
to microbes (and other antigens), including TLRs and lectins.
 Third, in response to microbes, dendritic cells are recruited to the T-
cell zones of lymphoid organs, where they are ideally located to
present antigens to T cells.
 Dendritic cells express high levels of MHC and other molecules
needed for presenting antigens to and activating T cells.
Another type of cell with dendritic morphology is present in the germinal
centers of lymphoid follicles in the spleen and lymph nodes and is called the
follicular dendritic cell. Such cells play a role in humoral immune responses
by presenting antigens to B cells and selecting the B cells that have the highest
affinity for the antigen, thus improving the quality of the antibody produced.

Natural killer cells
• Natural killer (NK) cells are large granular lymphocytes which play
a major role in defence against tumours and viruses.
• NK cells account for ~5–15% of peripheral blood lymphocytes.
• NK cells express surface receptors for the Fc portion of IgG (FcR)
(CD16) and for NCAM-I (CD56),and many NK cells express T
lineage markers, particularly CD8,and proliferate in response to IL2.
NKcells arise in both bone marrow and thymic microenvironments.
• Functionally, NK cells share features with both monocytes-
macrophages and neutrophils in that they mediate both ADCC
(antibody-dependent cellular cytotoxicity) and NK cell activity.
• NK cell cytotoxicity is the nonimmune (i.e., effector cell never
having had previous contact with the target), MHC-unrestricted,
non-antibody-mediated killing of target cells, which are usually
malignant cell types, transplanted foreign cells, or virus-infected
cells.
• NK cell cytotoxicity may play an important role in immune
surveillance and destruction of malignant and virus-infected host
cells.

• NK cells have a variety of surface receptors that have inhibitory or
activating functions and belong to two structural families. These
families include the immunoglobulin superfamily and the lectin-like
type II trans membrane proteins.
• NK immunoglobulin superfamily receptors include the killer cell
immunoglobulin-like activating or inhibitory receptors (KIRs).
• The KIRs are made up proteins with either two (KIR2D) or three
(KIR3D) extracellular immunoglobulin domains (D).
• Their function as either inhibitory KIRs with a long (L) cytoplasmic
tail (KIRDL) or activating KIRs with a short (S) cytoplasmic tail
(KIRDS).
• NK cell inactivation by KIRs is a central mechanism to prevent
damage to normal host cells.
• NK cell signaling is highly coordinated series of inhibiting and
activating signals that prevent NK cells from responding to
uninfected, nonmalignant self-cells; however, they are activated to
attack malignant and virally infected cells

• NK cells also secrete cytokines such as interferon-γ (IFN-γ), which
activates macrophages to destroy ingested microbes, and thus NK cells
provide early defense against intracellular microbial infections.
• The activity of NK cells is regulated by many cytokines, including the
interleukins IL-2, IL-15, and IL-12. IL-2 and IL-15 stimulate
proliferation of NK cells, whereas IL-12 activates killing and secretion of
IFN-γ.

Neutrophils, Eosinophils, and Basophils
• Neutrophils, also known as polymorphonuclear leucocytes, are derived
from the bone marrow.
• They are short-lived cells with a half-life of 6 hours in the blood stream,
and are produced at the rate of approximately 10ˉ11 cells daily.
• Neutrophils express Fc receptor IIIa for IgG (CD16) as well as
receptors for activated complement components (C3b or CD35).
• Upon interaction of neutrophils with antibody-coated (opsonized)
bacteria or immune complexes, azurophilic granules (containing
myeloperoxidase, lysozyme, elastase, and other enzymes) and specific
granules (containing lactoferrin, lysozyme, collagenase, and other
enzymes) are released, and microbicidal superoxide radicals (O2-) are
generated at the neutrophil surface.
• The generation of superoxide leads to inflammation by direct injury to
tissue and by alteration of macromolecules such as collagen and DNA.

• Eosinophils express Fc receptor II for IgG (CD32) and are potent
cytotoxic effector cells for various parasitic organisms.
• As the eosinophil granule contains anti-inflammatory types of enzymes
(histaminase, arylsulfatase, phospholipase D), eosinophils may
homeostatically downregulate or terminate ongoing inflammatory
responses.
• Basophils and tissue mast cells are potent reservoirs of cytokines such as
IL-4 and can respond to bacteria and viruses with antipathogen cytokine
production through multiple TLRs expressed on their surface.
• Mast cells and basophils can also mediate immunity through the binding
of antipathogen antibodies. This is a particularly important host defense
mechanism against parasitic diseases.
• Basophils express high-affinity surface receptors for IgE (FcεRII)
(CD23) and, upon cross-linking of basophil-bound IgE by antigen, can
release histamine, eosinophil chemotactic factor of anaphylaxis, and
neutral protease— all mediators of allergic immediate (anaphylaxis)
hypersensitivity responses.

CYTOKINES
Cytokines are soluble proteins that interact with specific cellular
receptors that are involved in the regulation of the growth and
activation of immune cells and mediate normal and pathologic
inflammatory and immune responses.
 The action of cytokines may be
• (1) autocrine when the target cell is the same cell that secretes the
cytokine,
• (2) paracrine when the target cell is nearby
• (3) endocrine when the cytokine is secreted into the circulation and
acts distal to the source.
 Cytokines have been named based on presumed targets or based on
presumed functions.
 Those cytokines that are thought to primarily target leukocytes have
been named interleukins (IL-1, -2, -3, etc.).

• Cytokines belong in general to three major structural families: the
hematopoietin family; the TNF, IL-1, platelet-derived growth factor
(PDGF), and transforming growth factor (TGF) β families; and
the CXC and C-C chemokine families.
• Chemokines are cytokines that regulate cell movement and
trafficking; they act through G protein coupled receptors and have a
distinctive three-dimensional structure.
• Cytokine receptors can be grouped into five general families based
on similarities in their extracellular amino acid sequences and
conserved structural domains.
 The immunoglobulin (Ig) superfamily(IL-1)
 Hematopoietic growth factor (type 1) receptor family((GM-CSF)
 Interferon (type II) receptor family(IFN-γ and –β)
 TNF (type III) receptor family(TNF, CD40, CD27 and CD30,)
 Seven transmembrane helix family(CXC chemokine receptor type 4
(CXCR4) and β chemokine receptor type 5 (CCR5), have been found to serve
as the two major co-receptors for binding and entry of HIV into CD4-
expressing host cells)

Cytokines contribute to different types of immune
responses.
1. In innate immune responses, cytokines are produced rapidly after
encounter with microbes and other stimuli, and function to induce
inflammation and inhibit virus replication. These cytokines include TNF,
IL-1, IL-12, type I IFNs, IFN-γ, and chemokines. Their major sources are
macrophages, dendritic cells, and NK cells, but endothelial and epithelial
cells can also produce them.
2. In adaptive immune responses, cytokines are produced principally by
CD4+ T lymphocytes activated by antigen and other signals, and function
to promote lymphocyte proliferation and differentiation and to activate
effector cells. The main ones in this group are IL-2, IL-4, IL-5, IL-17, and
IFN-γ. Some cytokines serve mainly to limit and terminate immune
responses; these include TGF-β and IL-10.
3. Some cytokines stimulate hematopoiesis and are called colony-stimulating
factors because they are assayed by their ability to stimulate formation of
blood cell colonies from bone marrow progenitors. Their functions are to
increase leukocyte numbers during immune and inflammatory responses,
and to replace leukocytes that are consumed during such responses. They
are produced by marrow stromal cells, T lymphocytes, macrophages, and
other cells. Examples include the colonystimulating factors (CSFs) such as
GM-CSF, and IL-7.

Complement
• The complement system is a group of more than 20 tightly regulated,
functionally linked proteins that act to promote inflammation and eliminate
invading pathogens.
• Complement proteins are produced in the liver and are present in the
circulation as inactive molecules.
• There are three mechanisms by which the complement cascade may be
triggered
A. The alternative pathway is triggered directly by binding of C3 to bacterial
cell wall components, such as lipopolysaccharide of Gram-negative
bacteria and teichoic acid of Gram-positive bacteria.
B. The classical pathway is initiated when two or more IgM or IgG antibody
molecules bind to antigen, forming immune complexes. The associated
conformational change exposes binding sites on the antibodies for C1. C1
is a multiheaded molecule which can bind up to six antibody molecules.
Once two or more ‘heads’ of a C1 molecule are bound to antibody, the
classical cascade is triggered.

C. The lectin pathway is activated by the direct binding of mannose-binding
lectin to microbial cell surface carbohydrates. This mimics the binding of C1
to immune complexes and directly stimulates the classical pathway.
• Activation of complement by any of these pathways results in activation
of C3. This, in turn, activates the final common pathway, in which the
complement proteins C5–C9 assemble to form the membrane attack
complex. This can puncture target cell walls, leading to osmotic cell lysis.
• Complement fragments generated by activation of the cascade can also
act as opsonins, rendering microorganisms more susceptible to
phagocytosis by macrophages and neutrophils.
• They are chemotactic agents, promoting leucocyte trafficking to sites of
inflammation.
• Some fragments act as anaphylotoxins, binding to complement receptors
on mast cells and triggering release of histamine, which increases
vascular permeability.
• The products of complement activation also help to target immune
complexes to antigen-presenting cells, providing a link between the innate
and the acquired immune systems.

The adaptive immune system
• If the innate immune system fails to provide effective protection against
an invading pathogen, the adaptive immune system is mobilised.
• This has three key characteristics:
 It has exquisite specificity and is able to discriminate between very small
differences in molecular structure.
 It is highly adaptive and can respond to an unlimited number of
molecules.
 It possesses immunological memory, such that subsequent encounters
with a particular antigen produce a more effective immune response than
the first encounter.
 There are two major arms of the adaptive immune response: humoral
immunity involves antibodies produced by B lymphocytes; cellular
immunity is mediated by T lymphocytes, which release cytokines and kill
immune targets.

Tissues of the Immune System
• Primary lymphoid organs. The primary lymphoid organs are involved
in lymphocyte development. They include the bone marrow, where
both T and B lymphocytes are derived from haematopoietic stem cells
and where B lymphocytes also mature, and the thymus, where T
lymphocytes mature.
• Secondary lymphoid organs. After maturation, lymphocytes migrate to
the secondary lymphoid organs. These include the spleen, lymph nodes
and mucosa-associated lymphoid tissue. These organs trap and
concentrate foreign substances, and are the major sites of interaction
between naïve lymphocytes and microorganisms.
 Thymus --The thymus is a bilobed structure organised into cortical and
medullary areas. The cortex is densely populated with immature T
cells, which migrate to the medulla to undergo selection and
maturation.
 Spleen --the largest of the secondary lymphoid organs---major site of
antibody synthesis--It is particularly important for defence against
encapsulated bacteria.

• Lymphatics--Lymphoid tissues are physically connected by a network of
lymphatics, which has three major functions:
a) It provides access to lymph nodes.
b) Returns interstitial fluid to the venous system
c) Transports fat from the small intestine to the blood stream.
Lymphatics may be either deep or superficial, and in general, follow the
distribution of major blood vessels.
• Lymph nodes and mucosa-associated lymphoid tissue---Lymph nodes are
nodular aggregates of lymphoid tissues located along lymphatic channels
throughout the body.
• As lymph slowly suffuses through lymph nodes, antigen-presenting cells in
the nodes are able to sample the antigens of microbes that may enter through
epithelia into tissues and are carried in the lymph.
• In addition, dendritic cells pick up and transport antigens of microbes from
epithelia and tissues via lymphatic vessels to the lymph nodes. Thus, the
antigens of microbes that enter through epithelia or colonize tissues become
concentrated in draining lymph nodes.

T Lymphocytes
• Helper T lymphocytes stimulate B lymphocytes to
make antibodies and activate other leukocytes (e.g.,
phagocytes) to destroy microbes.
• Cytotoxic T lymphocytes (CTLs) kill infected cells
• Regulatory T lymphocytes limit immune responses
and prevent reactions against self antigens.

 T lymphocytes develop in the thymus from precursors that arise from
hematopoietic stem cells.
 Mature T lymphocytes constitute 70–80% of normal peripheral blood
lymphocytes (only 2% of the total-body lymphocytes are contained in
peripheral blood), 90% of thoracic duct lymphocytes, 30–40% of lymph
node cells, and 20–30% of spleen lymphoid cells.
 Each T cell recognizes a specific cell-bound antigen by means of an
antigen-specific TCR.
 In approximately 95% of T cells, the TCR consists of a disulfide-linked
heterodimer made up of an α and a β polypeptide chain , each having a
variable (antigen-binding) region and a constant region.
 The αβ TCR recognizes peptide antigens that are presented by major
histocompatibility complex (MHC) molecules on the surfaces of antigen-
presenting cells.
 By limiting the specificity of T cells for peptides displayed by cell surface
MHC molecules, called MHC restriction, the immune system ensures that
T cells see only cell-associated antigens.

• Each TCR is noncovalently linked to six polypeptide chains, which form the
CD3 complex and the ζ chain dimer. The CD3 and ζ proteins are identical in
all T cells. They are involved in the transduction of signals into the T cell that
are triggered by binding of antigen to the TCR. Together with the TCR, these
proteins form the TCR complex.
• A small population of mature T cells expresses another type of TCR composed
of γ and δ polypeptide chains. The γδ TCR recognizes peptides, lipids, and
small molecules, without a requirement for display by MHC proteins.
• γδ T cells tend to aggregate at epithelial surfaces, such as the skin and mucosa
of the gastrointestinal and urogenital tracts, suggesting that these cells are
sentinels that protect against microbes that try to enter through epithelia.
• Another small subset of T cells expresses markers that are also found on NK
cells; these cells are called NK-T cells. NK-T cells express a very limited
diversity of TCRs, and they recognize glycolipids that are displayed by the
MHC like molecule CD1.
• T cells express several other proteins that assist the TCR complex in
functional responses. These include CD4, CD8, CD28, and integrins.
• Approximately 60% of mature T cells are CD4+ and about 30% are CD8+.

• Most CD4+ T cells function as cytokine-secreting helper cells that assist
macrophages and B lymphocytes to combat infections.
• Most CD8+ cells function as cytotoxic (killer) T lymphocytes (CTLs) to
destroy host cells harboring microbes.
• During antigen recognition, CD4 molecules bind to class II MHC
molecules that are displaying antigen ,and CD8 molecules bind to class I
MHC molecules, and the CD4 or CD8 coreceptor initiates signals that are
necessary for activation of the T cells.
• Integrins are adhesion molecules that promote the attachment of T-cells to
APCs.
• To respond, T cells have to recognize not only antigen- MHC complexes
but additional signals provided by antigen- presenting cells. In this process
CD28 plays an important role,

Cell-Mediated Immunity: Activation of T Lymphocytes
and Elimination of Intracellular Microbes
• Earliest responses of CD4+ helper T cells is secretion of the
cytokine IL-2 and expression of high-affinity receptors for IL-2.
• IL-2 is a growth factor that acts on these T lymphocytes and
stimulates their proliferation, leading to an increase in the number of
antigen-specific lymphocytes.
• The functions of helper T cells are mediated by the combined
actions of CD40-ligand (CD40L) and cytokines. When CD4+ helper
T cells recognize antigens being displayed by macrophages or B
lymphocytes, the T cells express CD40L, which engages CD40 on
the macrophages or B cells and activates these cells.
• Some of the activated CD4+ T cells differentiate into effector cells
that secrete different sets of cytokines and perform different
functions.

• Cells of the TH1 subset secrete the cytokine IFN-γ, which is a potent
macrophage activator.
• The combination of CD40- and IFN-γ- mediated activation results in
“classical” macrophage activation , leading to the induction of microbicidal
substances in macrophages and the destruction of ingested microbes.
• TH2 cells produce IL-4, which stimulates B cells to differentiate into IgE-
secreting plasma cells, and IL-5, which activates eosinophils.
• Eosinophils and mast cells bind to IgE-coated microbes such as helminthic
parasites, and function to eliminate helminths.
• TH2 cells also induce the “alternative” pathway of macrophage activation,
which is associated with tissue repair and fibrosis.
• TH17 recruit neutrophils and monocytes, which destroy some extracellular
bacteria and fungi and are involved in some inflammatory diseases.
• Activated CD8+ T lymphocytes differentiate into CTLs that kill cells
harboring microbes in the cytoplasm. By destroying the infected cells,
CTLs eliminate the reservoirs of infection.

B lymphocytes
• B lymphocytes are the only cells in the body capable of producing
antibody molecules, the mediators of humoral immunity.
• B cells recognize antigen via the B-cell antigen receptor complex.
• Membrane-bound antibodies of the IgM and IgD isotypes, present on the
surface of all mature, naive B cells, are the antigen-binding component of
the B-cell receptor complex.
• After stimulation by antigen and other signals , B cells develop into
plasma cells, veritable protein factories for antibodies.
• In addition to membrane Ig, the B-cell antigen receptor complex contains
a heterodimer of two invariant proteins called Igα and Igβ.
• Igα (CD79a) and Igβ (CD79b) are essential for signal transduction
through the antigen receptor.
• B cells also express several other molecules that are essential for their
responses. These include the type 2 complement receptor (CR2, or
CD21), which recognizes complement products generated during innate
immune responses to microbes, and CD40, which receives signals from
helper T cells. CR2 is also used by the Epstein-Barr virus (EBV) as a
receptor to enter and infect B cells.

Humoral Immunity: Activation of B Lymphocytes and
Elimination of Extracellular Microbes
• Upon activation, B lymphocytes proliferate and then differentiate
into plasma cells that secrete different classes of antibodies with
distinct functions.
• Antibody responses to most protein antigens require T cell help and
are said to be T-dependent. In these responses, B cells ingest protein
antigens into vesicles, degrade them, and display peptides bound to
class II MHC molecules for recognition by helper T cells.
• The helper T cells are activated and express CD40L and secrete
cytokines, which work together to stimulate the B cells.
• Many polysaccharide and lipid antigens cannot be recognized by T
cells but have multiple identical antigenic determinants (epitopes)
that are able to engage many antigen receptor molecules on each B
cell and initiate the process of B-cell activation; these responses are
said to be T-independent.
• Each plasma cell is derived from an antigen-stimulated B cell and
secretes antibodies that recognize the same antigen that was bound
to the BCR and initiated the response.

• Polysaccharides and lipids stimulate secretion mainly of IgM antibody. Protein
antigens, by virtue of CD40L- and cytokine-mediated helper T-cell actions,
induce the production of antibodies of different classes, or isotypes (IgG, IgA,
IgE).
• Helper T cells also stimulate the production of antibodies with high affinities for
the antigen. This process, called affinity maturation, improves the quality of
the humoral immune response.
• The humoral immune response combats microbes in many ways .
• Antibodies bind to microbes and prevent them from infecting cells, thus
neutralizing the microbes.
• IgG antibodies coat (opsonize) microbes and target them for phagocytosis, since
phagocytes (neutrophils and macrophages) express receptors for the Fc tails of
IgG.
• IgG and IgM activate the complement system by the classical pathway, and
complement products promote phagocytosis and destruction of microbes.

Immunoglobulins
• Immunoglobulins are the products of differentiated B cells and mediate the
humoral arm of the immune response.
• All immunoglobulins have the basic structure of two heavy and two light
chains.
• Immunoglobulin isotype (i.e., G, M, A, D, E) is determined by the type of Ig
heavy chain present.
• IgG and IgA isotypes can be divided further into subclasses (G1, G2, G3, G4,
and A1, A2) based on specific antigenic determinants on Ig heavy chains.
• The four chains are covalently linked by disulfide bonds. Each chain is made
up of a V region and C regions (also called domains), themselves made up of
units of ~110 amino acids.

• Light chains have one variable (VL) and one constant (CL) unit; heavy chains
have one variable unit (VH) and three or four constant (CH) units, depending on
isotype.
• the constant, or C, regions of Ig molecules are made up of homologous
sequences and share the same primary structure as all other Ig chains of the
same isotype and subclass.
• Constant regions are involved in biologic functions of Ig molecules.
• The CH2 domain of IgG and the CH4 domain of IgM are involved with the
binding of the C1q portion of C1 during complement activation.
• The CH region at the carboxy-terminal end of the IgG molecule, the Fc region,
binds to surface Fc receptors (CD16, CD32, CD64) of macrophages, DCs, NK
cells, B cells, neutrophils, and eosinophils.
• The Fc of IgA binds to FcαR (CD89), and the Fc of IgE binds to FcεR (CD23).
• Variable regions (VL and VH) constitute the antibody-binding (Fab) region of
the molecule.

CD classification of human lymphocyte differentiation antigens
• The development of monoclonal antibody technology led to the discovery
of a large number of new leukocyte surface molecules.
• In 1982, the First International Workshop on Leukocyte Differentiation
Antigens was held to establish a nomenclature for cell-surface molecules of
human leukocytes.
• From this and subsequent leukocyte differentiation workshops has come
the cluster of differentiation (CD) classification of leukocyte antigens.
• In terms of physiology, CD molecules can act in numerous ways, often
acting as receptors or ligands important to the cell
• CD for humans is numbered up to 371(as on 21st April,2016)("HCDM,
responsible for HLDA workshop and CD molecules". Human Cell
Differentiation Molecules Council (successor to the HLDA Workshops).
Retrieved 2016-04-21.)

Major Histocompatibility Complex (MHC)
Molecules: The Peptide Display System of
Adaptive Immunity
• The function of MHC molecules is to display peptide fragments of protein
antigens for recognition by antigenspecific T cells.
• MHC molecules were discovered as products of genes that evoke rejection
of transplanted organs, and their name derives from their role in
determining tissue compatibility between individuals.
• In humans the MHC molecules are called human leukocyte antigens (HLA)
because they were initially detected on leukocytes by the binding of
antibodies. The genes encoding HLA molecules are clustered on a small
segment of chromosome 6
 On the basis of their structure, cellular distribution and function, MHC
gene products are classified into two major classes.

Class I MHC molecules
• Class I MHC molecules are expressed on all nucleated cells and platelets.
• They are heterodimers consisting of a polymorphic α, or heavy, chain (44-
kD) linked noncovalently to a smaller (12-kD) nonpolymorphic protein
called β2-microglobulin.
• The α chains are encoded by three genes, designated HLA-A, HLA-B, and
HLA-C, that lie close to one another in the MHC locus
• The extracellular region of the α chain is divided into three domains: α1,
α2, and α3.
• The α1 and α2 domains form a cleft, or groove, where peptides bind.

• Class I MHC molecules display peptides that are derived from proteins,
such as viral and tumor antigens, that are located in the cytoplasm and
usually produced in the cell, and class I–associated peptides are recognized
by CD8+ T lymphocytes.
• Cytoplasmic proteins are degraded in proteasomes and peptides are
transported into the endoplasmic reticulum (ER) where the peptides bind to
newly synthesized class I molecules. Peptide-loaded MHC molecules
associate with β2-microglobulin to form a stable trimer that is transported
to the cell surface.
• The α3 domain of class I MHC molecules has a binding site for CD8, and
therefore the peptide-class I complexes are recognized by CD8+ T cells.
• The TCR recognizes the MHC-peptide complex, and the CD8 molecule,
acting as a coreceptor, binds to the class I heavy chain.
• Since CD8+ T cells recognize peptides only if presented as a complex with
class I MHC molecules, CD8+ T cells are said to be class I MHC-
restricted.

Class II MHC molecules
• Class II MHC molecules are encoded in a region called HLA-D, which has
three subregions: HLA-DP, HLA-DQ, and HLA-DR.
• Each class II molecule is a heterodimer consisting of a noncovalently
associated α chain and β chain, both of which are polymorphic.
• The extracellular portions of the α and β chains both have two domains
designated α1 and α2, and β1 and β2.
• Crystal structure of class II molecules has revealed that, similar to class I
molecules, they have peptide-binding clefts facing outward.
• This cleft is formed by an interaction of the α1 and β1 domains.

• Class II MHC molecules present antigens that are internalized into vesicles, and
are typically derived from extracellular microbes and soluble proteins.
• The internalized proteins are proteolytically digested in endosomes or
lysosomes.
• Peptides resulting from proteolytic cleavage then associate with class II
heterodimers in the vesicles, and the stable peptide-MHC complexes are
transported to the cell surface.
• The class II β2 domain has a binding site for CD4, and therefore, the class II-
peptide complex is recognized by CD4+ T cells, which function as helper cells.
• In this interaction, the CD4 molecule acts as the coreceptor. Because CD4+ T
cells can recognize antigens only in the context of self class II molecules, they
are referred to as class II MHCrestricted.
• In contrast to class I molecules, class II MHC molecules are mainly expressed on
cells that present ingested antigens and respond to T-cell help (macrophages, B
lymphocytes, and dendritic cells).

Hypersensitivity: Immunologically
Mediated Tissue Injury
• Injurious immune reactions, called hypersensitivity, are the basis of the
pathology associated with immunologic diseases.
• This term arose from the idea that individuals who have been previously
exposed to an antigen manifest detectable reactions to that antigen and are
therefore said to be sensitized.
• There are several important general features of hypersensitivity disorders:--
 Hypersensitivity reactions can be elicited by exogenous environmental antigens
(microbial and nonmicrobial) or endogenous self antigens.
 Hypersensitivity usually results from an imbalance between the effector
mechanisms of immune responses and the control mechanisms that serve to
normally limit such responses.
 The development of hypersensitivity diseases (both allergic and autoimmune) is
often associated with the inheritance of particular susceptibility genes.
 The mechanisms of tissue injury in hypersensitivity reactions are the same as the
effector mechanisms of defense against infectious pathogens.

Immediate (Type I) Hypersensitivity
Immediate, or type I, hypersensitivity is a rapid immunologic reaction
occurring in a previously sensitized individual that is triggered by the binding
of an antigen to IgE antibody on the surface of mast cells. These reactions are
often called allergy, and the antigens that elicit them are allergens.

Activation of TH2 Cells and Production of IgE Antibody along with Sensitization and
Activation of Mast Cells

Mediators of Immediate Hypersensitivity
Mast cell activation leads to degranulation, with the discharge of preformed
(primary) mediators that are stored in the granules, and de novo synthesis and
release of secondary mediators, including lipid products and cytokines.
 Preformed Mediators:--Mediators contained within mast cell granules are the
first to be released and can be divided into three categories:
 Vasoactive amines-Histamine causes intense smooth muscle contraction,
increased vascular permeability, and increased mucus secretion by nasal,
bronchial, and gastric glands.
 Enzymes—like neutral proteases (chymase, tryptase) and several acid
hydrolases that cause tissue damage and lead to the generation of kinins and
activated components of complement (e.g., C3a) by acting on their precursor
proteins.
 Proteoglycans--These include heparin, a well-known anticoagulant, and
chondroitin sulfate.
 Lipid Mediators:--The major lipid mediators are arachidonic acid–derived
products . This is the parent compound from which leukotrienes and
prostaglandins are produced by the 5-lipoxygenase and cyclooxygenase
pathways respectively.

 Leukotrienes--Leukotrienes C4 and D4 are the most potent vasoactive and
spasmogenic agents. they are several thousand times more active than
histamine in increasing vascular permeability and causing bronchial smooth
muscle contraction. Leukotriene B4 is highly chemotactic for neutrophils,
eosinophils, and monocytes.
 Prostaglandin D2:--This is the most abundant mediator produced in mast
cells by the cyclooxygenase pathway. It causes intense bronchospasm as
well as increased mucus secretion.
 Platelet-activating factor (PAF)--- PAF is a lipid mediator produced by
some mast cell populations but it is not derived from arachidonic acid. It
causes platelet aggregation, release of histamine, bronchospasm, increased
vascular permeability, and vasodilation.
 Cytokines:--The cytokines include: TNF, IL-1, and chemokines, which
promote leukocyte recruitment (typical of the late-phase reaction); IL-4,
which amplifies the TH2 response.
In the late-phase reaction, leukocytes are recruited that amplify and sustain the
inflammatory response without additional exposure to the triggering antigen. It is
now believed that the late-phase reaction is a major cause of symptoms in some type I
hypersensitivity disorders, such as allergic asthma. treatment of these diseases requires
the use of broad-spectrum antiinflammatory drugs, such as steroids, rather than anti-
histamine drugs, which are of benefit in the immediate reaction as occurs in allergic
rhinitis (hay fever).

Antibody-Mediated (Type II) Hypersensitivity
• Antibodies(mainly IgG , rarely IgM) that react with antigens present on cell
surfaces or in the extracellular matrix cause disease by destroying these
cells, triggering inflammation, or interfering with normal functions.
• The antibodies may be specific for normal cell or tissue antigens
(autoantibodies) or for exogenous antigens, such as chemical or microbial
proteins, that bind to a cell surface or tissue matrix.
1. Opsonization and Phagocytosis—
 Cells opsonized by IgG antibodies are recognized by phagocyte Fc
receptors, which are specific for the Fc portions of some IgG subclasses.
 When IgM or IgG antibodies are deposited on the surfaces of cells, they
may activate the complement system(C3b and C4b) by the classical
pathway. Complement deposited on the surfaces of the cells and recognized
by phagocytes that express receptors for these proteins.
 The net result is phagocytosis of the opsonized cells and their destruction.
 Complement activation on cells also leads to the formation of the
membrane attack complex, which disrupts membrane integrity by
“drilling holes” through the lipid bilayer, thereby causing osmotic lysis of
the cells.

• Antibody-mediated destruction of cells may occur by another process called
antibody-dependent cellular cytotoxicity (ADCC).
• Cells that are coated with IgG antibody are killed by a variety of effector cells,
mainly NK cells and macrophages, which bind to the target by their receptors
for the Fc fragment of IgG, and cell lysis proceeds without phagocytosis.
2. Inflammation :--When antibodies deposit in fixed tissues, such as basement
membranes and extracellular matrix, the resultant injury is due to inflammation.
The deposited antibodies activate complement, generating by-products, including
chemotactic agents (mainly C5a), which direct the migration of
polymorphonuclear leukocytes and monocytes, and anaphylatoxins (C3a and
C5a), which increase vascular permeability.
• The leukocytes are activated by engagement of their C3b and Fc receptors.
3. Cellular Dysfunction:--In some cases, antibodies directed against cell surface
receptors impair or dysregulate function without causing cell injury or
inflammation. Eg :--myasthenia gravis(antibodies reactive with acetylcholine
receptors in the motor end plates of skeletal muscles block neuromuscular
transmission and therefore cause muscle weakness.)

Immune Complex–Mediated
(Type III) Hypersensitivity
 In immune complex–mediated disorders (type III hypersensitivity), IgG and IgM
antibodies bind antigens usually in the circulation, and the antigen-antibody
complexes deposit in tissues and induce inflammation.
 The leukocytes that are recruited (neutrophils and monocytes) produce tissue
damage by release of lysosomal enzymes and generation of toxic, free radicals.
 Systemic Immune Complex Disease(Acute serum sickness)—
1. Formation of immune complexes
2. Deposition of immune complexes---complexes that are of medium size, formed
in slight antigen excess, are the most pathogenic. Organs where blood is filtered
at high pressure to form other fluids, like urine and synovial fluid, are sites
where immune complexes become concentrated and tend to deposit; hence,
immune complex disease often affects glomeruli and joints.
3. Inflammation and tissue injury--Once immune complexes are deposited in the
tissues, they initiate an acute inflammatory reaction. During this phase
(approximately 10 days after antigen administration), clinical features such as
fever, urticaria, joint pains (arthralgias), lymph node enlargement, and
proteinuria appear.

Local Immune Complex
Disease (Arthus Reaction)
• The Arthus reaction is a
localized area of tissue
necrosis resulting from
acute immune complex
vasculitis, usually elicited
in the skin.
• The reaction can be
produced experimentally
by intracutaneous
injection of antigen in a
previously immunized
animal that contains
circulating antibodies
against the antigen.
• As the antigen diffuses
into the vascular wall, it
binds the preformed
antibody, and large
immune complexes are
formed locally

T Cell–Mediated (Type IV) Hypersensitivity
The cell-mediated type of hypersensitivity is caused by inflammation resulting
from cytokines produced by CD4+ T cells and cell killing by CD8+ T cells.
 CD4+ T cell–mediated hypersensitivity induced by environmental and self
antigens is the cause of many chronic inflammatory diseases, including
autoimmune diseases.
 CD8+ cells may also be involved in some of these autoimmune diseases and
may be the dominant effector cells in certain reactions, especially those that
follow viral infections.
CD4+ T Cell–Mediated Inflammation:-
• In CD4+ T cell–mediated hypersensitivity reactions, cytokines produced by
the T cells induce inflammation that may be chronic and destructive.
• The prototype of T cell–mediated inflammation is delayed-type
hypersensitivity (DTH).
• Both TH1 and TH17 cells contribute to organ-specific diseases in which
inflammation is a prominent aspect of the pathology.
• The inflammatory reaction associated with TH1 cells is dominated by
activated macrophages, and that triggered by TH17 cells has a greater
neutrophil component

Activation of CD4+ T Cells.---
• Naïve CD4+ T cells recognize peptides displayed by dendritic cells and
secrete IL-2, which functions as an autocrine growth factor to stimulate
proliferation of the antigen responsive T cells.
• The subsequent differentiation of antigen-stimulated T cells to TH1 or TH17
cells is driven by the cytokines produced by APCs at the time of T-cell
activation.
• In some situations the APCs (dendritic cells and macrophages) produce IL-
12, which induces differentiation of CD4+ T cells to the TH1 subset.
• IFN-γ produced by these effector cells promotes further TH1 development,
thus amplifying the reaction.
Responses of Differentiated Effector T Cells:--
• Upon repeat exposure to an antigen, TH1 cells secrete cytokines, mainly IFN-
γ, which are responsible for many of the manifestations of delayed-type
hypersensitivity.
• IFN-γ-activated (“classically activated”) macrophages are altered in several
ways: their ability to phagocytose and kill microorganisms is markedly
augmented; they express more class II MHC molecules on the surface, thus
facilitating further antigen presentation; they secrete TNF, IL-1, and
chemokines, which promote inflammation; and they produce more IL-12,
thereby amplifying the TH1 response.

• Thus, activated macrophages serve to eliminate the offending antigen; if
the activation is sustained, continued inflammation and tissue injury result.
CD8+ T Cell–Mediated Cytotoxicity:--
• In this type of T cell–mediated reaction, CD8+ CTLs kill antigen-
expressing target cells.
• In a virus-infected cell, viral peptides are displayed by class I MHC
molecules and the complex is recognized by the TCR of CD8+ T
lymphocytes.
• The principal mechanism of T cell–mediated killing of targets involves
perforins and granzymes, preformed mediators contained in the
lysosome-like granules of CTLs.
• CTLs that recognize the target cells secrete a complex consisting of
perforin, granzymes, and other proteins which enters target cells by
endocytosis.
• In the target cell cytoplasm, perforin facilitates the release of the granzymes
from the complex.
• Granzymes are proteases that cleave and activate caspases, which induce
apoptosis of the target cells
• CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in
inflammatory reactions , especially following virus infections and exposure
to some contact sensitizing agents.

BIBLIOGRAPHY
• Diseases of immune system, ROBBINS AND COTRAN Pathologic
Basis of Disease, 9th edition.
• Barton F. Haynes, Kelly A. Soderberg, Anthony S. Fauci, The
Immune System in Health and Disease, Harrison’s Principles of
internal medicine,19th edition.
• David Male, Jonathan Brostoff, David B Roth and Ivan Roitt,
immunology, 7th edition.
• S.E. Marshall, Immunological factors in disease, Davidson’s
Principles and Practice of Medicine,22nd edition.
• Immunology, Jawetz, Melnick, & Adelberg’s, Medical Microbiology,
26th Edition.
• Harper’s illustrated Biochemistry ,13th edition.
• Anantanarayan and panikar’s Text book of Microbiology.

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