1-Properties and Overview of Immune Responses

-Protective immunity against microbes is mediated by the early reactions of innate immunity and the later responses of
adaptive immunity. Innate immune responses are stimulated by molecular structures shared by groups of microbes and by
molecules expressed by damaged host cells. Adaptive immunity is specific for different microbial and nonmicrobial antigens
and is increased by repeated exposures to antigen (immunologic memory).
-Humoral immunity is mediated by B lymphocytes and their secreted products, such as antibodies,
and is the mechanism of defense against extracellular microbes.
-Cell-mediated immunity is mediated by T lymphocytes and their products, such as cytokines, and is important for defense
against intracellular microbes.
-Immunity may be acquired by a response to antigen (active immunity) or conferred by transfer of antibodies or effector cells
(passive immunity). Features of the immune system are of fundamental importance for its normal functions. These include
specificity for different antigens, a diverse repertoire capable of recognizing a wide variety of antigens, memory of antigen
exposure, the capacity for rapid expansion of clones of antigen-specific lymphocytes in response to the antigen, specialized
responses to different microbes, maintenance of homeostasis, and the ability to discriminate between foreign antigens and
self-antigens.
-Lymphocytes are the only cells capable of specifically recognizing antigens and are thus the principal cells of adaptive
immunity. The total population of lymphocytes consists of many clones, each with a unique antigen receptor and specificity.
The two major subsets of lymphocytes are B cells and T cells, and they differ in their antigen receptors and functions.
Specialized antigen-presenting cells capture microbial antigens and display these antigens for recognition by lymphocytes.
The elimination of antigens often requires the participation of various effector cells.
-The adaptive immune response is initiated by the recognition of foreign antigens by specific lymphocytes. Lymphocytes
respond by proliferating and by differentiating into effector cells, whose function is to eliminate the antigen, and into memory
cells, which show enhanced responses on subsequent encounters with the antigen. The activation of lymphocytes requires
antigen and additional signals that may be provided by microbes or by innate immune responses to microbes.
-CD4+ helper T lymphocytes help macrophages to eliminate ingested microbes and help B cells to produce antibodies.
CD8+ CTLs kill cells harboring intracellular pathogens, thus eliminating reservoirs of infection.
-Antibodies, the products of B lymphocytes, neutralize the infectivity of microbes and promote the elimination of microbes by
phagocytes and by activation of the complement system.

2-Cells and Tissues of the Immune System

-The anatomic organization of the cells and tissues of the immune system is of critical importance for the generation of
effective innate and adaptive immune responses. This organization permits the rapid delivery of innate immune cells,
including neutrophils and monocytes, to sites of infection and permits a small number of lymphocytes specific for any one
antigen to locate and respond effectively to that antigen regardless of where in the body the antigen is introduced.
-The cells that perform the majority of effector functions of innate and adaptive immunity are phagocytes (including
neutrophils and macrophages), APCs (including macrophages and dendritic cells), and lymphocytes.
-Neutrophils, the most abundant blood leukocyte with a distinctive multilobed segmented nucleus and abundant cytoplasmic
lysosomal granules, are rapidly recruited to sites of infection and tissue injury, where they perform phagocytic functions.
-Monocytes are the circulating precursors of tissue macrophages. All tissues contain resident macrophages, which are
phagocytic cells that ingest and kill microbes and dead host cells and secrete cytokines and chemokines that promote the
recruitment of leukocytes from the blood and initiate the repair of damaged tissues.
-APCs function to display antigens for recognition by lymphocytes and to promote the activation of lymphocytes. APCs
include dendritic cells, mononuclear phagocytes, and FDCs.
-B and T lymphocytes express highly diverse and specific antigen receptors and are the cells responsible for the specificity
and memory of adaptive immune responses. Many surface molecules are differentially expressed on different subsets of
lymphocytes as well as on other leukocytes, and these are named according to the CD nomenclature.
-Innate lymphoid cells are effector cells of the innate immune system, some of which perform similar functions to CD4+ or
CD8+ effector T cells. These cells, which include NK cells, do not express highly diverse, clonally distributed antigen
receptors.
-Both B and T lymphocytes arise from a common precursor in the bone marrow. B cell development proceeds in the bone
marrow, whereas T cell precursors migrate to and mature in the thymus. After maturing, B and T cells leave the bone
marrow and thymus, enter the circulation, and populate peripheral lymphoid organs.
-Naive B and T cells are mature lymphocytes that have not been stimulated by antigen. When they encounter antigen, they
proliferate, and differentiate into effector lymphocytes that have functions in protective immune responses.
-Effector B lymphocytes are antibody-secreting plasma cells. Effector T cells include cytokine secreting CD4+ helper T cells
and CD8+ cytotoxic T lymphocytes.
-Some of the progeny of antigen-activated B and T lymphocytes differentiate into memory cells that survive for long periods
in a quiescent state. These cells are responsible for the rapid and enhanced responses to subsequent exposures to antigen.
-The organs of the immune system may be divided into the generative, or primary, lymphoid organs (bone marrow and
thymus), where lymphocytes mature, and the peripheral, or secondary, organs (lymph nodes, spleen, and mucosal and
cutaneous
immune systems), where naive lymphocytes are activated by antigens.
-Bone marrow contains the stem cells for all blood cells, including lymphocytes, and is the site of maturation of all of these
cell types except T cells, which mature in the thymus.
-Extracellular fluid (lymph) is constantly drained from tissues through lymphatics into lymph nodes and eventually into the
blood. Microbial antigens are carried in soluble form and within dendritic cells in the lymph to lymph nodes, where they are
recognized by lymphocytes.
-Lymph nodes are encapsulated secondary lymphoid organs located throughout the body along lymphatics, where naive B
and T cells respond to antigens that are collected by the lymph from peripheral tissues.
-The spleen is an encapsulated organ in the abdominal cavity where senescent or opsonized blood cells are removed from
the circulation, and in which lymphocytes respond to blood-borne antigens.
-Lymph nodes and the white pulp of the spleen are organized into B cell zones (the follicles) and T cell zones. The T cell
areas are also the sites of residence of mature dendritic cells, which are APCs specialized for the activation of naive T cells.
FDCs reside in the B cell areas and serve to activate B cells during humoral immune responses to protein antigens. The
development of secondary lymphoid tissues depends on cytokines and lymphoid tissue inducer cells.

3-Leukocyte Circulation and Migration into Tissues

-Leukocyte migration from blood into tissues occurs through post-capillary venules and depends on adhesion molecules
expressed on the leukocytes and vascular endothelial cells as well as chemokines.
-Selectins are carbohydrate-binding adhesion molecules that mediate low-affinity interaction of leukocytes with endothelial
cells, the first step in leukocyte migration from blood into tissues. E-selectin and P-selectin are expressed on cytokine
activated endothelial cells and bind to selectin ligands on leukocytes, and L-selectin is expressed on leukocytes and binds
ligands on endothelial cells.
-Integrins are a large family of adhesion molecules, some of which mediate tight adhesion of leukocytes with activated
endothelium, a critical step in leukocyte migration from blood into tissues. The important leukocyte integrins include LFA-1
and VLA-4, which bind to ICAM-1 and VCAM-1, respectively, on endothelial cells. Chemokines and other signals at sites
of infection increase the affinity of integrins on leukocytes, and various cytokines (TNF, IL-1) increase the expression of
integrin ligands on endothelium.
-Migration of leukocytes from blood into tissues involves a series of sequential interactions with endothelial cells, starting with
low-affinity leukocyte binding to and rolling along the endothelial surface (mediated by selectins and selectin ligands). Next,
the leukocytes become firmly bound to the endothelium through interactions of leukocyte integrins binding to Ig superfamily
ligands on the endothelium.
-Lymphocyte recirculation is the process by which naive lymphocytes continuously migrate from the blood into the secondary
lymphoid organs through HEVs, back into the blood through lymphatics, and into other secondary lymphoid organs. This
process maximizes the chance of naïve T cell encounter with the antigen it recognizes and is critical for the initiation of
immune responses.
-Naive B and T cells migrate preferentially to lymph nodes; this process is mediated by binding of L-selectin on lymphocytes
to peripheral lymph node addressin on HEVs in lymph nodes and by binding of the CCR7 receptor on lymphocytes to the
chemokines CCL19 and CCL21, which are produced in lymph nodes.
-The effector and memory lymphocytes that are generated by antigen stimulation of naive cells exit the lymph node by a
process dependent on the sphingosine-1 phosphate receptor on the lymphocytes and a gradient of sphingosine-1
phosphate.
-Effector T cells have decreased expression of L-selectin and CCR7 but increased expression of integrins and E-selectin
and P-selectin ligands, and these molecules mediate binding to endothelium at peripheral inflammatory sites. Effector and
memory lymphocytes also express receptors for chemokines that are produced in infected peripheral tissues

4- Innate Immunity

-The innate immune system provides the first line of host defense against microbes. The mechanisms
of innate immunity exist before exposure to microbes.
-The cellular components of the innate immune system include epithelial barriers, leukocytes (neutrophils, macrophages, NK
cells, lymphocytes with invariant antigen receptors, and mast cells).
-The innate immune system uses cell-associated pattern recognition receptors, present on plasma and endosomal
membranes and in the cytosol, to recognize structures called pathogen-associated molecular patterns (PAMPs), which are
shared by microbes, are not present on mammalian cells, and are often essential for survival of the microbes, thus limiting
the capacity of microbes to evade detection by mutating or losing expression of these molecules. In addition, these receptors
recognize molecules made by the host but whose expression or location indicates cellular damage; these are called
damage-associated molecular patterns (DAMPs).
-TLRs, present on the cell surface and in endosomes, are the most important family of pattern recognition receptors,
recognizing a wide variety of ligands, including bacterial cell wall components and microbial nucleic acids. Cytosolic pattern
recognition receptors exist that recognize microbial molecules. These receptors include the RIG-like receptors (RLRs), which
recognize viral RNA, cytosolic DNA sensors (CDSs), and NOD-like receptors (NLRs), which recognize bacterial cell wall
constituents and also sense intracellular crystals, reactive oxygen species, and various other indicators of infection or cell
injury.
-Pattern recognition receptors, including TLRs and RLRs, signal to activate the transcription factors NF-κB and AP-1, which
promote inflammatory gene expression, and the IRF transcription factors, which stimulate expression of the antiviral type I
interferon genes. The inflammasome, a specialized NLR-containing complex that forms in response to PAMPs and DAMPs,
is composed of a NOD-like receptor, an adaptor, and the enzyme caspase-1, the main function of which is to produce active
forms of the inflammatory cytokines IL-1 and IL-18.
-Soluble pattern recognition and effector molecules are found in the plasma, including pentraxins (e.g., CRP), collectins (e.g.,
MBL), and ficolins. These molecules bind microbial ligands and enhance clearance by complement-dependent and
complement-independent mechanisms.
-NK cells are one of several kinds of innate lymphoid cells that have effector functions shared by T lymphocytes, but do not
express T cell receptors for antigen. NK cells defend against intracellular microbes by killing infected cells and providing a
source of the macrophage-activating cytokine IFN-γ. NK cell recognition of infected cells is regulated by a combination
of activating and inhibitory receptors. Inhibitory receptors recognize class I MHC molecules, because of which NK cells do
not kill normal host cells but do kill cells in which class I MHC expression is reduced, such as virus-infected cells.
-The complement system includes several plasma proteins that become activated in sequence by proteolytic cleavage to
generate fragments of the C3 and C5 proteins, which promote inflammation, or opsonize and promote phagocytosis of
microbes. Complement activation also generates membrane pores that kill some types of bacteria. The complement system
is activated on microbial surfaces and not on normal host cells because microbes lack regulatory proteins that inhibit
complement.
-In innate immune responses, complement is activated mainly spontaneously on microbial cell surfaces and by mannose-
binding lectin to initiate the alternative and lectin pathways, respectively.
-The two major effector functions of innate immunity are to induce inflammation, which involves the delivery of microbe-killing
leukocytes and soluble effector molecules from blood into tissues, and to block viral infection of cells by the antiviral actions
of type 1 interferons. Both types of effector mechanism are induced by the PAMPs and DAMPs, which initiate signaling
pathways in tissue cells and leukocytes that activate transcription factors and lead to the expression of cytokines and other
inflammatory mediators
-Several cytokines produced mainly by activated macrophages mediate inflammation. TNF and IL-1 activate endothelial
cells, stimulate chemokine production, and increase neutrophil production by the bone marrow. IL-1 and TNF both induce IL-
6 production, and all three cytokines mediate systemic effects, including fever and acute-phase protein synthesis by the liver.
IL-12 and IL-18 stimulate production of the macrophage-activating cytokine IFN-γ by NK cells and T cells. These cytokines
function in innate immune responses to different classes of microbes, and some (IL-1, IL-6, IL-12, IL-18) modify adaptive
immune responses that follow the innate immune response.
-Neutrophils and monocytes (the precursors of tissue macrophages) migrate from blood into inflammatory sites during innate
immune responses because of the effects of cytokines and chemokines produced by PAMP- and DAMP-stimulated tissue
cells. Neutrophils and macrophages phagocytose microbes and kill them by producing ROS, nitric oxide, and enzymes in
phagolysosomes. Macrophages also produce cytokines that stimulate inflammation and promote tissue remodeling at sites
of infection. Phagocytes recognize and respond to microbial products by several different types of receptors, including TLRs,
C-type lectins, scavenger receptors, and N-formyl met-leu-phe receptors.
-Molecules produced during innate immune responses stimulate adaptive immunity and influence the nature of adaptive
immune responses.
-Dendritic cells activated by microbes produce cytokines and costimulators that enhance T cell activation and differentiation
into effector T cells.
-Complement fragments generated by the alternative pathway provide second signals for B cell activation and antibody
production.
-Innate immune responses are regulated by negative feedback mechanisms that limit potential damage to tissues. IL-10 is a
cytokine that is produced by and inhibits activation of macrophages and dendritic cells.
-Inflammatory cytokine secretion is regulated by autophagy gene products. Negative signaling pathways
block the activating signals generated by pattern recognition receptors and inflammatory cytokines.

5- Antibodies and Antigens

-Antibodies, or immunoglobulins, are a family of structurally related glycoproteins produced in membrane-bound or secreted
form by B lymphocytes.
-Membrane-bound antibodies serve as receptors that mediate the antigen-triggered activation of B cells.
-Secreted antibodies function as mediators of specific humoral immunity by engaging various effector mechanisms that
serve to eliminate the bound antigens.
-The antigen-binding regions of antibody molecules are highly variable, and any one individual has the potential to produce
millions of different antibodies, each with distinct antigen specificity.
-All antibodies have a common symmetric core structure of two identical covalently linked heavy chains and two identical
light chains, each linked to one of the heavy chains. Each chain consists of two or more independently folded Ig domains of
about 110 amino acids containing conserved sequences and intrachain disulfide bonds.
-The N-terminal domains of heavy and light chains form the V regions of antibody molecules, which differ among antibodies
of different specificities. The V regions of heavy and light chains each contain three separate hypervariable regions of about
10
amino acids that are spatially assembled to form the antigen-combining site of the antibody molecule.
-Antibodies are classified into different isotypes and subtypes on the basis of differences in the heavy chain C regions, which
consist of three or four Ig C domains, and these classes and subclasses have different functional properties. The antibody
classes are called IgM, IgD, IgG, IgE, and IgA. Both light chains of a single Ig molecule are of the same light chain isotype,
either κ or λ, which differ in their single C domains.
-Most of the effector functions of antibodies are mediated by the C regions of the heavy chains, but these functions are
triggered by binding of antigens to the combining site in the V region.
-Monoclonal antibodies are produced from a single clone of B cells and recognize a single antigenic determinant.
Monoclonal antibodies can be generated in the laboratory and are widely used in research, diagnosis, and therapy.
-Antigens are substances specifically bound by antibodies or T lymphocyte antigen receptors. Antigens that bind to
antibodies include a wide variety of biologic molecules, including sugars, lipids, carbohydrates, proteins, and nucleic acids.
This is in contrast to most T cell antigen receptors, which recognize only peptide antigens.
-Macromolecular antigens contain multiple epitopes, or determinants, each of which may be recognized by an antibody.
Linear epitopes of protein antigens consist of a sequence of adjacent amino acids, and conformational determinants are
formed by folding of a polypeptide chain.
-The affinity of the interaction between the combining site of a single antibody molecule and a single epitope is generally
represented by the dissociation constant (Kd) calculated from binding data. Polyvalent antigens contain multiple identical
epitopes to which identical antibody molecules can bind. Antibodies can bind to two or, in the case of IgM, up to 10 identical
epitopes simultaneously, leading to enhanced avidity of the antibody-antigen interaction.

-The relative concentrations of polyvalent antigens and antibodies may favor the formation of immune complexes that may
deposit in tissues and cause damage.
-Antibody binding to antigen can be highly specific, distinguishing small differences in chemical structures, but cross-
reactions may also occur in which two or more antigens may be bound by the same antibody.
-Several changes in the structure of antibodies made by one clone of B cells may occur in the course of an immune
response. B cells initially produce only membrane-bound Ig, but in activated B cells and plasma cells, Ig with the same
antigen-binding
specificity as the original membrane-bound Ig receptor is secreted.
-Changes in the use of C region gene segments without changes in V regions are the basis of isotype switching, which leads
to changes in effector function without a change in specificity. Point mutations in the V regions of an antibody specific for an
antigen lead to increased affinity for that antigen (affinity maturation).

6-Major Histocompatibility Complex Molecules and Antigen Presentation to T Lymphocytes

-Most T cells recognize antigens only in the form of peptides displayed by the products of self MHC genes on the surface of
APCs. CD4+ helper T lymphocytes recognize antigens in association with class II MHC gene products (class II MHC–
restricted recognition), and CD8+ CTLs recognize antigens in association with class I MHC gene products (class I MHC–
restricted recognition).
-Specialized APCs, such as dendritic cells, macrophages, and B lymphocytes, capture extracellular protein antigens,
internalize and process them, and display class II–associated peptides to CD4+ T cells. Dendritic cells are the most efficient
APCs for initiating primary responses by activating naïve T cells, and macrophages and B lymphocytes present antigens to
differentiated helper T cells in the effector phase of cell-mediated immunity and in humoral immune responses, respectively.
All nucleated cells can present class I–associated peptides, derived from cytosolic proteins such as viral and tumor antigens,
to CD8+ T cells.
-The MHC is a large genetic region coding for highly polymorphic, codominantly expressed class I and class II MHC
molecules.

-Class I MHC molecules are composed of an α (or heavy) chain in a non-covalent complex with a non-polymorphic

polypeptide called β2-

microglobulin. Class II MHC molecules contain

two MHC-encoded polymorphic chains, an α chain

and a β chain. Both classes of MHC molecules

consist of an extracellular peptide-binding cleft,

a non-polymorphic Ig-like region, a transmembrane

region, and a cytoplasmic region. The peptide-

binding cleft of MHC molecules has α-helical

sides and an eight-stranded antiparallel β-pleated

sheet floor. The Ig-like domains of class I and class

II MHC molecules contain the binding sites for the

T cell coreceptors CD8 and CD4, respectively. The

polymorphic residues of MHC molecules are localized

to the peptide-binding domain.

The function of class I and class II MHC molecules

is to bind peptide antigens and display them for recognition

by antigen-specific T lymphocytes. Peptide

antigens associated with class I MHC molecules are

recognized by CD8+ T cells, whereas class II MHC–

associated peptide antigens are recognized by CD4+

T cells. MHC molecules bind only one peptide at

a time, and all of the peptides that bind to a particular

MHC molecule share common structural

motifs. Every MHC molecule has a broad specificity

for peptides and can bind multiple peptides that

have common structural features, such as anchor

residues.

The peptide-binding cleft of class I MHC molecules

can accommodate peptides that are 6 to 16

amino acid residues in length, whereas the cleft

of class II MHC molecules allows larger peptides

(up to 30 amino acid residues in length or more)

to bind. Some polymorphic MHC residues determine

the binding specificities for peptides by

forming structures called pockets that interact

with complementary residues of the bound peptide,

called anchor residues. Other polymorphic

MHC residues and some residues of the peptide

are not involved in binding to MHC molecules

but instead form the structure recognized by T

cells.

Class I MHC molecules are expressed on all nucleated

cells, whereas class II MHC molecules are

expressed mainly on specialized APCs, such as

dendritic cells, macrophages, and B lymphocytes,

and a few other cell types, including endothelial

cells and thymic epithelial cells. The expression

of MHC gene products is enhanced by inflammatory

and immune stimuli, particularly cytokines

like IFN-γ, which stimulate the transcription of

MHC genes.

Antigen processing is the conversion of native proteins

into MHC-associated peptides. This process

consists of the introduction of exogenous protein

antigens into vesicles of APCs or the synthesis of

antigens in the cytosol, the proteolytic degradation

of these proteins into peptides, the binding

of peptides to MHC molecules, and the display of

the peptide-MHC complexes on the APC surface

for recognition by T cells. Thus, both extracellular

and intracellular proteins are sampled by these

antigen-processing pathways, and peptides derived

from both normal self proteins and foreign

proteins are displayed by MHC molecules for surveillance

by T lymphocytes.

For the class I MHC pathway, cytosolic proteins

are proteolytically degraded in the proteasome,

generating peptides that bind to class I MHC molecules.

These peptides are delivered from the cytosol

to the ER by an ATP-dependent transporter

called TAP. Newly synthesized class I MHC–β2-

microglobulin dimers in the ER are associated

with the TAP complex and receive peptides transported

into the ER. Stable complexes of class I

MHC molecules with bound peptides move out

of the ER, through the Golgi complex, to the cell

surface.

For the class II MHC pathway, extracellular proteins

are internalized into endosomes, where these

proteins are proteolytically cleaved by enzymes

that function at acidic pH. Newly synthesized

class

II MHC molecules associated with the Ii are transported

from the ER to the endosomal vesicles.

Here the Ii is proteolytically cleaved, and a small

peptide remnant of the Ii, called CLIP, is removed

from the peptide-binding cleft of the MHC molecule

by the DM molecules. The peptides that were

generated from extracellular proteins then bind to

the available cleft of the class II MHC molecule,

and the trimeric complex (class II MHC α and β

chains and peptide) moves to and is displayed on

the surface of the cell.

These pathways of MHC-restricted antigen presentation

ensure that most of the body’s cells are

screened for the possible presence of foreign antigens.

The pathways also ensure that proteins

from extracellular microbes preferentially generate

peptides bound to class II MHC molecules for

recognition by CD4+ helper T cells, which activate

effector mechanisms that eliminate extracellular

antigens. Conversely, proteins synthesized by intracellular

(cytosolic) microbes generate peptides

bound to class I MHC molecules for recognition

by CD8+ CTLs, which function to eliminate cells

harboring intracellular infections. The immunogenicity

of foreign protein antigens depends on

the ability of antigen-processing pathways to generate

peptides from these proteins that bind to self

MHC molecules.