IMMUNOPATHOLOGY

1 By
Dr. Uchechukwu Brian Eziagu
UNIUYO Medical Students Lecture 2023
If you are always trying to be normal,
you will never know how

AMAZING
you can be.

Maya Angelou – American Poet

BE THE CHANGE

you want to see

IN THE WORLD. Mahatma Gandhi – Civil Rights Activist

 COMPONENTS OF THIS
IMMUNOPATHOLOGY LECTURE SERIES
•The Normal Immune Response
•Hypersensitivity and Autoimmune
Disorders
•Rejection of Tissue Transplants
•Immunodeficiency Syndromes
•Amyloidosis 4
5
 水滴石穿，绳锯木断
WATER DROPS PIERCE STONE;
ROPE SAWS CUT WOOD.
Chinese Saying
 Insert or Drag & Drop Photo

THE
NORMAL
IMMUNE
RESPONSE
There is not a particle of life which does not bear

Poetry within it.

Gustav Flaubert – French Novelist

 OUTLINE FOR THE NORMAL IMMUNE RESPONSE

• Introduction to Immunity
• Cells of the Immune System
• Cytokines
• Tissues of the Immune System
• Major Histocompatibility Complex (MHC)
Molecules
• Overview of Lymphocyte Activation and Immune
Responses
9
Introduction
to Immunity

10
 INTRODUCTION TO IMMUNITY

• The normal immune system is essential

for protection against infection.
• Immune system is like a double-edged
sword.
• Though it is protective in most of the
situations, sometimes a hyperactive
immune system may cause fatal diseases. 11
 INTRODUCTION TO IMMUNITY

• Definition: Immunity is resistance (i.e.,

defense mechanism) exhibited by the host
against invasion by any foreign antigen,
including microorganisms.
• Types: There are two types namely:
• Innate and
• Adaptive immunity.
12
 INTRODUCTION TO IMMUNITY

• Innate (Natural/Native) Immunity

• General Features
• First line of defense present at birth.
• Provides immediate initial protection against an invading
pathogen.
• Does not depend on the prior contact with foreign antigens or
microbes.
• Lacks specificity, but is highly effective.
• No memory, and no self/non-self recognition.
• Triggers the adaptive immune response.
• No memory is seen. 13
 INTRODUCTION TO IMMUNITY
• Major Components
• 1. Physical/anatomical barriers: These include epithelium lining skin,
gastrointestinal and respiratory tracts act as mechanical barriers, and
produce anti-microbial molecules such as defensins.
• 2. Cells:
• a. Phagocytic cells consist mainly of monocytes (macrophages in
tissue) and neutrophils in the blood. Phagocytic cells use several
receptors to sense microbes and are called “microbial sensors”
(pattern recognition receptors).
• a) Pathogen-associated molecular patterns (PAMPs): Microbes have
few highly conserved common molecular structures shared by entire
classes of pathogens. These structures are called pathogen-associated
molecular patterns (PAMPs) and are essential for the infectivity of
these pathogens. 14
 INTRODUCTION TO IMMUNITY
• b) Pattern recognition receptors (PRRs): Phagocytic cells
involved in innate immunity recognize PAMP using a group of
cellular receptors (microbial sensors) called pattern recognition
receptors. Examples of PRRs:
• ◆ Toll-like receptors (TLRs). These are transmembrane receptors
and about 10 types of human TLRs have been identified. Each
receptor recognizes a unique set of microbial patterns. E.g., TLR2
recognizes various ligands (e.g., lipoteichoic acid) expressed by
gram +ve bacteria, TLR4 recognizes gram -ve
lipopolysaccharides (LPS)
• ◆ Receptors for mannose residues
• ◆ Nucleotide-Oligomerization Domain protein-like (NOD-like)
receptors: They are in the cytoplasm and serve as intracellular
sensors for microbial products. 15
 INTRODUCTION TO IMMUNITY
• b. Dendritic cells: These cells function as antigen-presenting cells (APCs) to
T cells. They produce type I interferons (IFN) (e.g., IFN-α), which inhibit
viral infection and replication.
• c. Natural killer (NK) cells: They provide defense against many viral
infections and other intracellular pathogens.
• 3. Soluble molecules in the blood and tissues:
• Complement system
• Proteins that coat microbes and aid in phagocytosis, e.g., mannose-
binding lectin
• C-reactive protein
• Functions of Innate Immune Response
• Inflammation and destruction of invading microbe
• Antiviral defense is mediated by dendritic cells and NK cells. 16
17
 Activation of
complement.
The activated
complement factors
remain attached to the
antigen-antibody
complex on the surface
of the antigen-bearing
cell. Soluble
complement fragments
such as C3a and C5a are
split off and pass into
the surrounding
interstitial tissue. The
roles of other
fragments (eg, C3d,
C3g) are not clear at
present. 18
 INTRODUCTION TO IMMUNITY
• Adaptive Immunity
• If the innate immune system fails to provide effective protection against invading
microbes, the adaptive immune system is activated.
• General Features
• Second line of defense acquired during life
• Capable of recognizing both microbial and nonmicrobial substances
• Takes more time to develop and is more powerful than innate immunity
• Long-lasting protection
• Prior exposure to antigen is present
• Three characteristic features are:
• 1) Specificity,
• 2) Diversity and
• 3) Memory. 19
 INTRODUCTION TO IMMUNITY
• Components
• 1. Humoral immunity: B lymphocytes (  Plasma cells and their soluble
protein products called antibodies) and helper T cells.
• 2. Cellular immunity: T lymphocytes and their soluble products are called
cytokines.
• Functions of Adaptive Immune Response
• Antibodies: Protection against extracellular microbes in the blood, mucosal
secretions, and tissues.
• T lymphocytes:
• Defense against viruses, fungi, and intracellular bacteria either by direct
killing of infected cells by cytotoxic T lymphocytes or by activation of
phagocytes to kill the ingested microbes.
• Important immunoregulatory role, orchestrating and regulating the
responses of other components of the immune system. 20
INTRODUCTION TO IMMUNITY

21
22
CELLS OF
THE
IMMUNE
SYSTEM
23
 CELLS OF THE IMMUNE SYSTEM
• Cells of immune responses (lymphocytes and other cells) migrate
among lymphoid and other tissues and the vascular and lymphatic
circulations.
• Naïve Lymphocytes
• These are mature lymphocytes which have not encountered the
antigen (immunologically inexperienced).
• After the lymphocytes are activated by recognition of antigens,
they differentiate into
• Effector cells: They perform the function of eliminating microbes.
• Memory cells: They live in a state of heightened awareness and
are better able to combat the microbe in case it infects again.
24
 CELLS OF THE IMMUNE SYSTEM
• T LYMPHOCYTES
• Development: T (thymus derived) lymphocytes develop from precursors in the
thymus.
• Distribution: Mature T cells are found in
• – Peripheral blood where it constitute 60% to 70% of lymphocytes
• – T-cell zones of peripheral lymphoid organs namely paracortical region of
lymph node and periarteriolar sheaths of spleen.
• T-cell Receptor: T cell recognizes a specific cell-bound antigen by means of an
antigen specific T-cell receptor (TCR).
• Markers: Leukocyte cell surface molecules are named systematically by assigning
them a 'cluster of differentiation' (CD) antigen number that helps in their
identification.
• – Primarily T-cell associated CD molecules: CD1, CD3, CD4, CD5, and CD8.
• – CD3 is involved in signal transduction and is also known as pan T-cell marker.25
 CELLS OF THE IMMUNE SYSTEM
• T LYMPHOCYTES
• Subsets of T lymphocytes: Naïve T cells can differentiate into two
subtypes namely CD4 and CD8.
• Both subtypes serve as “coreceptors” in T-cell activation.
• They are called coreceptors because they work with the antigen
receptor in response to antigen.
• CD4+ T cell: This subset of T cells have CD4 molecules and are
called helper T cells.
• They constitute about 60% of mature T cells.
• The CD4 cells function as cytokine-secreting helper cells that
help macrophages and B lymphocytes to combat infections.
• They are subcategorized as TH1, TH2 and TH17 CD4+ T cells. 26
 CELLS OF THE IMMUNE SYSTEM
• CD8+ T cell: This subset of T cells have CD8
molecules and are called cytotoxic/killer T cells.
• They constitute about 30% of T cells.
• CD8+ T cells function as cytotoxic (killer) T
lymphocytes (CTLs) to destroy host cells harboring
microbes and tumor cells.
• When the antigen-presenting cells (APCs) present
antigen to T cells, CD4+ T cells recognize and bind
only to class II MHC molecules present on the
antigen and CD8+ T cells bind only to class I MHC 27
28
 CELLS OF THE IMMUNE SYSTEM

• B LYMPHOCYTES
• Development: B (bone marrow derived) lymphocytes develop
from precursors in the bone marrow.
• Distribution:
• – Peripheral blood: Mature B cells constitute 10% to 20% of the
circulating peripheral lymphocyte population
• – Peripheral lymphoid tissues: Lymph nodes (cortex), spleen
(white pulp), and mucosa-associated lymphoid tissues {MALT},
pharyngeal tonsils, and Peyer's patches of GIT.
• B-cell Receptor (BCR): B cells have receptors composed of IgM
and IgD on their surface and have unique antigen specificity. 29
 CELLS OF THE IMMUNE SYSTEM
• B LYMPHOCYTES
• Functions of B cells:
• All the mature, naive B cells express membrane-bound immunoglobulins
(Ig) on their surface that functions as B cell receptors (BCRs) for
antigen recognition and interactions.
• Thus B cells recognize antigen via these BCRs.
• – Production of antibodies:
• The primary function of B cells is to produce antibodies.
• After stimulation by antigen and other signals, B cells develop into plasma cells.
• These cells secrete antibodies which are the mediators of humoral immunity.
• – Antigen presenting cell: B cells also serve as APCs and are very efficient
at antigen processing.
• Markers: B cell markers include CD 10 (CALLA), CD19, CD20, CD21
(EBV receptor), CD23, CD79a. 30
31
 Lymphocyte proliferation.
Lymphocyte proliferation in the
fetus is genetically controlled—a
small number of stem cells
proliferate to produce the
numerous T and B lymphocytes
populating the lymphoid tissues
at birth. Diversification of
antigen receptors takes place at
this stage. Lymphocyte
proliferation in postnatal life
occurs as part of the immune
response—only those
lymphocytes capable of
recognizing a particular antigen
respond to produce effector cells
that respond to the given
antigen. 32
Gene rearrangement in the kappa
(ƙ) multigene, producing multiple
antibodies.
The kappa multigene contains more
than 300 V gene segments, any one
of which can become apposed to a J
chain (note that only 4 of the 5 J
chains are functionally active) to
produce more than 1200 (300 x 4)
possible kappa chain variable
regions. When conjoined with a
heavy chain, for which there are
more than 9600 choices (200 [VH
segments] x 12 [DH segments] x 4
[JH segments]), the number of
different possible antibody
specificities is very large.
Recombination of J segments is 33
omitted in this figure for simplicity.
Reaction of antibody with
antigen.
The same or different
antibodies acting in the
ways depicted in the
diagram have often been
called precipitins,
agglutinins, opsonins,
lysins, or neutralizing
antibodies, depending on
the specific effect
produced. (M,
macrophage; NK, natural
killer cell; C*, 34
 T cell development in the
human fetal thymus,
depicting the appearance and
disappearance of T cell
phenotypic markers—
detected by monoclonal
antibodies—during T cell
proliferation and maturation.
*CD71 is an early T cell
proliferation marker. CD38
(stem cell marker) and
nuclear tdt (terminal
deoxynucleotidyl transferase)
occur in early T cells but also
are found in early B cells. 35
B cell development in the fetus and
in postnatal life. Like T cell
differentiation, B cell differentiation
occurs in the fetus and is
accompanied by phenotypic
changes. Gene rearrangement
occurs, involving the immunoglobulin
genes, to produce a multiplicity of B
cells, each potentially able to
produce immunoglobulins of a
different specificity. Expansion of this
population gives rise to the B cells
present at birth. Exposure to
antigens postnatally produces
selective proliferation of B cells able
to recognize the antigen. The end
result is differentiation of plasma
cells and production of antibody.
Surface immunoglobulins and other
phenotypic markers are expressed at
various times during this 36

differentiation process.
 The immunoglobulin gene superfamily is defined as a series of genes that appear to share an evolutionary homology (i.e., a
common ancestry). Gene family members have in common the ability to code for polypeptide chains containing one or more
peptide loops stabilized by disulfide bonds. In attempting to understand the complexities of the immune system, it may be
helpful to realize that many of the surface molecules that play a part in cell recognition are closely related, including
immunoglobulins, T cell antigen receptors, MHC molecules, and the T cell surface antigens CD2, CD3, CD4, and CD8.

37
 Structure of the basic
immunoglobulin molecule
(IgG).
IgD and IgE have a similar
structure; secreted IgA is a dimer
of this configuration; IgM is a
pentamer.
Fab and Fc are fragments
produced by enzyme digestion
of the immunoglobulin molecule
at the hinge region. Fc contains
part of both heavy chains; Fab
contains a light chain and part of
a heavy chain, with one antigen-
binding site. F(ab)'2 represents
two Fab units still conjoined. The
structure, as shown, is simplified
by omission of polypeptide loops
stabilized by disulfide bonds in
both heavy and light chains 38
39
 CELLS OF THE IMMUNE SYSTEM
• DENDRITIC CELLS
• As the name suggests these cells have numerous fine cytoplasmic processes that resemble
dendrites.
• These are important antigen presenting cells (APC) in the body and can be of the following
types:
• Types: Two functionally different types of dendritic cells are
• – Interdigitating dendritic cells (IDC) or dendritic cells: They are the most important
antigen-presenting cells (APCs) for initiating primary T-cell responses against protein
antigens.
• ◆ Location:
• 1) Common location is below the epithelial lining: Immature dendritic cells
within the epidermis are known as Langerhans cells.
• 2) Interstitia of all tissues.
• – Follicular dendritic cell:
• ◆ Location: It is present in the germinal centers of lymphoid follicles in the spleen and
lymph nodes (hence named as follicular dendritic cell). 40
 CELLS OF THE IMMUNE SYSTEM
• MACROPHAGES
• Macrophages are a part of the mononuclear phagocyte system.
• Role in adaptive immune responses:
• Processing of antigen: Macrophages process the antigens present in the phagocytosed
microbes and protein antigens. After processing the antigen is presented to T cells
and thus, they function as APCs in T-cell activation.
• Effector cell in immunity:
• Cell-mediated immunity: Macrophages are main effector cells in certain types of
cell mediated immunity, the reaction that serves to eliminate intracellular
microbes. In this type of response, T cells activate macrophages and increase their
capability to kill ingested microbes.
• Humoral immunity: Macrophages also participate in the effector phase of humoral
immunity. Macrophages get activated by INF-α.
• Phagocytosis: Macrophages efficiently phagocytose and destroy microbes which are
opsonized (coated) by IgG or C3b through their respective receptors. 41
 CELLS OF THE IMMUNE SYSTEM
• NATURAL KILLER (NK) CELLS
• Non-phagocytic large (little larger than small lymphocytes) granular
(numerous cytoplasmic azurophilic granules) lymphocytes.
• Markers: They do not bear the markers for T or B cells.
• Two cell surface molecules, CD16 and CD56, are commonly used to identify
them.
• Comprise about 5% to 15% of human peripheral lymphoid cells.
• Function:
• NK cells provide defense against many viral infections and other intracellular
pathogens and also has antitumor activity, causing lysis of cells with which they
react.
• Killing of the cells is performed without prior exposure to or activation by
these microbes or tumors.
• Because of this ability NK cells acts an early line of defense against viral 42
 CELLS OF THE IMMUNE SYSTEM
• NATURAL KILLER (NK) CELLS
• They recognize abnormal cells in two ways:
• Antibody-dependent cellular cytotoxicity (ADCC): NK cells
bear (CD16) immunoglobulin receptors (FcR) and bind
antibody-coated targets leading to lysis of these cells.
• This phenomenon is called as antibody-dependent cell-
mediated cytotoxicity (ADCC).
• Perforin-granzymes system: NK cells have a variety of surface
receptors for MHC (major histocompatibility complex) class I.
These receptors can be either having inhibitory or activating
functions. The function of NK cells is regulated by a balance
between signals from these activating and inhibitory 43
 CELLS OF THE IMMUNE SYSTEM
• NATURAL KILLER (NK) CELLS
• Inhibitory receptors: MHC class I molecules are normally expressed on healthy/normal
host cells.
• NK cell inhibitory receptors recognize self–class I MHC molecules, which are
expressed on all normal healthy host cells (MHC class I positive).
• They prevent NK cells from killing normal host cells by inhibiting the death pathway.
• Activating receptors: If the target cell with which NK cells interact, do not have MHC
molecules on their surface, there is no binding of MHC receptor of NK cells.
• The downregulation of class I MHC molecules (leading to absence of MHC molecules)
may occur in cells due to various kinds of stress such as infection by viruses and DNA
damage as in tumor.
• These activating receptors makes holes in the target cell membrane by secreting
perforins.
• Granzymes secreted by NK cells are injected through these pores and cause apoptosis of
target cell.
• NK cells kills cells that are infected by some microbes or cells that are damaged 44
45
46
47
CYTOKINE
S

48
 CYTOKINES
• CYTOKINES
• Immune responses involve multiple interactions among
many cells.
• These include lymphocytes, dendritic cells, macrophages,
other inflammatory cells (e.g., neutrophils), and endothelial
cells.
• Some of these interactions are cell-to-cell contact.
• However, many interactions and effector functions of leukocytes
are mediated by short-acting soluble proteins called cytokines.
• These cytokines represent the messenger molecules of the
immune system and mediate communications between 49
 CYTOKINES
• Classification
• Most of the cytokines have a many effects and can be
classified depending on their functions.
• Cytokines of Innate Immunity
• These cytokines are produced rapidly in response to
microbes and other stimuli
• Mainly secreted by macrophages, dendritic cells, and NK
cells
• Mediate inflammation and anti-viral defense
• These cytokines include TNF, IL-1, IL-12, type I IFNs
(IFN-Ɣ), and chemokines.
50
 CYTOKINES
• Cytokines of Adaptive Immune Responses
• These cytokines are produced mainly by CD4+ T lymphocytes in
response to antigen and other signals
• They promote lymphocyte proliferation and differentiation and
activate effector cells
• This category include IL-2, IL-4, IL-5, IL-17, and IFN-Ɣ.
• Colony-Stimulating Factors (CSF)
• These cytokines stimulate hematopoiesis and are assayed by their
ability to stimulate formation of blood cell colonies from bone
marrow progenitors.
• They increase leukocyte numbers during immune and
inflammatory responses. 51
TISSUES
OF THE
IMMUNE
SYSTEM
52
 Thymus (diagrammatic).
The intimate relationship between
thymic epithelial cells—derived
from the third pharyngeal pouch—
and lymphocytes is important for
lymphocyte maturation. Thymic
epithelial cells release the hormone
thymopoietin (thymosin), which
induces lymphocyte maturation.
They also express major
histocompatibility (MHC) antigens
that appear to condition the T cells
to the types of MHC antigens
expressed on antigen-processing
cells with which T cells interact in
the immune response. Mature T
lymphocytes leave the thymus
through the venules to populate
the blood and peripheral lymphoid
tissues. 53
 Lymph node (diagrammatic).
The lymph node is a dynamic tissue.
Its histologic appearance is
governed by the immune responses
occurring at the time of biopsy.
Antigen enters through the afferent
lymphatics and is processed by
dendritic reticulum cells in the
cortex or interdigitating reticulum
cells in the paracortex (A).
Focal B cell proliferation around the
dendritic reticulum cells produces
collections of transforming B cells—
these are the reactive (or germinal)
centers (or follicles) (B).
T cell transformation occurs
diffusely in the paracortex in
conjunction with interdigitating
reticulum cells (D).
The products of transformation
(plasma cells and sensitized T cells)
move centrally into the medulla and
leave via efferent lymphatics (C).
Lymphocytes are recruited into the
lymph via the afferent lymphatics
and through the postcapillary 54
 Diagrammatic representation of lymphocyte exchange among lymph nodes, tissues, and blood.
Lymphocytes enter the node via afferent lymphatics and through specialized postcapillary venules that favor
movement of lymphocytes into the node. Lymphocyte proliferation occurs in the lymph node in response to any
antigen present, and the progeny leave via efferent lymphatics, disseminating the immune response throughout
the body.

55
 Diagrammatic
representation of the
spleen, showing white pulp
and red pulp.
The reactive centers have
the same basic structure
already described for
centers in lymph nodes; the
T cell domains resemble
lymph node paracortex.
Antigen is presented to the
spleen via the bloodstream,
which serves also as the
route for entry and exit of
lymphocytes.
56
MAJOR
HISTOCOMPATIBILITY
COMPLEX (MHC)
MOLECULES
57
 MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
• Location: Short arm of chromosome 6 (6p)
• Human leukocyte antigen (HLA) genes: Code for HLA proteins that are
unique to each individual
• Class I MHC molecules:
• Coded by HLA-A, -B, and -C genes
• Present on the membranes of all nucleated cells
• Not present on mature RBCs; present on platelets
• Recognized by CD8+ T cells and natural killer (NK) cells
• Class II MHC molecules:
• Coded by HLA-DP, -DQ, and -DR genes
• Present on antigen-presenting cells (APCs)  B cells, macrophages,
dendritic cells 58
• Recognized by CD4+ T cells
59
•HLA association with disease:
MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

•HLA-B27 with ankylosing

spondylitis
•HLA-DR2 with multiple
sclerosis
•HLA-DR3 and -DR4 with type
1 diabetes mellitus 60
 MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

• HLA testing:
• Transplantation workup
• Close matches of HLA-A, -B, and -D loci in
both the donor and graft recipient increase the
chance of graft survival.
• Determining disease risk
• Example: HLA-B27-positive individuals have
an increased risk of ankylosing spondylitis.
61
62
OVERVIEW OF
LYMPHOCYTE
ACTIVATION AND
IMMUNE RESPONSES
63
 Summary of the immune
response.
Lymphocytes (both B and T)
bearing specific antigen receptors
are induced to proliferate
(amplification phase) after they
react with an antigen. The process
by which lymphocytes recognize
an antigen commonly involves an
antigen-processing cell (various
types of macrophages).
Proliferation produces the
effector cells of the immune
response. Effector B cells (plasma
cells) produce specific antibody,
which mediates humoral
immunity. Effector T cells exert a
direct cytotoxic effect and
mediate cellular immunity.
Humoral immunity is so called
because it can be transferred from
an immune individual to a
susceptible one by injection of
serum containing antibody;
cellular immunity can be
transferred only by injection of
live T cells. (MHC, major 64
histocompatibility complex.)
Antigens are molecules that induce an
immune response in an appropriate
recipient (host).
From the point of view of an individual
organism, antigens can be self (i.e., part
of the host's own tissues) or foreign.
The developing fetal immune system
usually encounters only self antigens,
to which tolerance occurs. After birth,
foreign antigens are encountered, and
the nature of the host response
changes to an immune response
designed to neutralize and remove the
antigen. Note that if a foreign antigen
is presented in fetal life, natural
tolerance may result. If a self antigen is
hidden from the immune system in
fetal life and first presented in postnatal
life, an immune response may result.
Tolerance, then, is an active decision
by the immune system not to mount
an immune response to a specific
antigen (specific nonreactivity). By
contrast, an immune response is an
active decision that mobilizes the
immune system into a complex
response against that antigen
(specific reactivity). This immune
response usually is protective
(immunity) but occasionally may be 65
harmful to the host (hypersensitivity).
 Antigen, epitopes, and
antibody specificity.
In A, macromolecule A has a
single antigenic determinant site
(epitope 1) that has combined
with one of two identical binding
sites on antibody 1.
In B, macromolecule B has two
epitopes (1 and 2) that have
bound two different antibodies
(1 and 2).
Note that binding sites on the
antibodies have different
three-dimensional shapes that
correspond exactly to those of
the epitopes, ie, they are
specific. 66
 TYPES OF ANTIGENS
• Extrinsic Antigens
• Antigens may be extrinsic, i.e., introduced into the body from outside; these
include microorganisms, transplanted foreign cells, and foreign particles that
may be ingested, inhaled, or injected into the body.
• Intrinsic Antigens
• Intrinsic antigens are derived from molecules in the body so altered—eg, by
addition of hapten, partial denaturation of native molecules, or transformation
in the development of cancer cells—as to be regarded as foreign, or non-self, by
the immune system.
• Sequestered Antigens
• Certain antigens such as lens protein and spermatozoa are anatomically
sequestered from the immune system from early embryonic life; consequently,
tolerance to these molecules does not develop, and their release into the
circulation in later life may result in an immune response. Immunologic
reactivity against altered or sequestered self antigens is responsible for some 67
 RECOGNITION OF ANTIGENS
• Foreign antigens must be recognized by the immune system before
an immune response can develop.
• The mechanisms by which recognition occurs are uncertain and vary
with the nature of the antigen, its route of entry into the body, etc.
• An optimal immune response to most antigens occurs only after
interaction of the antigen with macrophages, T lymphocytes, and B
lymphocytes.
• A macrophage acting in this role is termed an antigen-processing cell
(APC).
• Dendritic reticulum cells in lymphoid follicles and interdigitating
reticulum cells in the paracortical zone of lymph nodes are believed to
be specialized macrophages adapted to process antigens for B cells
and T cells, respectively. 68
 RECOGNITION OF ANTIGENS
• Processing appears to involve internalization of antigen by the
macrophage, followed by re-expression of antigen on the cell
surface in conjunction with major histocompatibility complex
(MHC) molecules.
• Antigen receptors on T cells recognize the combination of antigen-
MHC molecules on the macrophage, leading to T cell activation and
the release of various lymphokines.
• Helper T cells recognize antigen in association with MHC class II
molecules; suppressor T cells, with MHC class I molecules.
• The usual form of B cell activation (T cell-dependent) appears to
involve cooperation with both macrophages and T cells.
• B cells recognize some multivalent antigens directly (T cell- 69
 T cell transformation in the
immune response occurs when T
cells are activated by antigen that
has been processed by an antigen-
processing cell (macrophage). This
interaction induces T cell
proliferation. The T cell enters the s
phase of the cell cycle with RNA and
protein synthesis prior to mitotic cell
division (m). The daughter cells
either reenter the cycle, revert to
resting memory cells, or leave the
cycle to mature into effector T cells.
In practice, several cycles occur
sequentially during the immune
response prior to the production of
effector cells. (g1, gap 1; s, synthesis
phase; g2, gap 2; m, mitosis; g0,
resting phase.) 70
 B cell transformation in the
immune response begins with
reaction of an antigen with specific
receptors on the surface of the B cell:
For most antigens, participation of
helper T cells and antigen-
processing cells (macrophages) is
necessary at this stage. The B cell
then enters the cell cycle from the
resting stage to begin proliferation.
Before mitosis, the activated
(transformed) B cell is termed a B
immunoblast. After mitosis, the
daughter cells either reenter the cell
cycle, revert to resting B
lymphocytes (memory cells), or
leave the cell cycle to mature to
plasma cells after passing through
intermediate forms. Maturation
occurs not in a single cycle but over 71
six to eight successive cycles
72
 SUMMARY
• ■ The innate immune system uses several families of receptors, notably the Toll-like receptors, to
recognize molecules present in various types of microbes and produced by damaged cells.
• ■ Lymphocytes are the mediators of adaptive immunity and the only cells that produce specific
and diverse receptors for antigens.
• ■ T (thymus-derived) lymphocytes express antigen receptors called T cell receptors (TCRs) that
recognize peptide fragments of protein antigens that are displayed by MHC molecules on the
surface of antigen-presenting cells.
• ■ B (bone marrow–derived) lymphocytes express membrane-bound antibodies that recognize a
wide variety of antigens.
• B cells are activated to become plasma cells, which secrete antibodies.
• ■ Natural killer (NK) cells kill cells that are infected by some microbes or are stressed and damaged
beyond repair.
• NK cells express inhibitory receptors that recognize MHC molecules that are normally
expressed on healthy cells and are thus prevented from killing normal cells.
• ■ Antigen-presenting cells (APCs) capture microbes and other antigens, transport them to lymphoid
organs, and display them for recognition by lymphocytes.
• The most efficient APCs are dendritic cells, which live in epithelia and most tissues.
 SUMMARY
• ■ The cells of the immune system are organized in tissues, some of which are the sites of
production of mature lymphocytes (the generative lymphoid organs, the bone marrow and
thymus), and others are the sites of immune responses (the peripheral lymphoid organs,
including lymph nodes, spleen, and mucosal lymphoid tissues).
• ■ The early reaction to microbes is mediated by the mechanisms of innate immunity, which are
ready to respond to microbes.
• These mechanisms include epithelial barriers, phagocytes, NK cells, and plasma proteins,
for example, of the complement system.
• The reaction of innate immunity is often manifested as inflammation.
• Innate immunity, unlike adaptive immunity, does not have fine antigen specificity or
memory.
• ■ The defense reactions of adaptive immunity develop slowly but are more potent and
specialized.
• ■ Microbes and other foreign antigens are captured by dendritic cells and transported to
lymph nodes, where the antigens are recognized by naïve lymphocytes.
• The lymphocytes are activated to proliferate and differentiate into effector and memory 74
 SUMMARY
• Cell-mediated immunity is the reaction of T lymphocytes, designed to combat cell-
associated microbes (e.g., phagocytosed microbes and microbes in the cytoplasm of
infected cells).
• Humoral immunity is mediated by antibodies and is effective against
extracellular microbes (in the circulation and mucosal lumens).
• CD4+ helper T cells help B cells to make antibodies, activate macrophages to destroy
ingested microbes, stimulate recruitment of leukocytes, and regulate all immune
responses to protein antigens.
• The functions of CD4+ T cells are mediated by secreted proteins called cytokines.
• CD8+ cytotoxic T lymphocytes kill cells that express antigens in the cytoplasm
that are seen as foreign (e.g., virus-infected and tumor cells) and can also
produce cytokines.
• ■ Antibodies secreted by plasma cells neutralize microbes and block their infectivity
and promote the phagocytosis and destruction of pathogens.
• Antibodies also confer passive immunity to neonates. 75
 If you can't fly, then RUN.
If you can't run, then WALK.
If you can't walk, then CRAWL.
But whatever you do,
YOU HAVE TO KEEP MOVING.

Martin Luther King, Jr. – Civil Rights Activist and Pastor

Thank
You