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then would you

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If you doubted

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then would you

let it

,your back door,

be unlocked tonight?

Dual Nature of Adaptive Immunity

I. Overview of Specific Immunity
 A. Specific immune system
1. Has three major functions
a. Recognize anything that is nonself
b. Respond to this foreign material (effector response)-involves the
recruitment of various defense molecules and cells to either destroy
foreign material or render it harmless
c. Remember the foreign invader (amnestic response)-a more rapid and
intense responses to foreign material that occurs upon later encounters
with the material
2. The characteristics of specificity and memory distinguish the specific immune
response from nonspecific resistance
3. There are two arms of specific immunity
a. Humoral (antibody-mediated) immunity-based on action of antibodies that
bind bacteria, toxins, and extracellular viruses, tagging or marking them
for destruction
b. Cellular (cell-mediated) immunity-based on action of T cells that directly
attack cells infected with viruses or parasites, transplanted cells or organs,
and cancer cells
B. Types of acquired immunity-specific immunity that develops after exposure to antigen or
after transfer of antibodies or lymphocytes from an immune donor
1. Naturally acquired immunity
a. Naturally acquired active immunity-an individual comes in contact with
an antigen via a natural process (e.g., infection) and produces sensitized
lymphocytes and/or antibodies that inactivate or destroy the antigen
b. Naturally acquired passive immunity-transfer (e.g., transplacentally or in
breast milk) of antibodies from one individual (where they were actively
produced) to another (where they are passively received)
2. Artificially acquired immunity
a. Artificially acquired active immunity-deliberate exposure of an individual
to a vaccine (a solution containing antigen) with subsequent development
of an immune response
b. Artificially acquired passive immunity-deliberate introduction of
antibodies from an immune donor into an individual

II. Antigens
 A. Prior to birth, the immune system removes most T cells specific for self-recognition
determinants
B. Antigens are substances, such as proteins, nucleoproteins, polysaccharides, and some
glycolipids that elicit an immune response and react with products of that response
1. Epitopes (antigenic determinant sites) are areas of an antigen that can stimulate
production of specific antibodies and that can combine with them
2. Valence-the number of epitopes on an antigen; determines number of antibody
molecules an antigen can combine with at one time
C. Hapten-a small organic molecule that is not itself antigenic but that may become
antigenic when bound to a larger carrier molecule

D. Superantigens-bacterial proteins that provoke a dramatic immune response by

nonspecifically stimulating T cells to proliferate; occurs when superantigen interacts both
with class II MHC molecules and T-cell receptors; superantigens cause symptoms by way
of release of massive quantities of cytokines; superantigens are associated with various
chronic diseases including rheumatic fever, arthritis, and others
E. Cell-associated differentiation antigens (CDs)-functional cell surface proteins that are
used to differentiate between leukocyte subpopulations; concentration of these molecules
in serum is usually low and elevated levels are associated with disease (e.g., various
cancers, autoimmune diseases, HIV infection); levels in serum can be used in disease
management

III. Antibodies
A. Antibody (immunoglobulin, Ig)-glycoprotein made in response to an antigen; recognizes
and binds the antigen that caused its production; five different classes: IgG, IgA, IgM,
IgD, and IgE
B. Immunoglobulin structure
1. Multiple antigen-combining sites (usually two; some can form multimeric
antibodies with up to ten combining sites)
2. Basic structure is composed of four polypeptide chains
a. There are two heavy chains and two light chains
b. Within each chain is a constant region (little amino acid sequence
variation within the same class of Ig) and a variable region
3. The four polypeptides are arranged in the form of a flexible Y
a. Fc (crystallizable fragment) is stalk of the Y; contains site at which
antibody can bind to a cell; composed only of constant region
b. Fab (antigen binding fragments) are at the top of the Y; they bind
compatible epitopes of an antigen; composed of both constant and variable
regions
c. Domains-homologous units, each about 100 amino acids long, observed in
heavy chains and in light chains
4. Light chain exists in two distinct forms kappa (k) and lambda (l)
 5. There are five types of heavy chains: gamma (g), alpha (a), mu (m), delta (d), and
epsilon (e); these determine, respectively, the five classes (isotypes) of
immunoglobulins: IgG, IgA, IgM, IgD, and IgE
6. In IgG there are four subclasses, and in IgA there are two subclasses; these
subclasses result from variations in the amino acid composition of the heavy
chains; the variations are classified as:
a. Isotypes-variations normally present in all individuals
b. Allotypes-genetically controlled allelic forms of the immunoglobulin
molecules; allelic forms that are not present in all individuals
c. Idiotypes-individual-specific immunoglobulin molecules that differ in the
Fab segments
C. Immunoglobulin function
1. Fab region binds to antigen whereas Fc region mediates binding to host tissue,
various cells of the immune system, some phagocytic cells, or the first component
of the complement system
2. Binding of antibody to an antigen does not destroy the antigen, but marks (targets)
the antigen for immunological attack and activates nonspecific immune responses
that destroy the antigen
3. Opsonization-coating a bacterium with antibodies to stimulate phagocytosis
D. Immunoglobulin classes
1. IgG-monomeric protein, 70% to 75% of Ig pool
a. Antibacterial and antiviral
b. Enhances opsonization; neutralizes toxins
c. Only IgG is able to cross placenta (naturally acquired passive immunity
for newborn)
d. Activates the complement system by the classical pathway
e. Four subclasses with some differences in function
2. IgM-pentameric protein, 10% of Ig pool
a. First antibody made during B-cell maturation and first antibody secreted
into serum during primary antibody response
b. Never leaves the bloodstream
c. Agglutinates bacteria and activates complement by classical pathway;
enhances phagocytosis of target cells
d. Some may be red blood cell agglutinins
e. Up to 5% may be hexameric; hexameric form is better able to activate the
complement system than pentameric IgM; bacterial cell wall antigens may
directly stimulate B cells to produce hexameric form
3. IgA-15% of Ig pool
a. Some monomeric forms in serum, but most is dimeric and associated with
a protein called the secretory component (secretory IgA or sIgA)
b. sIgA is primary Ig of mucosal-associated lymphoid tissue; also found in
saliva, tears, and breast milk (protects nursing newborns); helps rid the
body of antigen-antibody complexes by excretion; functions in alternate
complement pathway
4. IgD-monomeric protein, trace amounts in serum
a. Does not activate the complement system and cannot cross the placenta
 b. Abundant on surface of B cells where it plays a role in signaling B cells to
start antibody production
5. IgE-monomeric protein, less than 1% of Ig pool
a. Skin-sensitizing and anaphylactic antibodies
b. When an antigen cross-links two molecules of IgE on the surface of a mast
cell or basophil, it triggers release of histamine; stimulates eosinophilia
and gut hypermotility, which helps to eliminate helminthic parasites
E. Diversity of antibodies-three mechanisms contribute to the generation of antibody
diversity
1. Combinatorial joining
a. Ig genes are interrupted or split genes with many exons; in light chain
gene, there are three types of exons (C,V, and J); in heavy chain gene
there are four types of exons (C, V, J, and D)
b. During differentiation of B cells, one C exon, one V exon, and one J exon
are joined together to make a functional light chain gene; one C, one V,
one J, and one D are joined together to make a functional heavy chain
gene; since there are numerous C, V, J, and D exons, many different
combinations are possible (2x108)
c. The number of different antibodies possible is the product of the number
of light chains possible and the number of heavy chains possible
2. Somatic mutations-the V regions of germ-line DNA are susceptible to a high rate
of somatic mutation during B-cell development
3. Alternate joining points-the same exons can be joined at different nucleotides,
thus increasing the number of codons and the possible diversity
F. Specificity of antibodies-clonal selection theory
1. Because of combinatorial joining and somatic mutation, there are a small number
of B cells capable of responding to any given antigen; each group of cells is
derived asexually from a parent cell and is referred to as a clone; there is a large,
diverse population of B-cell clones that collectively are capable of responding to
many possible antigens
2. Identical antibody molecules, specific to each B cell and a single antigen, are
integrated into the plasma membrane of B cell; when these bind the appropriate
antigen the B cell is stimulated to divide and differentiate into two populations of
cells: plasma cells and memory cells
a. Plasma cells are protein factories that produce about 2,000 antibodies per
second for their brief life span (5-7 days)
b. Memory cells can initiate antibody-mediated immune response if they are
stimulated by being bound to the antigen; they circulate more actively
from blood to lymph and have long life spans (years or decades); are
responsible for rapid secondary response; are not produced unless B cell
has been appropriately signaled by activated T-helper cell
G. Sources of antibodies
1. Immunization-purified antigen is injected into host; specific B-cell clone
recognizes and responds by proliferating and producing antibodies
a. To promote antigen stimulation, antigen may be mixed with an adjuvant (a
molecule that enhances rate and quantity of antibodies produced)
 b. Blood withdrawn from immunized host is allowed to clot; fluid remaining
is called serum
c. Serum obtained from immunized host is called antiserum
d. Limitations 1) This method results in polyclonal antibodies, which have
different epitope specificities; thus sensitivity is lower, and the antibodies
often cross-react with closely related antigens 2) Repeated injections with
antiserum from one species into another can cause serious allergic
reactions 3) Antiserum contains a mixture of antibodies, not all of which
are of interest
2. Primary antibody response-with immunization and natural acquired immunity,
levels (titer) of antibody change over time
a. Initial lag phase of several days
b. Log phase-antibody titer rises logarithmically
c. Plateau phase-antibody titer stabilizes
d. Decline phase-antibody titer decreases because the antibodies are
metabolized or cleared from the circulation
e. Mostly IgM (low-affinity antibodies)
3. Secondary antibody response (amnestic response)-has shorter lag phase, higher
antibody titer, and more IgG, which have high affinity for antigens (affinity
maturation)
4. Hybridomas-overcome some of the limitations of antisera by producing a
monoclonal antibody with a single specificity
a. Made by injecting animals with antigen; when they begin to produce
antibodies, spleen is removed and plasma cells are isolated
b. Plasma cells are fused with myeloma cells (easily cultured tumor cells of
the immune system that produce large quantities of antibodies); the
resulting fused cells are hybridomas
c. Hybridomas are cultured so that each grows into a separate colony; these
are screened to identify those producing desired antibody
d. Monoclonal antibodies have a variety of uses: tissue typing for transplants,
identification and epidemiological study of infectious microorganisms,
identification of tumor and other surface antigens, classification of
leukemias and identification of T-cell populations

IV. T-Cell Biology

A. T-cell antigen receptors-bind to antigens only when antigen is presented by an antigen-

presenting cell
B. Major histocompatibility complex (MHC)-proteins encoded by a group of genes called
the major histocompatibility complex (MHC) genes; comprise three classes; only class I
and class II are involved in antigen presentation
1. Both class I and class II MHC molecules consist of two protein chains and are
attached to cytoplasmic membrane
2. Both class I and class II MHC molecules fold into similar shapes, each having a
deep groove into which a short peptide or other antigen fragment can bind; the
 presence of a foreign peptide in this groove alerts immune system and activates T
cells or macrophages
3. Class I MHC molecules bind to peptides that originate in the cytoplasm
(endogenous antigens, such as those from replicating viruses); class II MHC
molecules bind to fragments that arise from exogenous antigen
a. Endogenous proteins-pumped by specific transporter proteins from
cytoplasm to endoplasmic reticulum, where they become associated with
newly synthesized class I MHC molecules; the peptide-class I MHC
complex is then carried to and incorporated within the plasma membrane;
detected by cytotoxic T cells
b. Exogenous proteins arise from bacteria and viruses taken in
endocytotically; digestion of bacterium or virus in phagolysosome creates
peptides; these peptides combine with class II MHC and are delivered to
cell surface; detected by T-helper cells
4. Class I MHC-made by all cells except red blood cells; function to identify cells as
Aself@; primary basis of HLA typing for organ transplant
5. Class II MHC-produced only by activated macrophages, mature B cells, some T
cells, and certain cells of other tissues; function in T-cell communication with
macrophages and B cells
6. Class III-involved in the classical and alternate complement pathways
C. Types of T cells
1. Effector cells (cytotoxic T cells-TC)-attach by their T-cell receptor to virus-
infected cells that display class I MHC proteins and viral antigens; are then
stimulated by T-helper cells; activated cytotoxic T cells produce cytokines that
limit viral reproduction and activate macrophages and other phagocytic cells;
ultimately cytotoxic T cell destroys target cell; two mechanisms are:
a. CD95 pathway-transmembrane signal transduction leads to initiation of
apoptosis
b. Perforin pathway-release of perforins that damage the target cell
membrane, resulting in cytolysis of target cell
2. Regulator T cells
a. T-helper cells (TH) 1) Three subsets: TH1, TH2, and TH0; each produces
and secretes a specific mixture of cytokines 2) TH1-requires two signals
for activation (presentation of antigen by an antigen-presenting cell and
binding of a TH1 receptor to a macrophage surface protein); activated
TH1 secretes cytokines that activate cytotoxic T cells and macrophages 3)
TH2-requires two signals for activation (antigen presentation and
interleukin-1); activated TH2 releases cytokines that stimulate B-cell
proliferation and differentiation
b. T-suppressor cells (TS)-suppress B-cell and T-cell responses; activated by
interleukin-2, which is produced by activated T-helper cells; proliferation
of TS occurs slowly and provides negative feedback control for acquired
immune tolerance

V. B-Cell Biology
 A. Have surface molecules important to their function
1. Surface molecules include B-cell antigen receptors (BCRs-IgM and IgD on
surface of B cell), Fc receptors, and complement receptors
2. Binding of receptors to target molecules is involved in activation of B cell and in
phagocytosis, processing, and presentation of antigens
B. Antigen-antibody binding-occurs within the pocket formed by folding the VH and VL
regions of Fab; binding is due to weak, noncovalent bonds and in most cases shapes of
epitope and binding site must be highly complementary (i.e., lock and key) for efficient
binding; in at least one case, it is known that the antigen induces a shape change of the
antigen-binding site (induced fit mechanism); high complementarity of epitope and
binding site provides for the high specificity associated with antigen-antibody binding
C. B-cell activation
1. T-dependent antigen triggering
a. Macrophage ingests the antigen or antigen-bearing organism, processes
the antigen, and displays a fragment of the antigen and with its Class II
MHC to a T-helper cell; macrophage also secretes interleukins (IL-1 and
IL-6) b IL-1 and IL-6 stimulate the T-helper cell to divide and secrete
interleukins (IL- 2, IL-4, IL-5, and IL-6); IL-1 also induces fever
b. IL-2, IL-4, IL-5 and IL-6 stimulate proliferation of the T-helper cell
c. The resulting T-helper clones bind to B cells presenting the appropriate
antigen on their surface; they also secrete B-cell growth factor (BCGF),
which causes B cells to divide, and B-cell differentiation factor (BCDF),
which causes the B cells to differentiate into plasma cells and produce
antibodies
d. Note that this pathway for B-cell activation also requires an interaction
between the B cell and the antigen; B cell recognizes antigen through its
BCRs
2. T-independent antigen triggering-causes production of IgM; occurs with
polymeric antigens, which have a large number of identical epitopes; antibodies
produced, which have low affinity for antigen, never switch to high-affinity IgG
or other isotypes; no memory cells are produced

VI. Action of Antibodies

A. Toxin neutralization-antibody (antitoxin) binding to toxin renders the toxin incapable of

attachment or entry into target cells
B. Viral neutralization-binding prevents viral attachment to target cells
C. Adherence inhibition-sIgA prevents bacterial adherence to mucosal surfaces
D. IgE and parasitic infection-in the presence of elevated IgE levels, eosinophils bind
parasites and release lysosomal enzymes that lead to destruction of parasite
E. Opsonization-enhancement of phagocytosis; results form coating of microorganisms or
other material by antibodies or complement; this prepares the microorganism for
phagocytosis
F. Immune complex formation-two or more antigen-binding sites per antibody molecule
lead to cross-linking, forming molecular aggregates called immune complexes; these
complexes are more easily phagocytized
 1. Precipitation (precipitin) reaction-soluble particles are cross-linked, causing them
to precipitate from solution; the antibody involved is called a precipitin antibody
2. Agglutination reaction-particles or cells are cross-linked, forming an aggregate;
the antibody involved is called an agglutinin
3. Hemagglutination-agglutination of red blood cells; antibody is called a
hemagglutinin

VII. The Classical Complement Pathway

A. Activation of this pathway requires interaction of antibody with an antigen that is usually
cell bound
B. Following antigen-antibody binding, a complement component (C1) attaches to Fc; this
leads to a cascade of enzymatic reactions that culminate in the production of a complex
of proteins (C5b67)
C. This complex binds membrane of the target cell; two other complement components then
bind, forming the membrane attack complex; this creates a pore in the membrane of the
target cell, causing it to lyse

VIII. Acquired immune tolerance

A. Nonresponse to self; three mechanisms have been proposed: negative selection by clonal
deletion, induction of anergy, and inhibition of immune response by T-suppressor cells
B. Negative selection by clonal deletion-T cells with ability to interact with self-antigens are
destroyed in the thymus
C. Induction of anergy-an example of peripheral tolerance (tolerance that develops in areas
other than thymus); lymphocytes that can interact with self-antigens are given incomplete
activation signals, causing them to enter into an unresponsive state known as anergy

IX. Summary: The Role of Antibodies and Lymphocytes in Resistance

A. Response of a host to any particular pathogen may involve a complex interaction between
host and pathogen, as well as the components of both nonspecific and specific immunity
B. Immunity to viral infection
1. Antibodies neutralize viruses
2. Antibodies enhance phagocytosis
3. Interferons shut down protein synthesis in virus-infected cells; interferons
stimulate the activity of T cells and NK cells
4. Activated macrophages and cytotoxic T cells destroy virus-infected cells
C. Immunity to bacterial infections
1. Antibodies trigger complement attack by the classical pathway, leading to the
formation of the membrane attack complex
2. Complement activation attracts neutrophils and macrophages to site of infection
3. Toxin neutralization
4. Activated macrophages and cytotoxic T cells destroy cells infected with
intracellular pathogenic bacteria