 Antibody synthesis typically involves the cooperation

of three cells: antigen presenting cells (e.g., dendritic

cells and macrophages), helper T cells, and B cells.
 After processing by an antigen-presenting cell,
fragments of antigen appear on the surface of that cell
in association with class II MHC proteins.
 The antigen–class-II MHC protein complex binds to
receptors on the surface of a helper T cell specific for
that antigen.
 This activates the helper T cells to produce interleukins
such as interleukin-2 (IL-2), IL-4, and IL-5.
 These interleukins activate the B cell to produce
antibodies specific for that antigen. (Note that the
interleukins are nonspecific; the specificity lies in the T
cells and B cells and is mediated by the antigen
receptors on the surface of these cells.)
 The activated B cell proliferates and differentiates to
form many plasma cells that secrete large amounts of
immunoglobulins (antibodies).
 Although antibody formation usually involves helper T
cells, certain antigens (e.g., bacterial polysaccharides)
can activate B cells directly, without the help of T cells,
and are called T-cell–independent antigens.
 In this T-cell–independent response, only IgM is
produced by B cells because it requires IL-4 and IL-5
made by the helper T cell for the B cell to “class
switch” to produce IgG, IgA, and IgE.
 “class switching,” the process by which the B cell
switches the antibody it produces from IgM to one of
the other classes.
 Right: Virus released by an infected cell is ingested
and processed by an antigen-presenting cell (APC)
(e.g., a macrophage).
 The viral epitope is presented in association with a
class II major histocompatibility complex (MHC)
protein to the virus-specific T-cell receptor (TCR) on
the CD4 cell.
 The macrophage makes interleukin (IL-1), which helps
activate the CD4 cell.
 The activated CD4 cell makes interleukins (e.g., IL-2,
which activates the CD8 cell to attack the virus-
infected cell, and IL-4 and IL-5, which activate the B
cell to produce antibody).
 The specificity of the cytotoxic response mounted by
the CD8 cell is provided by its TCR, which recognizes
the viral epitope presented by the virus-infected cell in
association with a class I MHC protein.
 Left: Virus released by an infected cell interacts
with the antigen receptor (IgM monomer) specific
for that virus located on the surface of a B cell.
 The virus is internalized, and the viral proteins are
broken down into small peptides.
 B cells (as well as macrophages) can present viral
epitopes in association with class II MHC proteins
and activate CD4 cells.
 The CD4-positive helper cell produces IL-4 and
IL-5, which induce the B cell to differentiate into a
plasma cell that produces antibody specifically
against this virus.
 B cells can perform two important functions during the
induction process:
 (1) they recognize antigens with their surface IgM that acts
as an antigen receptor, and
 (2) they present epitopes to helper T cells in association
with class II MHC proteins.
 Note that the IgM antigen receptor on the B cell can
recognize not only foreign proteins but also
carbohydrates, lipids, DNA, RNA, and other types of
molecules.
 It is this remarkable ability of the IgM antigen receptor
on the B cell to bind to an incredibly broad range of
molecules that enables B cells to produce antibodies
against virtually every molecule known.
 Our immune host defenses can be divided into
two major categories:
 innate (natural) and
 adaptive (acquired).
 Innate immunity is resistance that exists prior to
exposure to the microbe (antigen).
 It is nonspecific and includes host defenses such as
barriers to infectious agents (e.g., skin and mucous
membranes), certain cells (e.g., natural killer cells), and
certain proteins (e.g., the complement cascade and
interferons) and involves processes such as
phagocytosis and inflammation.
 Innate immunity does not improve after exposure to
the organism, in contrast to acquired immunity,
which does.
 In addition, innate immune processes have no
memory, whereas acquired immunity is characterized
by long-term memory.
 Note that the innate arm of our host defenses
performs two major functions:
 killing invading microbes and activating
adaptive immune processes.
 Some components of the innate arm, such as
neutrophils, only kill microbes, whereas
others, such as macrophages and dendritic cells,
perform both functions (i.e., they kill microbes and
present antigen to helper T cells, which activates
adaptive immune processes).
 Although innate immunity is often successful in
eliminating microbes and preventing infectious
diseases, it is not sufficient for human survival.
 This conclusion is based on the observation that
children with severe combined immunodeficiency
disease (SCID), who have intact innate immunity
but no adaptive immunity, suffer from repeated,
life-threatening infections.
 Several components of the innate arm recognize what
is foreign by detecting certain carbohydrates or lipids
on the surface of microorganisms that are different
from those on human cells.
 Components of the innate arm have receptors called
pattern-recognition receptors that recognize a
molecular pattern called a pathogen-associated
molecular pattern (PAMP) that is present on the
surface of many microbes but—very importantly—is
not present on human cells.
 By using this strategy, these components of the innate
arm do not have to have a highly specific receptor for
every different microbe but can still distinguish
between what is foreign and what is self.
 There are two classes of receptors on the surface of
cells (Toll-like receptors and mannan-binding lectin
receptors) that recognize microbes outside of cells and
two classes of receptors in the cytoplasm of cells
(NOD i.e. Nucleotide-binding and oligomerization
domain receptors and RIG-I i.e. retinoic acid-
inducible gene-I helicase receptors) that recognize
microbes within cells.
 Mutations in the genes encoding these pattern receptors
result in a failure to recognize the pathogen and
predispose to severe bacterial, viral, and fungal
infections.
 The most important of these pattern-recognition
receptors are the Toll-like receptors (TLR).
 This is a family of 10 receptors found mainly on the
surface of three types of cells: macrophages, dendritic
cells, and mast cells.
 Defensins are another important component of innate
immunity.
 Defensins are highly positively charged (i.e., cationic)
peptides that create pores in the membranes of bacteria and
thereby kill them.
 How they distinguish between microbes and our cells is
unknown.
 Defensins are located primarily in the gastrointestinal and
lower respiratory tracts.
 Neutrophils and Paneth cells in the intestinal crypts contain
one type of defensins (α-defensins), whereas the respiratory
tract produces different defensins called β-defensins.
 α-Defensins also have antiviral activity.
 They interfere with human immunodeficiency virus (HIV)
binding to the CXCR4 receptor and block entry of the
virus into the cell.
 Alpha and beta interferon are important antiviral
proteins.
 They are synthesized early in infection within virus-
infected cells.
 They exit that cell, bind to the surface of an adjacent
cell, and induce an anti-viral state in that adjacent
cell.
 The anti-viral state is mediated by a ribonuclease and a
protein kinase that, acting together, inhibit viral protein
synthesis.
 Gamma interferon is an important mediator of
inflammation but has only modest antiviral activity.
 It acts primarily to enhance killing by macrophages and
other phagocytes, and to increase the synthesis of class
1 and class 2 MHC proteins.
 Adaptive immunity occurs after exposure to an
agent, improves upon repeated exposure, and is
specific.
 It is mediated by antibody produced by B
lymphocytes and by two types of T lymphocytes,
namely, helper T cells and cytotoxic T cells.
 The cells responsible for adaptive immunity have
long-term memory for a specific antigen.
 Adaptive immunity can be active or passive
 Macrophages and other antigen-presenting cells such
as dendritic cells play an important role in both the
innate and the adaptive arms of the immune system.
 When they phagocytose and kill microbes, they
function as part of the innate arm, but when they
present antigen to a helper T lymphocyte, they activate
the adaptive arm that leads to the production of
antibody and of cells such as cytotoxic T
lymphocytes.
 Note that the adaptive arm can be activated only after
the innate arm has interacted with the microbe.
 Active immunity is resistance induced after contact
with foreign antigens (e.g. microorganisms).
 This contact may consist of clinical or subclinical
infection, immunization with live or killed infectious
agents or their antigens, or exposure to microbial
products (e.g., toxins and toxoids).
 In all these instances, the host actively produces an
immune response consisting of antibodies and
activated helper and cytotoxic T lymphocytes.
 The main advantage of active immunity is that
resistance is long-term.
 Its major disadvantage is its slow onset, especially the
primary response.
 Passive immunity is resistance based on antibodies
preformed in another host.
 Administration of antibody against diphtheria, tetanus,
botulism, etc., makes large amounts of antitoxin
immediately available to neutralize the toxins.
 Likewise, preformed antibodies to certain viruses (e.g.,
rabies and hepatitis A and B viruses) can be injected
during the incubation period to limit viral
multiplication.
 Other forms of passive immunity are IgG passed from
mother to fetus during pregnancy and IgA passed from
mother to newborn during breast feeding.
 The main advantage of passive immunization is the
prompt availability of large amounts of antibody;
disadvantages are the short life span of these
antibodies and possible hypersensitivity reactions if
globulins from another species are used.
 Passive–active immunity involves giving both
preformed antibodies (immune globulins) to provide
immediate protection and a vaccine to provide long-
term protection.
 These preparations should be given at different sites in
the body to prevent the antibodies from neutralizing the
immunogens in the vaccine.
 This approach is used in the prevention of tetanus,
rabies and hepatitis B.
 Antigens are molecules that react with antibodies,
whereas immunogens are molecules that induce an
immune response.
 In most cases, antigens are immunogens,
and the terms are used interchangeably.
 However, there are certain important exceptions (e.g.,
haptens).
 A hapten is a molecule that is not immunogenic by
itself but can react with specific antibody.
 Haptens are usually small molecules, but some high-
molecular-weight nucleic acids are haptens as well.
 Many drugs (e.g., penicillins) are haptens, and the
catechol in the plant oil that causes poison oak and
poison ivy is a hapten.
 Haptens are not immunogenic because they
cannot activate helper T cells.
 The failure of haptens to activate is due to their
inability to bind to MHC proteins; they cannot
bind because they are not polypeptides and
only polypeptides can be presented by MHC
proteins.
 Furthermore, haptens are univalent and
therefore cannot activate B cells by themselves.
(Compare with the T-independent response).
 Although haptens cannot stimulate a primary or
secondary response by themselves, they can do so
when covalently bound to a “carrier” protein.
 In this process, the hapten interacts with an IgM
receptor on the B cell and the hapten–carrier
protein complex is internalized.
 A peptide of the carrier protein is presented in
association with class II MHC protein to the helper
T cells.
 The activated helper T cell then produces
interleukins, which stimulate the B cells to
produce antibody to the hapten.
 1. Foreignness
 2. Molecular Size
 3. Chemical–Structural Complexity
 4. Antigenic Determinants (Epitopes)
 5. Dosage, Route, and Timing of Antigen
Administration
 6. Adjuvants
 In general, molecules recognized as
“self” are not immunogenic (i.e., we are
tolerant to those self-molecules).
 To be immunogenic, molecules must be
recognized as “nonself” (i.e., foreign).
 The most potent immunogens are proteins with
high molecular weights (i.e., above 100,000).
 Generally, molecules with molecular weight
below 10,000 are weakly immunogenic, and
very small ones (e.g., an amino acid) are
nonimmunogenic.
 Certain small molecules (e.g., haptens) become
immunogenic only when linked to a
carrier protein.
A certain amount of chemical
complexity is required (e.g., amino
acid homopolymers are less
immunogenic than heteropolymers
containing two or three different
amino acids).
 Epitopes are small chemical groups on the
antigen molecule that can elicit and react with
antibody.
 An antigen can have one or more determinants
(epitopes).
 Most antigens have many determinants (i.e., they
are multivalent).
 In general, a determinant is roughly five amino
acids or sugars in size.
 The overall three dimensional structure is the
main criterion of antigenic specificity.
 These factors also affect immunogenicity.
 In addition, the genetic constitution of the
host (HLA genes) determines whether a molecule
is immunogenic.
 Different strains of the same species of animal may
respond differently to the same antigen.
 Adjuvants enhance the immune response to an
immunogen.
 They are chemically unrelated to the
immunogen and differ from a carrier protein
because the adjuvant is not covalently bound to
the immunogen, whereas the carrier protein is.
 Adjuvants can act in a variety of ways; they
can cause slow release of immunogen, thereby
prolonging the stimulus; enhance uptake of
immunogen by antigen-presenting cells; and
induce costimulatory molecules (“second
signals”).
 Another important mechanism of action of
some adjuvants is to stimulate Toll-like
receptors on the surface of macrophages, which
results in cytokine production that enhances the
response of T cells and B cells to the
immunogenic (antigen).
 Some human vaccines contain adjuvants such
as aluminum hydroxide or lipids.