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Immunology
College of Dentistry
Third stage
Asst. Proff.Dina M.R. Alkhafaf
IMMUNE SYSTEM.
A. Specific and Nonspecific Defenses. The protection of the organism
against infectious agents involves many different mechanisms, some
nonspecific (i.e., generically applicable to many different pathogenic
organisms), and others specific (i.e., their protective effect is directed to
one single organism).
1. Nonspecific defenses, which as a rule are innate (i.e., all normal
individuals are born with it), include:
a. Mechanical barriers, such as the integrity of the epidermis and mucosal
membranes.
b. Physicochemical barriers, such as the acidity of the stomach fluid.
c. Antibacterial substances (e.g., lysozyme) present in external secretions.
d. Normal intestinal transit and normal flow of bronchial secretions and
urine, which eliminate infectious agents from the respective systems.
e. Ingestion and elimination of bacteria and particulate matter by
granulocytes, which is independent of the
immune response.
2. Specific defenses, as a rule, are induced during the life of the
individual as part of the complex sequence of events designated as the
immune response.
B. Unique Characteristics of the Immune Response. The immune
response has two unique characteristics:
1. Specificity for the eliciting antigen. For example, immunization with
poliovirus only protects against poliomyelitis, not against the flu. The
specificity of the immune response is due to the existence of exquisitely
discriminative antigen receptors on lymphocytes. Only a single or a very
limited number of similar structures can be accommodated by the
receptors of any given lymphocyte. When those receptors are occupied,
an activating signal is delivered to the lymphocytes. Therefore, only those
lymphocytes with specific receptors for the antigen in question will be
activated.
2. Memory, meaning that repeated exposures to a given antigen elicit
progressively more intense specific responses. Most immunizations
involve repeated administration of the immunizing compound, with the
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goal of establishing a long-lasting, protective response. The increase in
the magnitude and duration of the immune response with repeated
exposure to the same antigen is due to the proliferation of antigenspecific lymphocytes after each exposure. The numbers of responding
cells will remain increased even after the immune response subsides.
Therefore, whenever the organism is exposed again to that particular
antigen, there is an expanded population of specific lymphocytes
available for activation and, as a consequence, the time needed to mount a
response is shorter and the magnitude of the response is higher.
C. Stages of the Immune Response. To better understand how the
immune response is generated, it is useful to consider it as divided into
separate sequential stages (Table 1.1). The first stage (induction) involves
a small lymphocyte population with specific receptors able to recognize
an antigen or a fragment generated by specialized cells known as antigenpresenting cells (APC). The proliferation and differentiation of antigenresponding lymphocytes is usually enhanced by amplification systems
involving APC and specialized T-cell subpopulations (T helper cells,
defined below) and is followed by the production of effector molecules
(antibodies) or by the differentiation of effector cells (cells which directly
or indirectly mediate the elimination of undesirable elements). The final
outcome, therefore, is the elimination of the microbe or compound that
triggered the
The Cells of the Immune System
A. Lymphocytes and Lymphocyte Subpopulations. The peripheral
blood contains two large populations of cells: the red cells, whose main
physiological role is to carry oxygen to tissues, and the white blood cells,
which have as their main physiological role the elimination of potentially
harmful organisms or compounds. Among the white blood cells,
lymphocytes are particularly important because of their primordial role in
the immune response. Several subpopulations of lymphocytes have been
defined:
1. B lymphocytes, which are the precursors of antibody-producing cells,
known as plasma cells.
2. T lymphocytes, or T-cells, which are further divided into several
subpopulations:
a. Helper T lymphocytes (TH), which play a very significant
amplification role in the immune responses. Two functionally distinct
subpopulations of T helper lymphocytes have been well defined in mice.
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i. TH1 lymphocytes, which assist the differentiation of cytotoxic cells and
also activate macrophages, which after activation play a role as effectors
of the immune response.
ii. TH2 lymphocytes, which are mainly involved in the amplification of B
lymphocyte responses. These amplifying effects of helper T lymphocytes
are mediated in part by soluble mediators— interleukins—and in part by
signals delivered as a consequence of cell-cell contact.
b. Cytotoxic T lymphocytes, which are the main immunological effector
mechanisms involved in the elimination of non-self or infected cells.
3. Antigen-presenting cells, such as the macrophages and macrophagerelated cells, play a very significant role in
the induction stages of the immune response by trapping and presenting
both native antigens and antigen fragments in a most favorable way for
the recognition by lymphocytes. In addition, these cells also deliver
activating signals
to lymphocytes engaged in antigen recognition, both in the form of
soluble mediators (interleukins such as IL-12 and IL-1) and in the form of
signals delivered by cell-cell contact.
4. Phagocytic and cytotoxic cells, such as monocytes, macrophages, and
granulocytes, also play significant roles as effectors of the immune
response. Once antibody has been secreted by plasma cells and is bound
by the microbes, cells, or compounds that triggered the immune response,
it is able to induce their ingestion by phagocytic cells. If bound to live
cells, antibody may induce the attachment of cytotoxic cells that cause the
death of the antibody-coated cell (antibody-dependent cellular
cytotoxicity; ADCC). The ingestion of microorganisms or particles
coated with antibody is enhanced when an amplification effector system
known as complement is activated.
5. Natural killer (NK) cells play a dual role in the elimination of infected
and malignant cells. These cells are unique in that they have two different
mechanisms of recognition: they can identify directly virus-infected and
malignant cells and cause their destruction, and they can participate in the
elimination of antibody-coated cells by ADCC.
Antigens and Antibodies
A. Antigens are non-self substances (cells, proteins, polysaccharides) that
are recognized by receptors on lymphocytes, thereby eliciting the immune
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response. The receptor molecules located on the membrane of
lymphocytes interact with
small portions of those foreign cells or proteins, designated as antigenic
determinants or epitopes. An adult human being has the capability of
recognizing millions of different antigens, some of microbial origin,
others present in the environment, and even some artificially synthesized.
B. Antibodies are proteins that appear in circulation after immunization
and that have the ability to react specifically with the antigen used to
immunize. Because antibodies are soluble and are present in virtually all
body fluids (“humors”), the term humoral immunity was introduced to
designate the immune responses in which antibodies play the principal
role as effector mechanisms. Antibodies are also generically designated
as immunoglobulins. This term derives from the fact that antibody
molecules structurally belong to the family of proteins known as
globulins (globular proteins) and from their involvement in immunity.
C. Antigen-Antibody Reactions, Complement, and Phagocytosis. The
knowledge that the serum of an immunized animal contained protein
molecules able to bind specifically to the antigen led to exhaustive
investigations of the characteristics and consequences of the antigenantibody reactions.
1. If the antigen is soluble, the reaction with specific antibody under
appropriate conditions results in precipitation of large antigen-antibody
aggregates.
2. If the antigen is expressed on a cell membrane, the cell will be crosslinked by antibody and form visible clumps (agglutination).
3. Viruses and soluble toxins released by bacteria lose their infectivity or
pathogenic properties after reaction with the corresponding antibodies
(neutralization).
4. Antibodies complexed with antigens can activate the complement
system. This system is composed of nine major proteins or components
which are sequentially activated. Some of the complement components
are able to promote ingestion of microorganisms by phagocytic cells
(phagocytosis), while others are inserted into cytoplasmic membranes
and cause their disruption, leading to cell death.
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5. Antibodies can cause the destruction of microorganisms by promoting
their ingestion by phagocytic cells or their destruction by cytotoxic cells.
Phagocytosis is particularly important for the elimination of bacteria and
involves the binding of antibodies and complement components to the
outer surface of the infectious agent (opsonization) and recognition of
the bound antibody and/or complement components as a signal for
ingestion by the phagocytic cell.
6. Antigen-antibody reactions are the basis of certain pathological
conditions, such as allergic reactions. Antibodymediated allergic
reactions have a very rapid onset, in a matter of minutes, and are known
as immediate hypersensitivity reactions.
Characteristics of Immunogenicity
Many different substances can induce immune responses. The following
characteristics have an important influence in the ability that a substance
has to behave as an immunogen.
A. Foreigness. As a rule, only substances recognized as “non-self” will
trigger the immune response. Microbial antigens and heterologous
proteins are obviously “non-self” and are strongly immunogenic.
B. Molecular Size. The most potent immunogens are macromolecular
proteins [molecular weight (M.W.) > 100,000]. Molecules smaller than
10,000 daltons are weakly immunogenic.
C. Chemical Structure and Complexity. Proteins and polysaccharides
are among the most potent immunogens, although relatively small
polypeptide chains, nucleic acids, and even lipids can, given the right
circumstances, be immunogenic.
1. Proteins. Large heterologous proteins expressing a wide diversity of
antigenic determinants are potent immunogens.
a. The immunogenicity of a protein is strongly influenced by its chemical
composition. Positively charged (basic) amino acids, such as lysine,
arginine, and histidine are repeatedly present in the antigenic sites of
lysozyme and myoglobin, while aromatic amino acids (such as tyrosine)
are found in two of albumin's six antigenic sites. Therefore, it appears
that basic and aromatic amino acids may contribute more strongly to
immunogenicity than other amino acids; basic proteins with clusters of
positively charged amino acids are strong immunogens.
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b. There appears to be a direct relationship between antigenicity and
chemical complexity: aggregated or chemically polymerized proteins are
much stronger immunogens than their soluble monomeric counterparts.
2. Polysaccharides. Polysaccharides are among the most important
natural antigens, since either pure polysaccharides or the sugar moieties
of glycoproteins, lipopolysaccharides, glycolipid-protein complexes, etc.,
are immunogenic. Many microorganisms have polysaccharide-rich
capsules or cell walls, and a variety of mammalian antigens, such as the
erythrocyte antigens (A, B, Le, H), are short-chain polysaccharides
(oligosaccharides).
3. Nucleic acids. Nucleic acids usually are not immunogenic, but can
induce antibody formation if coupled to a protein to form a nucleoprotein.
The autoimmune responses characteristic of some of the so-called
autoimmune diseases (e.g., systemic lupus erythematosus) are often
directed to DNA and RNA that may have stimulated the immune system
as nucleoproteins.
4. Polypeptides. Hormones such as insulin and other polypeptides,
although relatively small in size (M.W. 1500), are usually immunogenic
when isolated from one species and administered over long periods of
time to an individual of a different species.
Antigens
An antigen is a substance that reacts with an antibody. Immunogens
induce an immune response and most antigens are also immunogens.
There are a wide variety of features that largely determine
immunogenicity. They include the following:
(1) Recognition of foreignness: Generally, molecules recognized
as “self” are not immunogenic. To be immunogenic, molecules must be
recognized as foreign (“nonself”).
(2) Size: The most potent immunogens are usually large, complex
proteins. Molecules with a molecular weight less than 10,000 are
weakly immunogenic, and as expected very small molecules are
nonimmunogenic. Some small molecules, called haptens, become
immunogenic only when linked to a carrier protein.
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An example is seen with lipids and amino acids that are nonimmunogenic
haptens. They require conjunction with a carrier protein or polysaccharide
before they can be immunogenic or generate an immune response
(3) Chemical and structural complexity: Chemical complexity is
another key feature of immunogenicity. For example, amino acid
homopolymers are less immunogenic than heteropolymers that contain
two or more different amino acids
(4) Genetic constitution of the host: Because of differences in MHC
alleles, two strains of the same species of animal may respond differently
to the same antigen.
(5) Dosage, route, and timing of antigen administration: Other factors
that affect immunogenicity include concentration of antigen administered,
route of administration, and timing of antigen administration. These
concepts of immunogenicity are important for designing vaccines in
which enhancing immunogenicity is key. However, methods to reduce
immunogenicity are also a consideration in protein drug design. This can
be seen in an individual who may respond to a certain drug and produce
anti-drug antibodies. These anti-drug antibodies may inhibit drug
efficacy. Finally, it should be noted that it is possible to enhance the
immunogenicity of a substance by combining it with an adjuvant.
Adjuvants are substances that stimulate the immune response by
facilitating uptake into APCs.
I. General Structure of Immunoglobulins
A. Information concerning the precise structure of the antibody molecule
started to accumulate as technological developments were applied to the
study of the general characteristics of antibodies. By the early 1940s
antibodies had been characterized electrophoretically as gamma
globulins (Fig. 5.1) and also classified into large families by their
sedimentation coefficient determined by analytical ultracentrifugation
(7S and 19S antibodies). It also became evident that plasma cells were
responsible for immunoglobulin synthesis and that a malignancy known
as multiple myeloma was a malignancy of immunoglobulin-producing
plasma cells.
B. As protein fractionation techniques became available, complete
immunoglobulins and their fragments were isolated in large amounts,
particularly from the serum and urine of patients with multiple myeloma.
These proteins were used both for studies of chemical structure and for
immunological studies that led to the definition of antigenic differences
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between proteins from different patients; this was the basis for the initial
identification of the different classes and subclasses of immunoglobulins
and the different types of light chains.
Immunoglobulin G (IgG): The Prototype Immunoglobulin Molecule.
A. General Considerations. IgG, a 7S immunoglobulin, is the most
abundant immunoglobulin in human serum and in the serum of most
mammalian species. It is also the immunoglobulin most frequently
detected in large concentrations in multiple myeloma patients. For this
reason, it was the first immunoglobulin to be purified in large quantities
and to be extensively studied from the structural point of view. The basic
knowledge about the structure of the IgG molecule was obtained from
two types of experiments:
1. Proteolytic digestion. The incubation of purified IgG with papain, a
proteolytic enzyme extracted from the latex of Carica papaya, results in
the splitting of the molecule into two fragments that differ both in charge
and antigenicity. These fragments can be easily demonstrated by
immunoelectro
The Minor Immunoglobulin Classes: IgD and IgE
A. General Concepts. IgD and IgE were the last immunoglobulins to be
identified due to their low concentrations in serum. Both are monomeric
immunoglobulins, similar to IgG, but their heavy chains are larger than
chains. IgE has five domains in the heavy chain (one variable and four
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constant); IgD has four heavy-chain domains (as most other monomeric
immunoglobulins).
B. IgD and IgM are the predominant immunoglobulin classes in the B
lymphocyte membrane, where they are the antigen-binding molecules in
the antigen-receptor complex. The B-cell antigen complex is composed of
membrane Ig
Immunoglobulin Classes
A. IgG
IgG is the major class of immunoglobulin present in the serum. The IgG
molecule consists of two L chains and two H chains (H2L2) (Figure 8-5).
There are four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. Each
subtype contains a distinct but related H chain and each differs somewhat
regarding their biological activities. IgG1 represents 65% of the total
IgG. IgG2 is directed against polysaccharide antigens and may be an
important host defense against encapsulated bacteria. IgG3 is an effective
activator of complement due to its rigid hinge region, whereas IgG4 does
not activate complement due to its compact structure. IgG is the only
immunoglobulin class to cross the placenta and therefore is the most
abundant immunoglobulin in newborns. Isotype-specific transport of IgG
across the placenta occurs with preference for IgG1 and IgG3 subclasses.
IgG also mediates opsonization of antigen through binding of antigenantibody complexes to Fc receptors on macrophages and other cells.
B. IgM
The first immunoglobulin produced in response to an antigen is IgM. IgM
is secreted as a pentamer and is composed of five H2L2 units (similar to
one IgG unit) and one molecule of a J chain (Figure 8- in the fetus or
newborn provides evidence of intrauterine infection.
C. IgA
IgA is the major immunoglobulin responsible for mucosal immunity. The
levels of IgA in the serum are low, consisting of only 10–15% of total
serum immunoglobulins present. In contrast, IgA is the predominate class
of immunoglobulin found in extravascular secretions. Thus, plasma cells
located in glands and mucous membranes mainly produce IgA.
Therefore, IgA is found in secretions such as milk, saliva, and tears, and
in other secretions of the respiratory, intestinal, and genital tracts. These
locations place IgA in contact with the external environment and
therefore can be the first line of defense against bacteria and viruses. The
properties of the IgA molecule are different depending on where IgA is
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located. In serum, IgA is secreted as a monomer resembling IgG. In
mucous secretions, IgA is a dimer and is referred to as secretory IgA.
This secretory IgA consists of two monomers that contain two additional
polypeptides: the J chain that stabilizes the molecule and a secretory
component that is incorporated into the secretory IgA when it is
transported through an epithelial cell. There are at least two IgA
subclasses: IgA1 and IgA2. Some bacteria (eg, Neisseria spp.) can
destroy IgA1 by producing a protease and can thus overcome antibodymediated resistance on mucosal surfaces.
D. IgE
The IgE immunoglobulin is present in very low quantities in the serum.
The Fc region of IgE binds to its high-affinity receptor on the surface of
mast cells, basophils, and eosinophils. This bound IgE acts as a receptor
for the specific antigen that stimulated its production and the resulting
antigen– antibody complex triggers allergic responses of the immediate
(anaphylactic) type through the release of inflammatory mediators such
as histamine.
E. IgD
Serum IgD is present only in trace amounts. However, IgD is the major
surface bound immunoglobulin on mature B lymphocytes that have not
yet encountered antigen. These B cells contain IgD and IgM at a ratio of
3 to 1. At the present time, the function of IgD is unclear.
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