Transcript Recognition of Antigens

Antibodies and Antigens
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Adaptive immune responses are initiated by the specific recognition of antigens by
lymphocytes
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This section is devoted to a discussion of the cellular and molecular basis of antigen
recognition and the specificities of B and T lymphocytes
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Antibodies are circulating proteins that are produced in vertebrates in response to
exposure to foreign structures known as antigens
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Antibodies are incredibly diverse and specific in their ability to recognize foreign
shapes, and are the primary mediators of humoral immunity against all classes of
microbes
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Earliest experimental demonstrations of adaptive immunity was the finding by von
Behring and Kitasato in 1890 that chemically inactivated toxins could induce protective
immunity when injected into experimental animals, and that protection could be
transferred to other susceptible animals by injecting serum from their immune
counterparts
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At first were Antitoxins and then called general name "antibodies"
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Antibodies, major histocompatibility complex (MHC) molecules, and T cell antigen
receptors (TCR) are the three classes of molecules used in adaptive immunity to
recognize antigens
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Antibodies can exist in two forms: membrane-bound antibodies on the surface of B
lymphocytes function as receptors for antigen, and secreted antibodies that reside in the
circulation, tissues, and mucosal sites bind antigens, neutralize toxins, and prevent the
entry and spread of pathogens
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Antibody-mediated effector functions include:
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neutralization of microbes or toxic microbial products;
activation of the complement system;
opsonization of pathogens for enhanced phagocytosis;
antibody-dependent ceIl-mediated cytotoxicity (ADCC);
immediate hypersensitivity
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Antibodies are distributed in biologic fluids throughout the body and are found on the
surface of a limited number of cell types
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B lymphocytes are the only cells that synthesize antibody molecules
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Initial antibody response occurs in lymphoid tissues, mainly the spleen, lymph nodes,
and mucosal lymphoid tissues but long-lived antibody-producing plasma cell may
persist in other tissues, especially in the bone marrow
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Any serum sample that contains detectable antibody molecules that bind to a particular
antigen is commonly called an antiserum
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The study of antibodies and their reactions with antigens is therefore classically called
serology
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A healthy 70-kg adult human produces about 2-3 gr of antibodies every day and almost
two thirds of this is an antibody called IgA
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Antibodies that enter the circulation have limited half-lives
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The most common type of antibody, called IgG and has a half-life of about 3 weeks
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Serum contains a mixture of different antibodies produced by many clones of B
lymphocytes that may respond to different portions (epitopes) of an antigen (so-called
polyclonal antibodies)
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Monoclonal antibodies, described by Georges Kohler and Cesar Milstein in 1975
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Specific for a particular antigenic determinant
Homogenous antibodies
Common applications of monoclonal antibodies include:
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Identification of phenotypic markers unique to particular cell types
Immunodiagnostic
Tumor diagnosis
Therapy
Functional analysis of cell surface and secreted molecules
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Antibody molecules can be divided into distinct classes and subclasses on the basis of
differences in the structure of their heavy chain C regions (FC)
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The classes of antibody molecules are also called isotypes and are named IgA, IgD, IgE,
IgG, and IgM
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In humans, IgA and IgG isotypes can be further subdivided into closely related
subclasses, or subtypes, called IgA1 and IgA2, and IgGl, IgG2, IgG3, and IgG4
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In mice, which are often used in the study of immune responses, differ in that the IgG
isotype is divided into the IgGl, IgG2a, IgG2b, and IgG3 subclasses
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Heavy chains are designated by the letter of the Greek alphabet corresponding to the
isotype of the antibody: IgA contains α1 heavy chains; IgA2,α2; IgD, δ; IgE, ε; IgG1, γ1;
IgG2, γ2; IgG3, γ3; IgG4, γ4; and IgM, μ
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In human IgM and IgE antibodies, the C regions contain four tandem Ig domains. The
C regions of IgG, IgA,and IgD contain only three Ig domains
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Different isotypes and subtypes of antibodies perform different effector functions
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Antibody molecules are flexible, permitting them to bind to different arrays of antigens
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The hinge region varies in length from 10 to more than 60 amino acid residues in
different isotypes
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There are two classes, or isotypes, of light chains, called κ and λ ,which are
distinguished by their carboxy-terminal constant (C) regions
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In humans, about 60% of antibody molecules have κ light chains, and about 40% have λ
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In mice, κ-containing antibodies are about 10 times more abundant than λ
- Allotype and anti
allotype (Fc)
- Idiotype and anti
idiotype (V)
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Ig heavy and light chains, like most secreted and membrane proteins, are synthesized on
membrane-bound ribosomes in the rough endoplasmic reticulum
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Proper folding of Ig heavy chains and their assembly with light chains are regulated by
proteins resident in the endoplasmic reticulum called chaperones
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Chaperones include calnexin and a molecule called BiP (binding protein), bind to newly
synthesized Ig polypeptides
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Covalent association of heavy and light chains, stabilized by the formation of disulfide
bonds, also occurs in the endoplasmic reticulum
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Released from the chaperones and directed into the cisternae of the Golgi complex,
where carbohydrates are modified, and the antibodies are then transported to the
plasma membrane in vesicles
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An antigen is any substance that may be specifically bound by an antibody molecule or
T cell receptor
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Antibodies can recognize as antigens almost every kind of biologic molecule, including
simple intermediary metabolites, sugars, lipids, aminoacoids, and hormones, as well as
macromolecules such as complex carbohydrates, phospholipids, nucleic acids, and
proteins
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This is in contrast to T cells, which mainly recognize peptides
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Although all antigens are recognized by specific lymphocytes or by antibodies, only
some antigens are capable of activating lymphocytes. Molecules that stimulate immune
responses are called immunogens
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Such as dinitrophenol, may bind to antibodies, and are therefore antigens, but cannot
activate B cells on their own (they are not immunogenic) called hapten
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Protein to which it is conjugated is called a carrier
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Presence of multiple identical determinants in an antigen is referred to as polyvalency
or multivalency. Most globular proteins do not contain multiple identical epitopes and
are not polyvalent, unless they are in aggregates
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Steric interference
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Epitopes formed by several adjacent amino acid residues are called linear determinants
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In contrast, conformational determinants are formed by amino acid residues that are
not in a sequence but become spatially juxtaposed in the folded protein
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Proteins may be subjected to modifications such as glycosylation, phosphorylation, or
proteolysis by altering the structure of the protein, can produce new epitopes such
epitopes are called neoantigenic determinants
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Antigen-binding sites of most antibodies are planar surfaces that can accommodate
conformational epitopes of macromolecules, allowing the antibodies to bind large
macromolecules
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Recognition of antigen by antibody involves non-covalent, reversible binding including
electrostatic forces, hydrogen bonds, van derWaals forces, and hydrophobic interactions
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Strength of the binding between a single combining site of an antibody and an epitope of
an antigen is called the affinity of the antibody that is commonly represented by a
dissociation constant (Kd)
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Kd of antibodies produced in typical humoral immune responses usually varies from
about 10-7 to 10-11
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Overall strength of attachment is called the avidity and is much greater than the affinity
of anyone antigen-binding site
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Cross-reaction
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Affinity maturation
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Somatic mutation
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Isotype switching