Immunoglobulins

Review

Antibody diversity diagram

Differentiation

At this point, the antigen specificity of the mature B-cell has been determined

IgD

B cell receptor

IgE

Binds mast cell surfaces Involved in allergic responses

Differentiation

During differentiation of the B-cells from precursor stem cells, rearrangement, recombination and mutation of the immunoglobulin V, D, and J regions occurs to produce functional VJ (light chain) and VDJ (heavy chain) genes

B-cells

Each cell can make only one heavy chain and one light chain, although the isotype of the heavy chain may change.

Antibody diversity can be generated in at least 3 possible ways

Multiple genes in the germ line DNA. Variable recombination during the differentiation of germ line cells into B-cells. Mutation during the differentiation of germ line cells into B-cells.

IgG

Placental transfer Binds phagocytic cell surfaces Activates complement Involved in opsonization and ADCC. Four subclasses; IgG1, IgG2, IgG3, IgG4

IgA

Two subclasses; IgA1, IgA2. Also found as dimer (sIgA) in secretions.

IgM

activates complement First Ab in development and response

Example of Basic Immunoglobulin Function

an antibody might bind to a toxin and prevent that toxin from entering host cells where its biological effects would be activated. Similarly, a different antibody might bind to the surface of a virus and prevent that virus from entering its host cell.

Idiotypes are so unique that..

an individual person is probably capable of generating antibodies directed against their own idiotypic determinants.

Variable regions

are contained within the amino (NH2) terminal end of the polypeptide chain (amino acids 1-110)

Some of the antibodies functions

are independent of the particular class (isotype) of immunoglobulin. These functions reflect the antigen binding capacity of the molecule as defined by the variable and hypervariable (idiotypic) regions.

The structural (three-dimensional) features that define isotypes

are not immunogenic in an animal of the same species, since they are not seen as "foreign" For ex:the five human isotypes, IgA, IgD, IgG, IgE and IgM are found in all humans and a result, injection of human IgG into another human would not generate antibodies directed against the structural features (determinants) that define the IgG isotype. However, injection of human IgG into a rabbit would generate antibodies directed against those same structural features.

The production of immunoglobulins

by B-cells or plasma cells occurs in different stages

Light chains

composed of 220 amino acid residues

Heavy chains

composed of 440-550 amino acids

Immunoglobulins

composed of four polypeptide chains: two "light" chains (lambda or kappa), and two "heavy" chains (alpha, delta, gamma, epsilon or mu).

Constant regions

comprising amino acids 111-220 (or 440-550), are rather uniform, in comparison, from one antibody to another, within the same isotope

4 polypeptide chains held together by

covalent disulfide (-S-S-) bonds

The type of heavy chain an immunoglobulin possesses

determines the immunoglobulin "isotype"

Each chain

has "constant" and "variable" regions as shown in the figure.

Antibodies function

in a variety of ways designed to eliminate the antigen that elicited their production

Classifications of Immunoglobulins

isotype allotype idiotype

Some cells will undergo a "class switch" during which a rearrangement of the DNA will occur

lacing the VDJ gene next to the genes encoding the IgG, IgE or IgA constant regions

Hypervariable regions

or "Complementarity Determining Regions" (CDRs) are found within the variable regions of both the heavy and light chains

The immune system has the capacity to

recognize and respond to about 10,000,000 different antigens

Unlike isotopes, allotypes

reflect genetic differences between members of the same species This means that not all members of the species will possess any particular allotype. Therefore, injection of any specific human allotype into another human could possibly generate antibodies directed against the structural features that define that particular allotypic variation.

Idiotypes

reflect the antigen binding specificity of any particular antibody molecule

Hypervariable regions

serve to recognize and bind specifically to antigen

Isotypes and allotypes are

similar

B-cell

the B-cell will differentiate into a plasma cell expressing large amounts of secreted IgM upon stimulation by antigen

An allotype is determined by

the amino acid sequence and corresponding three-dimensional structure of the constant region of the immunoglobulin molecule

An idiotype is determined by

the amino acid sequence and corresponding three-dimensional structure of the variable region of the immunoglobulin molecule.

Type of heavy chain determines?

the immunoglobulin isotype (IgA, IgD, IgG, IgE, IgM, respectively).

An isotype is determined by

the primary sequence of amino acids in the constant region of the heavy chain, which in turn determines the three-dimensional structure of the molecule

Upon, Secondary induction (i.e. the secondary response)

these B-cells will differentiate into plasma cells expressing the new isotype. Most commonly, this results in a switch from IgM (primary response) to IgG (secondary response). The factors that lead to production of IgE or IgA instead of IgG are not well understood.

Since immunoglobulins are proteins

they can act as an antigen, eliciting an immune response that generates anti-immunoglobulin antibodies

Other antibody functions are dependent

upon the immunoglobulin class (isotype). These functions are contained within the constant regions of the molecule.

A mature B-cell

will produce primarily IgD (and some membrane IgM) that will migrate to the cell surface to act as the antigen receptor.