IMMUNOLOGY

Bios 328a textbook-based study of immunologySpring 2003

http://www.lehigh.edu/~sk08/Courses/Bios328/mainpage.htm

FIRST HALF OF TODAY’S CLASS: THE IMMUNOGLOBULINS

A quick overview of the five immnoglobulin “classes”

• IgG ( globulin): the prototypic immunoglobulin. All three general functions (Ag binding, complement

activation, stimulation of phagocytosis) occur.

• IgM (macroglobulin): often the first

• IgA: the secretory immunoglobulin

• IgD: regulatory?

• IgE: functions with parasites and allergens

IgG ( globulin)

IgG is the principal immunoglobulin of the secondary response.

IgG is the principal immunoglobulin of the adult (but not the neonate.)

IgG constitutes 80% of the circulating immunoglobulin in the adult.

The concentration of IgG in serum is high: 8-16 mg ml-1.

The architecture of IgG is simple: two chains and two chains ortwo chains and two chains.

IgM (macroglobulin)

• a pentamer (in secreted form) attached by disulfide bonds between the C4 and C3 domains of adjacent heavy chains; in addition, there is a single J-protein.

•IgM is the first immunoglobulin to be synthesized in a primary response.

•The concentration of IgM in serum is ~ 1.5 mg ml-1.

•IgM is the first immunoglobulin to accumulate in the serum of neonates.

•IgM has a high valency which contributes to agglutination. Also, multimeric nature contributes to effective complement activation.

•mIgM is a monomer.

Some visual reinforcement…

Some more visual reinforcement…

co-los-trum \kc-‘läs-tram \ n \ [L. beestings] (1577) :

milk secreted for a few days after parturition and characterized by high protein and antibody content

IgA (the secreted antibody…)

Most often a dimer; sometimes a tetramer (or a trimer).

Multimers united by J-protein.

Secretion requires addition of “secretory component” produced in mucosal epithelial cells (in digestive, respiratory, genital, breast tissues and salivary and lacrimal glands).

Plasma cells secrete the Ab;

deliver IgA to epithelial cells having poly-Ig-receptor on their surface.

The poly-Ig-receptor is cleaved and the component that stays associated with IgA is the “secretory component.”

MW = 70,000 daltons; composed of 5 immunoglobulin-like domains;

binds to constant regions of heavy chains.

Movement of the receptor from one surface to another is transcytosis.

Visual reinforcement…

IgD and IgE

IgD is very rare.0.03 mg ml-1serum

What does this imply?

IgE is extremely rare.0.0003 mg ml-1 serum

IgE functions against parasites.

In the absence of para-sites, IgE responds to allergens.

IgE

IgE is extremely rare.IgE functions against

parasites.In the absence of para-

sites, IgE responds to allergens.

And, there are subtypes, too

Hinges versus domains…

• Hinges contribute to flexibility. They contain cysteine and proline. Cysteine provides interchain linkage. Proline cannot be incorporated into secondary structure.

• Immunoglobulins without hinge regions have an extra domain.

Isotypes, allotypes, & idiotypes

• ISOTYPE: one of the five (, , , , ) major kinds of heavy chains in immunoglobulins. Note that the

differences among the isotypes are in the constant region.

Indeed, different isotypes can share common variable regions! (Think about that.)

• ALLOTYPE: the allelic variation seen at loci specifying the light and heavy chains of immunoglobulins.

• IDIOTYPE: The set of antigenic determinants (idiotopes) characterizing each unique antibody (or T-cell receptor). Idiotopes are single antigenic determinant(s) in the

variable domains of an antibody (or T-cell receptor). Idiotopes are generated by the unique amino acid sequence specific for each antigen.

Isotypes, allotypes, & idiotypes

IMPORTANT

• One B-cell makes one type of antibody. (More exactly, one B-cell makes one idiotype.)

• (This equation is the basis of monoclonal antibodies but we are going to ignore monoclonals for the time being.)

• Ig’s first appear on the surface of B-cells; there they are selected.

• The B-cells mature to plasma cells and secrete antibodies with the same specificity (i. e., same idiotypic identity; same antigen specificity.)

Visual reinforcement…

Visual reinforcement…

• The carboxy terminus of the mIg, penetrates into the cytoplasm by only a few amino acids. But mIg is always associated with pairs of the dimer Ig- / Ig-.

• These associated dimers have longer carboxy tails, 61 amino acids and 48 amino acids respectively. The tails contain tyrosine residues which can be phosphorylated by kinases; the phosphorylated or un-phosphorylated states constitute a molecular switch conforming to an on / off switch.

• (Immunological phenomena affected by kinases tend to use tyrosine as the receptor of phosphates while other cellular phenomena tend to use serine or threonine.)

Time to review…

Time to review…

• Isotype, allotype, idiotype…– implies that epitopes (at least experimentally) are proteins

– proteins are specified by genes

– how do genes specify the numerous, diverse, highly specific immunoglobulins? (BIG question!)

• Time to review

& take a 5’ break!