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!