1. Immunoglobulin Expression and the Role of Antigen in
Immunoglobulin Diversity
March 20, 2009
10:00-11:00

2. REVIEW OF ANTIGEN INDEPENDENT GENERATION OF DIVERSITY

3. Genomic Ig Loci
Figure 2-14

4. Figure 2-18 V(D)J SEGMENT JOINING GENERATES VARIABLE REGION
NB—Joining deletes intervening gene segments

5. ANTIGEN BINDING SITES ARE HYPERVARIABLE

6. THE HEAVY CHAIN LOCUS AFTER VDJ JOINING
NB---the complete VH (VDJ segments) is juxtaposed to the C region
genes

7. H and L Proteins are Expressed from Rearranged Loci

8. MEMBRANE Ig IS ASSOCIATED WITH OTHER PROTEINS
Ig expression requires the presence
of other proteins
Iga and Igb are invariant proteins
that are necessary for mIg expression
Iga and Igb are also required for
signal transduction

9. ALLELIC EXCLUSION MAKES B CELLS MONOSPECIFIC
ALL THE Ig MOLECULES ON A B CELL ARE THE SAME
Every cell has 2 Alleles for each gene
B cells express only one heavy chain allele:
ALLELIC EXCLUSION
B cells express only one allele of either k or l
LIGHT CHAIN ISOTYPE EXCLUSION
ALLELIC EXCLUSION MAKES B CELLS MONOSPECIFIC

10. CO-EXPRESSION OF IgM AND IgD
Naïve B cells exit the bone marrow with both mIgM and mIgD
The same VDJ is juxtaposed to Cm and Cd
VDJ becomes associated with Cm or Cd by differential RNA processing
IgM and IgD EXPRESSION ARE ANTIGEN INDEPENDENT

11. THE EFFECT OF ANTIGEN ON IMMUNOGLOBULIN EXPRESSION

12. ANTIGEN CAUSES B CELLS TO BECOME PLASMA CELLS
The form of immunoglobulin on the membrane of a B cell is different
from secreted form of immunoglobulin

13. ALL HEAVY CHAIN GENES ARE ORGANIZED SIMILARLYCe Ca Cm Cg 4 3 2 1 s M1 M2
All isotypes have membrane and secreted forms

14. MEMBRANE AND SECRETED FORMS ARE GENERATED BY
DIFFERENTIAL RNA PROCESSING
Membrane form is longer: it has extracellular, transmembrane, and cytoplasmic regions
Secreted form is shorter : it only has an short tail

15. ANTIGEN INCREASES THE DIVERSITY OF V REGIONS
The process that increases diversity is called SOMATIC HYPERMUTATION
The result is AFFINITY MATURATION

16. ANTIGEN CAN CAUSE VDJ TO ASSOCIATE WITH A DIFFERENT CH

17. ISOTYPE SWITCHING OCCURS BY DNA REARRANGEMENT
S regions are repetitive sequence 5’ to every C except Cd
Recombination occurs between S regions
Intervening DNA is deleted and VDJ becomes associated with a new CH

18. THE EFFECTS OF ANTIGEN ON Ig EXPRESSION
Somatic hypermutation…affinity maturation
Alterations in RNA processing to yield secreted form of Ig
Isotype switching

19. The Effect of Isotype (Heavy Chain Class) Switching on Ig Function

20. GENOMIC ORGANIZATION VS PROTEIN STRUCTURECg 3 2 s M1 M2 1 Ca 3 2 1 s M1 M1 M2 Cm 1 2 3 4 s Ce 4 3 2 1 s M1 M2
Structural differences are responsible for functional differences

21. ISOTYPES HAVE DIFFERENT PHYSICAL PROPERTIES

22. IgA AND IgM FORM MULTIMERS

23. DIFFERENT ISOTYPES HAVE DIFFERENT FUNCTIONS

24. The importance of multiple isotypes
Dennis Fawcett
5 year old presenting with an acute sinus infection
Recurrent sinus infections since he was 1
Pneumocystis carinii at 3 years of age
Testing revealed:
IgG 25 mg/dl (normal )
IgA not detected
IgM 210 mg/dl (normal )
Point:
Absence of specific isotypes increases susceptibility to infection
Many bacteria are effectively cleared by opsonization