Structural and functional features of the B-cell receptor in IgG-positive chronic lymphocytic leukemia.
OBJECTIVE
To determine the origin and relationship of the rare IgG+ variant of chronic lymphocytic leukemia (CLL) to the two common IgM+IgD+ subsets that are distinguished by expression of unmutated or mutated V(H) genes, with the former having a worse prognosis.


METHODS
IgG+ CLL cells were characterized using phenotypic, functional, and immunogenetic analyses.


RESULTS
IgG+ CLL was phenotypically similar to mutated IgM+IgD+ CLL (M-CLL) and variably expressed CD38 (4 of 14). ZAP-70, a tyrosine kinase preferentially expressed in unmutated CLL, was found in only 2 of 14 cases. The ability to signal via surface IgM (sIgM) varies between the main subsets of CLL and is associated with expression of ZAP-70. In IgG(+) CLL, 9 of 14 responded to engagement of sIgG with no apparent requirement for expression of CD38 or ZAP-70. However, signal capacity correlated with intensity of sIgG expression. Most switched immunoglobulin variable region genes were somatically mutated without intraclonal variation, and no case expressed activation-induced cytidine deaminase. Derivation from a postgerminal center B cell is, therefore, likely, and a relationship with M-CLL is suggested. This is supported by a shared biased usage of the V4-34 gene. Similar bias in normal B cells developed with age, providing an expanded population for transforming events. However, conserved sequences detected in the CDR3 of V4-34-encoded gamma chains were not found M-CLL, indicating no direct path of isotype switch from M-CLL.


CONCLUSIONS
IgG+ CLL is likely to arise from an age-related expanded pool of B cells, on a path parallel to M-CLL, and perhaps with a similar clinical course.
Molecular Immunology Group, Tenovus Research Laboratory, Cancer Sciences Division, Southampton General Hospital, Southampton, UK. kp1@soton.ac.uk
Kathleen N
KN
Potter
C Ian
CI
Mockridge
Louise
L
Neville
Isla
I
Wheatley
Michael
M
Schenk
Jennifer
J
Orchard
Andrew S
AS
Duncombe
Graham
G
Packham
Freda K
FK
Stevenson
D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology; D000368:Aged; D000369:Aged, 80 and over; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium