Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status.
The 2 subsets of chronic lymphocytic leukemia (CLL), of worse or better prognosis, likely derive from pre-GC unmutated B cells, or post-GC mutated B cells, respectively. Different clinical behavior could relate to the ability of tumor cells to respond to surface (sIg)-mediated signals. Unmutated cases (U-CLL) have an increased ability to phosphorylate p72(Syk) in response to sIgM ligation compared to mutated cases (M-CLL). We now confirm and further investigate this differential signaling in a large cohort by [Ca(2+)](i) mobilization. Cases responding to sIgM ligation express higher levels of CD38, ZAP-70, and sIgM. However, CD38 does not influence signaling in vitro or associate with response in bimodal CD38-expressing cases. Similarly, ZAP-70 expression is not required for response in either U-CLL or M-CLL. Strikingly, partially or completely anergized sIgM responses from each subset can recover both sIgM expression and signal capacity spontaneously in vitro or following capping/endocytosis. This provides direct evidence for engagement of putative antigen in vivo. Signaling via sIgD differs markedly being almost universally positive in both U-CLL and M-CLL, with no association with CD38 or ZAP-70 expression. Downstream signaling pathways, therefore, appear intact in CLL, locating anergy to sIgM, mainly in M-CLL. Integration of differential isotype-specific effects mediated by (auto)antigen may determine tumor behavior.
Mockridge
C Ian
CI
Molecular Immunology Group, Tenovus Laboratory, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
Potter
Kathleen N
KN
Wheatley
Isla
I
Neville
Louise A
LA
Packham
Graham
G
Stevenson
Freda K
FK
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D000954:Antigens, Surface / Q000502:physiology*; D020013:Calcium Signaling / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics*; D004705:Endocytosis / Q000276:immunology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D007072:Immunoglobulin D / Q000378:metabolism; D007075:Immunoglobulin M / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics; D009154:Mutation; D011379:Prognosis; D020239:Receptor Cross-Talk / Q000276:immunology; D015398:Signal Transduction
D000954:Antigens, Surface; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1