Sequential triggering of apoptosis, somatic mutation and isotype switch during germinal center development.
Using an approach similar to that used to study primary B-lymphocyte development within bone marrow and primary T-lymphocyte development within thymus, the peripheral B-cell maturation pathway within secondary lymphoid tissue (human tonsils) was analysed on the expression of discrete surface antigens. sIgD and CD38 permit the identification of four subpopulations of tonsillar B lymphocytes, including sIgD+ CD38-, sIgD+, CD38+, sIgD-CD38+ and sIgD-CD38- B cells. Further phenotypic, functional and Ig gene analysis (IgV gene sequences, expression of sterile transcripts and DNA switch circles) allowed us to conclude the following: (1) sIgM+ IgD+ CD38- B cells are naive B cells (Bm1 + 2), which carry unmutated antigen-receptors; (2) sIgM+ IgD+ CD38+ B cells are germinal center founder cells (Bm2'), which become prone to undergo apoptosis before the onset of somatic mutation; (3) sIgM-IgD+ CD38+ are germinal center B cells (Bm 3 delta), that have accumulated the highest number of somatic mutations ever reported in normal B cells; these cells may have undergone C mu-deletion by homologous recombination through sigma mu-sigma delta sequences: (4) sIgD-CD38+ CD77+ B cells are centroblasts (Bm3), in which somatic mutation machinery is activated; (5) sIgD-CD38+ CD77- B cells are centrocytes (Bm4), in which the isotype switching machinery is activated; (6) sIgD-CD38- cells (Bm5) represent somatically mutated resting memory B cells. In conclusion, human peripheral B-cell subpopulations corresponding to the differentiation stages before, during and after the triggering of apoptosis program, somatic mutation and isotype switch have been identified and isolated using a combination of surface markers.
Liu
Y J
YJ
Schering-Plough, Laboratory for Immunological Research, Dardilly, France.
Arpin
C
C
de Bouteiller
O
O
Guret
C
C
Banchereau
J
J
Martinez-Valdez
H
H
Lebecque
S
S
D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand; D018858:Germinal Center / Q000502:physiology*; D006801:Humans; D017578:Immunoglobulin Class Switching; D008562:Membrane Glycoproteins / Q000502:physiology; D009154:Mutation
D008562:Membrane Glycoproteins; D023201:CD40 Ligand