B cells from a distinct subset of patients with common variable immunodeficiency (CVID) have increased CD95 (Apo-1/fas), diminished CD38 expression, and undergo enhanced apoptosis.
We investigated the role of apoptosis in the differentiation failure of B cells from a selected subpopulation of patients with CVID delineated by B cell surface marker analysis, in vitro IgE response, and molecular markers of B cell VH gene repertoire. These patients had altered display of B cell surface molecules that play a role in apoptosis. The patients' B cells had a 4.5-250-fold increase in CD95 (Apo-1, fas) expression and increased CD95 display on their T cells. CD38, a molecule important in preventing germinal centre B cell apoptosis, was reduced on the patients' B cells. The expression of this molecule was inducible on the CVID lymphocytes with retinoic acid. Increased spontaneous apoptosis in vitro was observed with the patients' B (23%) and T cells (10%) compared with normal cells (13% and 3%, respectively). Stimulation in vitro with IL-4 and CD40 rescued the B cells from apoptosis and allowed for their differentiation. However, IL-4 plus alpha CD40-driven immunoglobulin production was not quantitatively or qualitatively normal. Failure to overcome apoptosis, a normal step in germinal centre B cell development, may be involved in the lack of differentiation seen in this subset of CVID patients.
Saxon
A
A
Hart and Louise Lyon Laboratory, University of California Los Angeles School of Medicine, USA.
Keld
B
B
Diaz-Sanchez
D
D
Guo
B C
BC
Sidell
N
N
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000737:chemistry / Q000502:physiology*; D019013:CD40 Antigens / Q000494:pharmacology; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009699:N-Glycosyl Hydrolases / Q000032:analysis*; D019014:fas Receptor / Q000032:analysis*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D019014:fas Receptor; D016753:Interleukin-10; D015847:Interleukin-4; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1