Human B cell proliferative responses during aging. Reduced RNA synthesis and DNA replication after signal transduction by surface immunoglobulins compared to B cell antigenic determinants CD20 and CD40.
Age-related reductions in the DNA replication of human peripheral blood B cells have been reported after stimulation by cross-linking surface immunoglobulins (sIg) with the polyclonal activator Staphylococcus aureus Cowan I (SAC). However, little is known about the mechanisms of these age-related impairments. To examine whether these impairments represented defects unique to sIg mediated signalling, B cells from elderly humans were stimulated with SAC, immobilized anti-IgM and with monoclonal antibodies (mAbs) specific for B cell CD20 and CD40 determinants. Regardless of the stimuli or combinations of stimuli, the proliferative responses of B cells from elderly subjects remained 50% or less of the values observed for B cells from young subjects. Also, the failure to fully restore the age-related impairments of B cells could not be attributed to an absolute lack of potentially reactive cells. Supplementation of anti-IgM stimulated B cells from elderly subjects with IL-2, IL-4 or B cell growth factor (BCGF) revealed that BCGF was able to improve the reduced responses to levels approximating B cells of young subjects. The age-related defects were not restricted to B cell DNA replication because reductions in G1 progression of stimulated B cells from elderly subjects were directly demonstrated by decreased [3H]uridine incorporation into de novo RNA synthesis. However, the age-related impairments in RNA synthesis were less severe than those in DNA replication consistent with progressively greater reductions in the abilities of B cells to traverse the entire cell cycle. Other results showed that the reduced DNA replication of B cells from elderly subjects to immobilized anti-IgM with and without IL-2 did not represent a premature exit of B cells from DNA replication and accelerated maturation into antibody producing cells. Thus, these studies demonstrate that age-related impairments exist in activation signals mediated by several types of human B cell determinants and that abnormalities can be detected during pre-S phase events.
Whisler
R L
RL
William H. Davis Medical Research Center, Ohio State University, Columbus 43210.
Williams
J W
JW
Newhouse
Y G
YG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D015703:Antigens, CD; D018951:Antigens, CD20; D000944:Antigens, Differentiation, B-Lymphocyte; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens; D002453:Cell Cycle; D004261:DNA Replication; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008875:Middle Aged; D012313:RNA / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell; D015398:Signal Transduction / Q000276:immunology
D015703:Antigens, CD; D018951:Antigens, CD20; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D011947:Receptors, Antigen, B-Cell; D012313:RNA