Autoradiographic Studies on the Immune Response

Abstract

Since the early experiments of Fagraeus (1), the role of plasma cells in antibody formation has been extensively studied and reviewed (2-7). Plasma cells have been found to contain (8-15) and produce (16-23) antibody, and apparently are the chief mediators of a humoral immune response. After the second injection of an antigen, far more plasma cells appear than after the first; this appears to be the main reason for the characteristic booster serum antibody response (18). Burnet and Fenner (2) first suggested that the secondary response might represent the proliferation of cells specifically altered by the primary immunization. Since the development of the clonal selection theory of acquired immunity (6, 24--27), there has been renewed interest in the nature of the plasma cell ancestor, the carrier of specific immunological memory.The present experiments have used autoradiographic labeling techniques to study this question. They are predicated on the uptake of tritiated (H*-) thymidine as an index of desoxyribonucleic acid (DNA) synthesis (28-30), and the validity of our conclusions depends on a number of premises which are widely held, but still the subject of active discussion (31-33). The premises most directly relevant to our experiments are: (a) the tritium label on thymidine is stable and does not exchange; nor does thymine base exchange after incorporation into DNA; (b) DNA itself is metabolically stable and turnover is insignificant in resting mammalian cells; (c) HS-thymidine injected intravenously is rapidly distributed throughout the body, and either promptly incorporated into DNA or eliminated; (d) thymidine or H3-thymidine does not affect the normal behavior of the cells that have taken it up. This last premise has recently been challenged (34).

The Emergence of Antibodies With Either Identical or Unrelated Individual Antigenic Specificity During Repeated Immunizations With Streptococcal Vaccines

“…Recombinants of heavy and light chains from two different sera collected from the same rabbit at 6-month intervals in the course of immunization had 60-100 % as much binding capacity as recombinants from a single serum, and were much more active than heterologous recombinants. In view of the fact that an antibody-producing cell does not survive longer than a few days (32,33), recall of antibodies with a specificity similar to that present during the first immunization reinforces the suggestion that cells with a "memory" function must be involved in the recognition of the antigen and subsequent antibody synthesis (33,34).…”

A Division-Linked Mechanism for the Rapid Generation of Ig-Secreting Cells from Human Memory B Cells

“…Nevertheless, if the changing sensitivity of activated memory B cells to CD40L observed in vitro can be extrapolated to the in vivo situation, it is possible that CD38 Ϫ and CD38 ϩ ISCs represent short-lived and long-lived ISCs, respectively (14, 50 -53). Thus, acquisition of CD38 expression may correlate with selection into a population of T cell stimulation-independent, rapidly proliferating plasma cell precursors, which contribute to an initial expansion of the selected population of ISCs (9,10,47,49,54). The rapidly dividing CD38 ϩ ISCs presumably then acquire altered homing characteristics, resulting in their migration to sites including bone marrow (55,56), where they undergo terminal differentiation to yield long-lived quiescent CD38 ϩ plasma cells (38,45,52,53,57,58).…”

Potentiation of T-Cell-Mediated Immunity by Selective Suppression of Antibody Formation With Cyclophosphamide

“…They must derive, therefore, from rapidly replicating precursors. A relevant, and once disputed, finding of Nossal and M~kel~ (18) showed that a very high ( if not improbable) proportion of antibody-secreting cells became labeled by an injection of tritiated thymidine given 2 h before antigen. Though the labeling rates were probably inflated by reutilization, this finding gains significance from the fact that bone marrow ]ymphocytes (predominantly Ig-bearing B cells) have a very high turnover rate (19) and are a rich source of antibody-forming precursors.…”