Antibody Synthesis at the Cellular Level

The response of an animal to antigen is altered after its first exposure. The intensified secondary response has been attributed by some to the presence of qualitatively different "memory" cells. The concept of two types of antigen-sensitive ceils, occurring as successive stages in immunoeyte maturation, was elaborated by Burner (i) and Leduc et al. (2), and later into an X-Y-Z scheme by Sercarz and Coons (3). In the X-Y-Z formulation, the X ceil is the first antigen-sensitive ceil in the lymphocytic series, which upon stimulation is converted into a Y or memory cell. Triggering of Y ceils by antigen results in division and irreversible maturation to a plasmacytic series of Z cells whose terminal member is the mature, antibody-producing plasma cell. a ~terzl also uses this terminology (4).Two major states of antigen-induced unresponsiveness have been described; immune paralysis or tolerance (5, 6) and immune exhaustion (4). Although unresponsiveness in both immunologically naive and experienced animals has been documented and discussed, the two categories have never been dearly distinguished. Paralysis may be defined as complete and specific inhibition of immune responsiveness by a particular antigen; exhaustion, as the productive expenditure of a particular compartment of immunocytes. Empirically, paralysis should ensue with no detectable antibody formation, while exhaustion should be characterized by a period of significant antibody production followed by a transient state of unresponsiveness, until new antigen-sensitive cells are recruited.According to this hypothesis, four possible cellular types of unresponsiveness may be induced by antigen: paralysis of X cells, exhaustion of X cells, paralysis of Y cells, and exhaustion of Y cells. In some cases, two of these could coexist. We have undertaken (a) to investigate exhaustion at both the X cell and the Y cell level, and (b) to determine whether exhaustion is an indissociable component of paralysis induction.(a) Early experiments, which showed that continued administration of antigen did not lead to hyperimmunization but rather to a diminished state of reactivity, (7-10) seemed to favor the possibility of concurrent X and Y exhaustion. These papers suggested the cell-transfer experiment of Sercarz and Coons, which showed that for a short time following a secondary antibody response, cells transferred to a normal recipient were unable to produce a further response upon challenge. It was concluded that triggering the Y---*Z conversion in the donor animals resulted in a temporary 1 Sercarz, E. The X-Y-Z scheme of immunoeyte maturation. I. Immune paralysis, exhaustion, and memory.

Section: Discussionmentioning

confidence: 99%

The X-Y-Z Scheme of Immunocyte Maturation

Byers

Sercarz

1968

“…This antibody-mediated suppression of the immune capacity has been mainly viewed as an inhibition of recruitment of the immunocompetent progenitor cells, resulting from antigen-antibody interaction (28)(29)(30). Our data indicate that this indeed may be one aspect of the suppression; however, they further suggest that some of the progeny of the antigen-stimulated progenitor cell (X cell), as a consequence of lack of further antigenic stimulation, are forced into maturation arrest (block in Y --~ Z transformation).…”

Section: Discussionmentioning

confidence: 99%

Requirement for Continuous Antigenic Stimulation in the Development and Differentiation of Antibody-Forming Cells

Hanna

Nettesheim

Francis

1969

The levels of both antigen and specific immunoglobulin are considered important regulatory mechanisms which determine the size of the antibody-producing cell compartment. Uhr and Finkelstein (1) demonstrated that the presence of antigen is essential for continuous synthesis of 19S antibody at any stage after its initiation. Recent studies suggest that repeated antigen contact of immunocompetent cells is required for complete differentiation (2-4). The X-Y-Z immune cell maturation scheme of Sercarz and Coons (5) is established on this assumption.This concept of the continuous role of antigen in the immune response is consistent with the increasing body of evidence demonstrating that antigen does localize and persist in the lymphatic tissue during a primary response (6-9). One site in lymphatic tissue in which antigen has been demonstrated to be localized extracellularly is the germinal center (l(I-11). Although the functional significance of this antigen deposition is not completely resolved, experimental evidence demonstrates that there may be a causal relationship between the antigen localization and the presence and proliferation of the characteristic, large pyroninophilic cells of the germinal centers (8,12). These cells by morphologic and functional parameters are considered immunologically competent cells (13)(14)(15)(16)(17).We have further suggested that during the primary immune reaction the persistence of antigen in germinal centers is a dynamic process which is sensitive to and altered by the level of free specific antibody (18). Studies of Sahiar and Schwartz (19) showed that rabbits receiving heterologous passive antibody 1 hr after antigen had a marked decrease in germinal center hyperplasia during the primary response. Thus two parameters reflect antibody-mediated immune suppression, the decrease in the size of the 19S and 7S antibody-producing cell compartments (20) and decreased proliferation of pyroninophilic cells in germinal centers, this being reflected as lack of growth of the centers.

“…The characteristics of the system have been described elsewhere (7). Target cells in the plaque assays were sheep erythrocytes that had been coated with the respective antigen by the use of bisdiazotized benzidine (13).…”

Section: Methodsmentioning

confidence: 99%

“…The increase in affinity of the antibody produced with time after immunization (4,5) and the finding that passively administered "high" affinity antibodies are more efficient as inhibitors of active antibody formation than are "low" affinity antibodies (6) are also in agreement with the ceUbound antibody concept. Cells carrying high affinity receptors would have a selective advantage at the decreasing antigen concentrations with time after immunization, explaining both the rise in affinity of antibody produced and the increasing resistance with time after immunization towards antibody-induced supression of antibody formation (7).…”

mentioning

confidence: 99%

Cell Separation on Antigen-Coated Columns

Wigzell

Andersson

1969

Self Cite

290

The combination of antigen and specific, predetermined antibody receptors is commonly considered a necessary prelude to the induction of detectable antibody formation. Experimental evidence supporting such a concept has been accumulating in a variety of experimental systems. Administration of antigen will sdectivdy induce DNA synthesis in a small fraction of the lymphoid cell population, that is, in the cells capable of immunological reaction against the immunogen, while leaving cells potentially reactive against other antigens largely untouched (1). The specific inhibition by haptens of the in vitro induction of a secondary response indicates that a cellassociated antibody exists in the cell population containing primed cells, the antigenbinding specificity of the receptor being virtually identical with that of the releasable antibody product of these cells (2, 3). The increase in affinity of the antibody produced with time after immunization (4, 5) and the finding that passively administered "high" affinity antibodies are more efficient as inhibitors of active antibody formation than are "low" affinity antibodies (6) are also in agreement with the ceUbound antibody concept. Cells carrying high affinity receptors would have a selective advantage at the decreasing antigen concentrations with time after immunization, explaining both the rise in affinity of antibody produced and the increasing resistance with time after immunization towards antibody-induced supression of antibody formation (7).Further support for the cell-attached receptor has come from results obtained when using immune cells in vitro where trials were made to find a correlation between affinity of antibody being produced and the concentration of antigen needed to trigger the immune cells into mitosis (8). It can be demonstrated that with increasing affinity of antibody there was a corresponding decrease in the concentration of antigen needed to induce a detectable increase in the DNA synthesis of the cell population.The exact location of the cell-associated antigen-specific receptors is unknown, although they have been assumed to be present on the surface of the potential, antibodysynthesizing cells. The small lymphocyte is a cell type considered to be of major importance for the provision of antibody-producing cells (q), and ~mmunoglobulins have been demonstrated on the outer surface of these cells having a distribution pattern suggesting active synthesis by the small lymphocyte (10).