Barry J. Skidmore

Mechanism of Activation and Tolerance Induction in B Lymphocytes

Several different models have been suggested for the stimulation of B lymphocytes, some of which involve one signal, while others involve two signals. The most popular of the two signal models is that proposed by Bretscher & Cohn (1970) and Watson et al. (1973). They suggested that B lymphocytes were stimulated to differentiate after receiving a signal when antigen reacts with the Ig receptors on the cell surface followed by a second signal delivered by an activated T cell. Immimological tolerance resulted if only the first signal was received. It was further suggested that the responses to all antigens were, to some degree, thymus dependent. In contrast, the one signal model of Coutinho & Moller (1975) is based on the existence of thymus independent responses. They propose that all thymus independent antigens are mitogens and that the response by the B lymphocyte results from direct stimulation of the cell by the mitogen and does not result from interaction of antigen with Ig receptors. Another possible one signal model has been suggested in which the signal may arise directly from the interaction of antigen with Ig receptors (Feldmann & Nossal 1972). If both thymus dependent and thymus independent responses do occur, it may be that the mechanism involved in the activation of B lymphocytes in these two responses differs. Furthermore, all three; theories are compatible with the possibility that the final signal is delivered by mitogens. The present paper will brieffy discuss these three current and fundamentally different models of B Ijmiphocyte activation, with emphasis on how each explains

MANIPULATION OF A TOLERANT STATE: CELLS AND SIGNALS

ABSTRACT The state of immunological unresponsiveness induced in mice with a tolerogenic form of the antigen human IgG can be cellularly characterized into phases of either T and B cell tolerance or T cell tolerance. In those circumstances when specific T cells appear tolerant while B cells are not, bacterial lipopolysaccharide (LPS) was able to modulate the biological effect of tolerogen from its capacity to induce tolerance to a capacity to induce specific immunity. This property of LPS was demonstrated under conditions where it could also act as a B cell mitogen. In two experimental situations in which LPS could be shown to be non-mitogenic, namely in the C3H/HeJ mouse strain or after chemical modification as a result of base hydrolysis, it could not affect the normal induction process of tolerance.

CELLULAR PARAMETERS OF THE TOLERANT STATE INDUCED TO HUMAN γ GLOBULIN IN MICE AND OF ITS MODULATION BY BACTERIAL LIPOPOLYSACCHARIDES

Publisher Summary This chapter discusses the cellular parameters of a tolerant state in mice to human γ globulin and its modulation by bacterial lipopolysaccharides. The theoretical genesis for the concept of clonal elimination stems from the necessity to provide a means for the biological basis of self-non-self discrimination. If the immune system can be viewed as a functional network of finely attuned regulatory mechanisms that suppresses rather than eliminates the potential for detrimental reactions, then the necessity for clonal deletion as the pathway by which self fails to be recognized may not be a biological prerequisite. Nevertheless, an attraction still exists for the evolutionary selection of a recognition system that can respond either positively or negatively depending on the conditions of interactions between cells and antigens. In this regard, an ontogenetic basis for self tolerance could be viewed as occurring at a stage in the course of lymphoid cell differentiation when a negative response is the only consequence that can result from a specific interaction between lymphocyte and antigen.

The determination of lymphoid cell chimerism using peripheral blood lymphocytes from murine bone marrow chimeras.

A simple, rapid and accurate method was devised for deteriming lymphoid cell chimerism in bone marrow-reconstituted mice. Chimeras were produced by reconstituting lethally irradiated mice with semi-allogeneic bone marrow cells. Lymphocytes from the peripheral blood of individual chimeric mice were purified by sedimentation in dextran solution and differential flotation in Ficoll-Hypaque gradients. From 250--500 microliters of blood, 1--7 X 10(5) cells were routinely obtained. The extent of chimerism was determined serologically by using peripheral blood lymphocytes as target cells in a dye exclusion microcytotoxicity assay. Using this new technique, approximately 80% of the reconstituted mice were found to be repopulated with lymphocytes of the donor type.