Cellular and molecular mechanisms of B lymphocyte tolerance

A paradox of immunology is that the immune system is distributed so widely in the body, as a large number of cells that discharge most of their effector functions as single cells; but, at the same time, the elements of the system are so very interdependent, not only via specialized cell clusters and microenvironments, but also by mobile feedback loops, cellular and molecular. The end result is that one cannot really understand one element of the system without understanding every other, at least to a degree. Certainly, tolerance cannot be isolated from immune activation, nor B cell from T cell tolerance, rendering the task of the reviewer somewhat thankless. This being said, the last few years have seen wonderful progress in our grasp of B cell tolerance, to which the transgenic revolution has contributed a great deal. The fact that B cell tolerance exists as an important component of self-tolerance has been firmly established, as have the limits of the process in terms of both the survival of low-affinity antiself clonotypes and the question of location and concentration of antigen required for tolerance induction. Two processes have been identified as key alternatives: clonal abortion/maturation arrest/deletion and induction of clonal anergy. The latter requires a less strong Ig receptor crosslinking signal, may be partial, and is reversible. Recognition of these facts has prompted both experimentation and speculation on possible functions of the anergic cell. One unsatisfactory area, which we have not addressed because nothing like a consensus has been reached, is T cell-mediated suppression and its possible effects on tolerant states, including anergy induction in B cells. The phenomenology of suppression is too striking to sweep under the carpet, and suppressor T cell memory in particular (Adelstein et al., 1990) requires much more investigation; however, suppression has not been shown to play a major role in any of the best-studied transgenic models. These can readily be explained on the basis of direct interactions between the B cell target for abortion or anergy and the self antigen in question. The biochemical basis of discrimination between immunity and tolerance has also progressed, but not as fast. This is understandable, as so many signaling pathways have to come together for full immune induction, and as immaturity of the signal transduction pathway plays a profound role that must be studied in normal cells, with all the attendant difficulties of cell separation.(ABSTRACT TRUNCATED AT 400 WORDS)