Evidence for the clonal abortion theory of B-lymphocyte tolerance.

Abstract

This paper deals with the behavior of adult mouse bone marrow cells placed in tissue culture with or without antigen, and subsequently assessed for immune competence after adoptive transfer into lethally X- irradiated, syngeneic hosts. Attention was focussed on B lymphocytes through using hapten human gamma globulin (HGG) preparations as putative tolerogens in tissue culture, the T-cell-independent antigens DNP-POL and NIP-POL as challenge injections in adoptive hosts, and numbers of hapten-specific PFC in host spleens for the quantitation of immune competence. It was found that the capacity of bone marrow cells to mount an adoptive immune response rose by a factor of about fivefold over 3 days in tissue culture. This rise was completely abolished by the presence in the culture of hapten-HGG conjugates with about one mole of hapten per carrier molecule. The prevention of the emergence of immune competence amongst maturing B cells was termed clonal abortion tolerogenesis. Dose-response studies showed the lowest effective antigen concentration to be between 2.5 times 10- minus 10 and 2.5 times 10- minus 9 M, and a standard concentration of 2.5 times 10- minus 8 M was chosen as producing near maximal effects. The tolerance was antigen-specific and time-dependent, being maximal only when antigen was present continuously as the cultured cells was maturing. It did not depend on the presence of T lymphocytes in marrow, and was not of an "infectious" type. In contrast to tolerogenesis of mature B lymphocytes by high antigen concentrations, it could not be abolished by lipopolysaccharide. We speculate that clonal abortion may be a tolerance mechanism of great physiological significance for self- recognition, and discuss the results in the framework of other recent tolerance models, including those involving receptor blockade and suppressor T cells.

Ontogenic development of B-lymphocyte function and tolerance susceptibility in vivo and in an in vitro organ culture system.

“…Presumably, most of the progenitors that can acquire s-Ig receptors in vitro have done so within the incubation period, and the presence of tolerogen during this maturation phase almost totally eliminates the potential anti-DNP clones. This is consistent with our previous results in which immature B cells in the absence of T cells are highly susceptible to tolerance induction (18,20) and provides strong evidence in favor of the clonal abortion theory (38).…”

Differences in susceptibility of mature and immature mouse B lymphocytes to anti-immunoglobulin-induced immunoglobulin suppression in vitro. Possible implications for B-cell tolerance to self.

“…Nossal and Pike have recently reported that IgM antihaptenforming precursor B-cells in adult mouse bone marrow are much more sensitive to hapten-specific tolerance induced in vitro by deaggregated dinitrophenylhuman gammaglobulin than are similar cells in adult spleen (24). Their observations, together with our own, lend support to the old, but presently unfashionable hypothesis, that tolerance to self, at least in B cells, may be related to B cells passing through a stage in their normal differentiation where they are highly susceptible to tolerance induction (21,23).…”

BAFF and the plasticity of peripheral B cell tolerance

“…These notions, originally proposed by Nossal and Pike [3,4], were apparently supported by in vivo studies in the HEL/anti-HEL transgenic model, where high avidity BCR interactions led to the elimination of HEL-reactive cells in the bone marrow, while low avidity interactions indeed yielded self-reactive cells in the periphery [5]. However, following description of the TR compartment, Fulcher and Basten demonstrated that these 'anergic' B cells achieved entrance to the TR pools, but nonetheless died rapidly before entering mature pools [6].…”