Clonal anergy: the universally anergic B lymphocyte.

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Abstract
The clonal anergy theory of induction of immunological tolerance states that differentiating B lymphocytes that encounter multivalent antigen at the pre-B to B cell transition stage can receive and store a negative signal, which renders them anergic to later triggering stimuli. The theory was tested by using an anti-.mu. chain monoclonal antibody, E4, as a model tolerogen. The fluorescence-activated cell sorter was used to select B cell-free cell populations from adult murine bone marrow or newborn spleen, and later, to analyze B cell neogenesis in vitro. The presence of E4 at .gtoreq. 1 .mu.g/ml was required to impede the development of normal numbers of B cells with fall receptor status. The subsequent capacity of these B cells to respond in vitro to mitogens was assessed in a filler-cell free microculture system that allows single B cells to proliferate and differentiate. Concentrations of E4 far below those required to affect B cell neogenesis had profound inhibitory effects on the subsequent functional capacity of the B cells. In fact, 10-3 .mu.g/ml of E4 markedly impaired both proliferation and antibody formation and 10-1 .mu.g/ml, which had no effect on Ig receptor development, abrogated functional capacity. Thus, B cells formed in the presence of E4 at 10-1 .mu.g/ml, although possessing the receptor status typical of B cells, were functionally entirely anergic. Exposure to E4 appeared to accelerate the spontaneous death rate of newly formed B cells in vitro. Whether the anergic cell would also have a shortened life-span in vivo is not known.