B Cell Tolerance

Current Opinion in Immunology, 1992, 4:703 ­ 710

By Christopher C. Goodnow

Transgenic mouse models developed by the author and his colleagues have been the basis for investigating the physiological significance of B cell elimination (deletion) and inactivation (anergy). In these studies, transgenic mice are programmed to make hen egg lysozyme (HEL) as a "self" antigen expressed either in solution or on cell membranes. Other mice are programmed to make antibodies to HEL and still other mice are able to both express HEL and antibodies to HEL. The details of these models and the experimental results have been described in many of the papers in this collection.

Physiological fates of self-reactive B cells in vivo:

In mice whose B cells express genes for antibodies to HEL (self), the B cells are eliminated rather than inactivated if HEL is expressed on cells of the bone marrow. Similar findings have also been reported by other laboratories for the expression of self antigens such as red cell surface antigens, the MHC antigen, CD 8, and ssDNA.

Determination of self-reactive B cell fate

Antibody binding of soluble self antigen on the surface of immature B cells results in maturation, emigration and persistence in peripheral follicles, while nonetheless inactivating the B cell's ability to further respond to antigen. In more mature B cells, an encounter with self-antigen results in rapid cell death, presumably by apoptosis. Signal strength, that is, the amount of cross linking of antibodies on the surface of the B cell has a direct effect on cell fate. Binding by fifty percent of the B cell surface Ig with soluble self-antigen leads to inactivation, while, five percent binding fails to perturb development or function. Binding of membrane bound self-antigen which promotes cross linking, leads to elimination, not inactivation. Binding of B cells to highly multivalent self-antigens such as membrane expressed HEL, dsDNA, and MHC all lead to greater amounts of cross linking, and all result in elimination rather than inactivation.

Peripheral tolerance

Peripheral mature B cells become inactivated when they encounter soluble self-antigen in the absence of T cell help. Mature B cells are eliminated when they encounter membrane-bound multivalent antigen in the periphery. Later studies have shown (see Monroe above) that elimination is the result of cellular apoptosis. The censoring of high-affinity B cells is suggested primarily from the many studies using conjugates which cross link antibodies on the surface of B cells but do not activate T cells, such as La Jolla Pharmaceutical Company's Toleragen for dsDNA antibodies, LJP 394.