Receptor Editing in a Transgenic Mouse Model: Site, Efficacy, and Role of B Cell Tolerance and Antibody Diversification

Immunity, 1997, 7: 765 ­ 775

By Roberta Pelanda, Stephen Schwers, Eiichiro Sonoda, Raul M. Torres, David Nemazee and Klaus Rajewsky

The authors propose that as immature B cells mature, they undergo a selection process so that only cells that fail to recognize self and also bind to antigen with high-affinity survive as mature B cells. Several mechanisms exist to edit B cells as they mature. The first process, deletion, is the physical elimination of B cell clones by apoptosis. A second, clonal anergy is the functional inactivation of auto-reactive B cells. The third, and newly described process, is receptor editing. In receptor editing, as a potentially auto-reactive immature B cell grows and divides, its antibodies slowly mutate and change structure so that they no longer bind the self antigen and thus would not be eliminated or inactivated.

Normally, as an immature B cell grows and divides, the structure and affinity of the antibody it expresses changes due to mutation (receptor editing). The affinity to the target antigen may increase, decrease or change to bind a completely different antigen. This process is a normal part of antibody maturation. The authors have constructed two different forms of antibody gene. One form of the gene allows the antibody to slowly change structure over time as it matures, the other does not. They then insert these genes transgenically into different mouse strains so that they are either autoreactive or not.

The authors find that in animals where the B cells express an autoantibody that can not change structure over time, they are readily deleted. As these animals mature, they have many fewer peripheral, mature B cells. If they use the gene for the antibody that can mutate over time, the B cells escape from deletion and are produced in normal numbers in the periphery. Surprisingly, if they put the transgene into a non-autoreactive mouse, pre B cells were not detected nor receptor editing seen.

Non-autoreactive B cells develop directly into sIgM+ B cells in the bone marrow. Autoreactive B cells remain sIgM pre-B cells. While the non-autoreactive mice develop B cells expressing the transgenic antibody, the transgenic auto-reactive B cells are not longer detected.