Autoreactive B Cell Regulation: Peripheral Induction of Development Arrest by Lupus-Associated Autoantigens

Immunity, 1998, 8: 208 ­ 219

By Sandra Santulli-Marotto, Marc W. Retter, Renelle Gee, Mark J. Mamula, and Stephen J. Clark

These authors have investigated the regulatory mechanisms governing the production of lupus autoantibodies in normal mice. These studies are a model for the regulation of antibody production in normal individuals as compared to lupus patients. Their studies focus on the production of lupus autoantibodies to two well-known targets, Sm and ssDNA.

Antibodies Sm and to single stranded DNA ssDNA are common in lupus patients. Anti-ssDNA is present in 70% and anti-SM in 25% of patients. Antibodies to ssDNA do not bind or cross-react with double stranded DNA (dsDNA). The MRL lupus mouse model makes antibodies to Sm. which often also bind to ssDNA.

They have constructed a transgenic mouse model that has received a commonly expressed antibody gene to Sm called 2-12H from the MRL autoimmune mouse. The authors discover that the transgenic mice make large numbers of B cells to Sm that also bind to single stranded DNA. Nonetheless, they do not have elevated levels of these antibodies in the bloodstream.

Many of the B cells to Sm appear immature based on the levels of specific cells surface markers, have shorter half lives than typical and do not migrate out of the spleen. None have matured to antibody producing cells. The authors also find that these immature B cells, while present in large numbers in the bone marrow, are not present in large numbers in the lymph nodes as would be expected for normally maturing B cells.

Further study reveals that these immature B cells have the ability to produce antibodies to Sm or ssDNA if treated in culture with a biological reagent that nonspecifically activates all B cells, called LPS (like massive T cell help). In addition, immunization of the transgenic mice with another autoreactive complex, snRNP, results in the production of anti-Sm as if tolerance were being broken.

The authors conclude that these transgenic B cells, while capable of being manipulated to mature and produce antibodies, are not normally activated to mature in vivo, but are regulated and controlled by the immune system to become anergic. These experiments are a model of immune regulation of normal peripheral B cell tolerance to both ssDNA and to the Sm. Their studies do not explain the process of regulation. The authors speculate that their results are either due to insufficient levels or low affinity for antigen to promote B cell maturation or T cell activation or are due to a lack of T cell help after stimulation by antigen.