There is abundant evidence that autoantibodies (autoAbs) are generated through somatic hypermutation (SHM) and that tolerance of B cells that acquire self-reactivity through this process is impaired in systemic lupus erythematosus (SLE). Although recent studies have provided considerable insights into the participants and cellular dynamics in germinal center (GC) reactions where SHM takes place, there has been little progress in understanding the mechanisms for maintaining tolerance of newly generated self-reactive B cells, largely because of the absence of an appropriate model. We, in collaboration with other investigators, have recently used a novel ?2a-macroself antigen (Ag) transgenic (Tg) system to show that Fas-deficient mice are defective in censoring B cells that have acquired autoreactivity to a surface-bound Ag. This model, however, utilizes an artificial Ag with characteristics that differ substantially from the purported autoAgs in SLE. To address these limitations, we have developed a new B cell receptor Tg model, called FLEx-autoAb, that will allow conditional replacement of an innocuous antigen-receptor with a DNA-binding receptor in B cells and seek to use this model to investigate post-SHM tolerance mechanisms in normal and autoimmune mice. To accomplish this, two aims are proposed.
Specific aim 1 will use the FLEx-autoAb system to study tolerance of B cells that become autoreactive in the periphery in autoimmune B6-Faslpr mice specifically focusing on tolerance of germinal center B cells.
Specific aim 2 will use this new system to study tolerance of B cells in the periphery in four models of systemic autoimmunity. This project has the potential for discovering new regulatory mechanisms, relevant to SLE and likely other autoAb-mediated-diseases, that control B cells that acquire autoreactivity in the periphery.

Public Health Relevance

Defective tolerance of B cells to self is considered to be one of the major causes of systemic lupus erythematosus (SLE) responsible for the production of harmful autoantibodies;yet many aspects of this process remain poorly understood particularly tolerance mechanisms that keep in check B cells that acquire self-reactivity during somatic hypermutation. Currently none of the existing animal models are able to directly study mature B cells that acquire autoreactivity to self-antigens commonly targeted in SLE. To address this issue, we generated a new and more relevant model, called FLEx-autoAb, and propose using it to define B cell regulatory mechanisms relevant to SLE.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code