B cells are an important pathogenic component of autoimmunity. However, our current knowledge of the phenotype of pathogenic B cells in these diseases is still limited and more studies are needed to further characterize these cells and uncover their unique characteristics and mode of action. B cells are known to express only one type of antibody and be specific for one antigen. However, rare B cells co-expressing two different antibodies (i.e., dual-reactive B cells) exist in mice and are present in humans. Our goal is to understand whether dual-reactive B cells represent a relevant B cell subset in autoimmunity. Our novel findings demonstrate that autoimmune mice generate dual-reactive immature and mature B cells more frequently than nonautoimmune mice. The majority of these cells react with self-antigens indicating that they evade mechanisms of negative selection. Dual-reactive B cells generate autoantibodies more frequently than single-reactive B cells and are highly enriched in the antigen-activated B cell subsets of autoimmune mice. Finally, we have identified a molecular pathway for the positive selection of nonautoreactive immature B cells that we propose is used for the generation of dual-autoreactive B cells as well. In the previous grant cycle, we have established the bases for the proposed research by creating the mutant mice and methodologies with which to follow development and selection of dual-reactive B cells in autoimmune and nonautoimmune mice. Therefore, we are uniquely posed to carry out the proposed studies. Our innovative hypothesis is that dual-reactive B cells can evade mechanisms of B cell tolerance to become an important component of autoimmune diseases. The goal of the proposed research is to deepen our understanding of the relationship between dual-reactive B cells and autoimmunity in mice. We will investigate the mechanisms that cause increased generation, selection and enrichment of dual-reactive B cells in autoimmune-prone mice and whether these B cells contribute to the development of autoimmunity. We will also translate our mouse studies by examining the prevalence of dual-reactive B cells in individuals with autoimmunity. To achieve our goals we will develop the following specific aims: 1) To determine whether tonic B cell receptor signaling inhibits receptor editing in dual-autoreactive immature B cells and promotes their differentiation via the Ras-Erk pathway;2) To establish some of the mechanisms of antigen-mediated selection and activation of dual-reactive B cells in autoimmune mice;3) To determine whether dual-reactive B cells contribute to autoimmunity and are enriched in autoimmune patients. The studies proposed here will establish whether dual-reactive B cells are a diagnostic and/or pathogenic B cell subset in autoimmunity and will be of value for the development of methods to identify and target these B cells. Overall, these studies are important for understanding B cell-mediated mechanisms of autoimmune development and to uncover novel targets for autoimmune intervention.

Public Health Relevance

The role of B cells in autoimmune diseases has become increasingly evident. However, our current knowledge of the B cell types that are important in these diseases is still limited. More studies are needed to further characterize these B cell types and uncover their unique characteristics and mode of action. These studies will investigate a type of B cells that is increased in models of autoimmunity and that cause production of autoantibodies, a relevant component of this disease. These studies might lead to the recognition of a novel diagnostic and/or pathogenic cell component of autoimmunity and to the development of new specific therapies that target only pathogenic B cells leaving intact those B cells that fight off infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Peyman, John A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Medicine
United States
Zip Code
Hu, Jiancheng; Oda, Shannon K; Shotts, Kristin et al. (2014) Lysophosphatidic acid receptor 5 inhibits B cell antigen receptor signaling and antibody response. J Immunol 193:85-95
Teodorovic, Lenka S; Babolin, Chiara; Rowland, Sarah L et al. (2014) Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies. Proc Natl Acad Sci U S A 111:E2797-806
Pelanda, Roberta (2014) Dual immunoglobulin light chain B cells: Trojan horses of autoimmunity? Curr Opin Immunol 27:53-9
Feldman, Amy G; Tucker, Rebecca M; Fenner, Erika K et al. (2013) B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia. PLoS One 8:e73644
Larson, Jennifer D; Thurman, Joshua M; Rubtsov, Anatoly V et al. (2012) Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity. Proc Natl Acad Sci U S A 109:E1092-100
Teodorovic, Lenka Sinik; Riccardi, Carlo; Torres, Raul M et al. (2012) Murine B cell development and antibody responses to model antigens are not impaired in the absence of the TNF receptor GITR. PLoS One 7:e31632
Eschbach, Cathrin; Bach, Martina P; Fidler, Ingrid et al. (2011) Efficient generation of B lymphocytes by recognition of self-antigens. Eur J Immunol 41:2397-403
Rowland, Sarah L; DePersis, Corinne L; Torres, Raul M et al. (2010) Ras activation of Erk restores impaired tonic BCR signaling and rescues immature B cell differentiation. J Exp Med 207:607-21
Rowland, Sarah L; Leahy, Katelyn F; Halverson, Regina et al. (2010) BAFF receptor signaling aids the differentiation of immature B cells into transitional B cells following tonic BCR signaling. J Immunol 185:4570-81
Donovan, Erin E; Pelanda, Roberta; Torres, Raul M (2010) S1P3 confers differential S1P-induced migration by autoreactive and non-autoreactive immature B cells and is required for normal B-cell development. Eur J Immunol 40:688-98

Showing the most recent 10 out of 14 publications