In systemic lupus erythematosus (SLE), progressive immune dysregulation results in the production of autoantibodies that lead to the injury of multiple end organs and severe disease. Currently, standard therapy for lupus patients involves non-specific immune suppression, which has undesirable side effects. Therefore, there is great interest in gaining insights into new mechanisms that may result in novel, disease-specific treatments. Though SLE is antibody-mediated, the primary mechanism(s) of disease is not thoroughly understood. In the lyn-/- model of murine lupus, emerging evidence suggests that a hyperresponsive myeloid compartment may play a substantial role in autoimmune disease.
We aim to confirm and extend studies characterizing the hyperresponsive effector mechanisms of lyn-/- macrophages. We will evaluate effector mechanisms that might contribute to increased B cell differentiation and plasma cell survival such as IL-6 secretion and BAFF expression. We also propose to establish whether lupus pathogenesis is dependent on lyn-/- myeloid cell presence by generating B- and myeloid- specific conditional knockout mice and analyzing B, myeloid, and autoimmune phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM076982-05
Application #
7761215
Study Section
Minority Programs Review Committee (MPRC)
Program Officer
Toliver, Adolphus
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$29,733
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Luo, Wei; Mayeux, Jessica; Gutierrez, Toni et al. (2014) A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels. J Immunol 193:909-920
Gutierrez, Toni; Mayeux, Jessica M; Ortega, Sterling B et al. (2013) IL-21 promotes the production of anti-DNA IgG but is dispensable for kidney damage in lyn-/- mice. Eur J Immunol 43:382-93
Gutierrez, Toni; Halcomb, Kristina E; Coughran, Alanna J et al. (2010) Separate checkpoints regulate splenic plasma cell accumulation and IgG autoantibody production in Lyn-deficient mice. Eur J Immunol 40:1897-905
Halcomb, Kristina E; Musuka, Sandirai; Gutierrez, Toni et al. (2008) Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells. Mol Immunol 46:233-41