The study of tolerance to self-antigen in B-cells is of the utmost importance to understand how the immune system is regulated in health and disease. Unfortunately, the study of human B-cell tolerance has been hampered by the inability of investigators to identify an abundant population of autoreactive B-cells with homogenous antigenic reactivity and surface markers. We have identified such a population (termed VH4- 34 cells) and over the last three years we have validated the use of these cells for the study of human B-cell tolerance. ? ? VH4-34 cells recognize glycolipid autoantigens widely expressed in the surface of multiple cell types as well as microbial glycolipid antigens and probably play a homeostatic role in host defense by connecting the innate and adaptive immune systems. In healthy individuals, VH4-34 cells are prevented from inducing autoimmunity by positive selection into the marginal zone of the spleen and negative selection form the germinal centers. The latter mechanism prevents VH4-34 cells from expanding into the long-lived postgerminal center memory and plasma cell compartments thereby inhibiting the production of significant amounts of pathogenic autoantibodies. ? ? In this application we propose to study the phenotypic and functional properties of VH4-34 cells in healthy individuals and to compare them to VH4-34 cells obtained with patients with Systemic Lupus Erythematosus (SLE) in whom B-cell tolerance is defective. This will be accomplished by using multiparameter flow cytometry and immunocytochemistry. Furthermore, we will analyze the signaling processes responsible for the biological responses observed with VH4.34 cells and again determine how signaling differs in patients with SLE. Finally, we will ascertain what type of T-cells regulate the behavior of VH4-34 cells both in healthy subjects and SLE patients. ? ? The studies proposed herein should yield important insights into the regulation of autoimmunity and the pathogenesis of autoimmune diseases such as SLE. Furthermore, we believe that our results will improve our ability to treat patients with SLE and similar diseases. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049660-04
Application #
7005393
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Johnson, David R
Project Start
2003-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$307,598
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Sanz, Iñaki (2017) New Perspectives in Rheumatology: May You Live in Interesting Times: Challenges and Opportunities in Lupus Research. Arthritis Rheumatol 69:1552-1559
Halliley, Jessica L; Tipton, Christopher M; Liesveld, Jane et al. (2015) Long-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrow. Immunity 43:132-45
Jenks, Scott A; Palmer, Elise M; Marin, Elides Y et al. (2013) 9G4+ autoantibodies are an important source of apoptotic cell reactivity associated with high levels of disease activity in systemic lupus erythematosus. Arthritis Rheum 65:3165-75
Kaminski, Denise A; Wei, Chungwen; Rosenberg, Alexander F et al. (2012) Multiparameter flow cytometry and bioanalytics for B cell profiling in systemic lupus erythematosus. Methods Mol Biol 900:109-34
Quách, Tâm D; Manjarrez-Orduño, Nataly; Adlowitz, Diana G et al. (2011) Anergic responses characterize a large fraction of human autoreactive naive B cells expressing low levels of surface IgM. J Immunol 186:4640-8
Jacobi, Annett M; Huang, Weiqing; Wang, Tao et al. (2010) Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum 62:201-10
Calero, Ismael; Sanz, Iñaki (2010) Targeting B cells for the treatment of SLE: the beginning of the end or the end of the beginning? Discov Med 10:416-24
Sanz, Iñaki; Lee, F Eun-Hyung (2010) B cells as therapeutic targets in SLE. Nat Rev Rheumatol 6:326-37
Calero, Ismael; Nieto, Jose Antonio; Sanz, Iñaki (2010) B cell therapies for rheumatoid arthritis: beyond B cell depletion. Rheum Dis Clin North Am 36:325-43
Palanichamy, Arumugam; Barnard, Jennifer; Zheng, Bo et al. (2009) Novel human transitional B cell populations revealed by B cell depletion therapy. J Immunol 182:5982-93

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