As one of the most effective weapons in our anti-pathogen artillery, antibodies need to be made and released fast. To accomplish this, antigen-engaged B cells must interact rapidly with antigen-specific helper T cells. At the same time, autoantibody producing B cells must be kept tightiy in check. When B cells encounter antigen in the periphery, whether foreign or self, instead of migrating into B cell areas of secondary lymphoid organs, they move to the outer T cell zones. This relocalization is likely to be critical for favoring encounters with helper T cells and, in the case of autoantigen binding cells, may contribute to their rapid elimination. This study has two long-term goals: to define the mechanism of B cell exclusion from lymphoid follicles following encounter with antigen;and to determine the basis for the rapid elimination of autoantigen binding B cells in the periphery. These goals will be pursued by following three specific aims. First, the molecular cues directing antigen- and autoantigen-binding B cells to the outer T zone will be determined. Recent findings have established that the CXC chemokine, BLC, is important in guiding B cells to follicles, whereas the CC chemokines, ELC and SLC, guide T cells to the T zone. The possibility thai: increased responsiveness to ELC and SLC directs antigen-engaged B cells to the T zone will be explored by genetic approaches.
The second aim will characterize the intracellular signaling pathways downstream of the BCR that promote B cell migration to the outer T zone. A retroviral gene-transduction protocol will oe used to introduce molecules that activate or inhibit specific branches of the BCR signaling pathway, such as dominant negative Ras, MEK or PI3-kinase, to hen egg lysozyme (HEL) specific Ig-transgenic B cells. The genetically modified cells will be returned to mice that contain or lack HEL antigen and the effect of the modification on B cell positioning will be determined. Finally, the third aim is to determine the relationship between B cell positioning and B cell survival. B cells that lack chemokine receptors needed for migration to follicles or T cell areas will be used to test the contribution these compartments make to promcting B cell survival. The involvement of BAFF, a TNF family member, in enhancing the survival of autoreaclive B cells will be explored. As well as improving our understanding of factors regulating the efficiency of B cell antibody production to foreign pathogens, these studies are likely to provide insight into how defects in B rraffirkinp- anH hmnenstasisrnntrihutp tn aiitnimmiinitv or immnnnrlpfiripnrv.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI040098-14
Application #
7780405
Study Section
Special Emphasis Panel (NSS)
Program Officer
Miller, Lara R
Project Start
1997-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
14
Fiscal Year
2010
Total Cost
$337,610
Indirect Cost
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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