The peripheral primary B cell compartment in mammals is characterized by expression of antigen receptors (BCRs) with """"""""multi-reactivity"""""""" for both foreign and autoantigens. During the development of B cell memory the BCRS expressed by responding clonotypes are extensively altered by V gene somatic hypermutation. Hypermutation can create autoreactivity de novo, or enhance the autoreactivity intrinsic to precursor BCRS. We and others have proposed that a stringent self-tolerance process operates on B cells differentiating to the memory phenotype during foreign antigen driven immune responses. In the previous funding period we obtained evidence supporting this hypothesis. A B cell clonotype that dominates the memory compartment of the anti-arsonate immune response of A/J mice expresses BCRs with affinity for both arsonate and the self antigen DNA. In contrast, the hypermutated derivatives of these BCRs expressed by the memory compartment display increased affinity for arsonate and no affinity for DNA. However, if B cell apoptotic pathways are perturbed via enforced expression of Bcl-2 from a transgene, the BCRs expressed by members of this clonotype that enter the memory compartment display increased affinity for both arsonate and DNA. These data have led us to formulate the """"""""specificity maturation"""""""" hypothesis-that during a foreign antigen driven immune response precursors to memory B cells undergoing hypermutation are subject to iterative cycles of both positive selection (for increased or unaltered affinity for the driving foreign antigen) and negative selection (for affinity for self antigens). The end result is a memory B cell compartment expressing BCRS with high specificity for the driving foreign antigen-a compartment that would efficiently recognize the foreign antigen and pose little risk for the development of autoimmunity. In the next proposed application period, we wish to test several tenets of this hypothesis as well as to begin to gain insight into the mechanism(s) that result in the generation of a memory B cell compartment with a high degree of specificity for the driving foreign antigen. Three interrelated questions will be addressed: 1) can B cells not subjected to central tolerance mechanisms and whose BCRs display """"""""multi-reactivity,"""""""" including autoreactivity, be recruited into the primary immune response and germinal center (GC) reaction, despite displaying a """"""""self antigen regulated"""""""" phenotype?; 2) are members of such clones subsequently """"""""purged"""""""" of their autoreactivity via somatic hypermutation or receptor editing prior to entry into the memory compartment?; and, 3) is the primary microenvironmental locale in which specificity maturation takes place the GC?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038965-07
Application #
6631814
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Nasseri, M Faraz
Project Start
1996-05-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
7
Fiscal Year
2003
Total Cost
$238,500
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Nikbakht, Neda; Shen, Shixue; Manser, Tim (2013) Cutting edge: Macrophages are required for localization of antigen-activated B cells to the follicular perimeter and the subsequent germinal center response. J Immunol 190:4923-7
Shen, Shixue; Manser, Tim (2012) Direct reduction of antigen receptor expression in polyclonal B cell populations developing in vivo results in light chain receptor editing. J Immunol 188:47-56
Nikbakht, Neda; Migone, Thi-Sau; Ward, Chris P et al. (2011) Cellular competition independent of BAFF/B lymphocyte stimulator results in low frequency of an autoreactive clonotype in mature polyclonal B cell compartments. J Immunol 187:37-46
Coffey, Francis; Alabyev, Boris; Manser, Tim (2009) Initial clonal expansion of germinal center B cells takes place at the perimeter of follicles. Immunity 30:599-609
Vuyyuru, Raja; Mohan, Chandra; Manser, Tim et al. (2009) The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints. J Immunol 183:5716-27
Liu, Xiaohe; Shen, Shixue; Manser, Tim (2009) Influence of B cell antigen receptor expression level on pathways of B cell tolerance induction. J Immunol 182:398-407
Coffey, Francis; Liu, Xiaohe; Manser, Tim (2007) Primary development and participation in a foreign antigen-driven immune response of a chromatin-reactive B cell clonotype are not influenced by TLR9 or other MyD88-dependent TLRs. J Immunol 179:6663-72
Alabyev, Boris; Rahman, Ziaur S M; Manser, Tim (2007) Quantitatively reduced participation of anti-nuclear antigen B cells that down-regulate B cell receptor during primary development in the germinal center/memory B cell response to foreign antigen. J Immunol 178:5623-34
Heltemes-Harris, Lynn; Liu, Xiaohe; Manser, Tim (2005) An antibody VH gene that promotes marginal zone B cell development and heavy chain allelic inclusion. Int Immunol 17:1447-61
Liu, Xiaohe; Manser, Tim (2005) Antinuclear antigen B cells that down-regulate surface B cell receptor during development to mature, follicular phenotype do not display features of anergy in vitro. J Immunol 174:4505-15

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