The investigator will study the process of antigen selection and hypermatutation, and how they contribute to B cell memory, in the mouse response to phenylarsonate (Ars). This project involves the identification of clones in the Ars response at different stages of their differentiation, and the development of a correlation between this maturation stage and position in the spleen relative to the putative sites of antigen selection and somatic mutation. The Ars response is a well-characterized system by many laboratories. Two broad aims are proposed that are subdivided into several subaims. First, the investigator will characterize the anti-Ars response of A/J mice via the determination of spatial organization of anti-Ars-specific clones with the location of antibody forming cells (AFC) and germinal centers (GC). The first subaim will address the appearance and timing of Ars-specific clones by the use of an anti-Ars V gene antibody and PCR analysis. The investigator will distinguish between two principle models for antigen-driven B cell maturation. A second subaim will employ the same methodologies to evaluate the spatial organization of memory anti-Ars clones. The second broad aim will utilize the investigator s transgene system for study. In the previous period, the investigator has developed a transgene model where an anti-Ars specific rearranged IgVh gene is able to be recruited into the anti-Ars response (and undergo somatic mutation). Using these transgenic mice, they will study the organization of the transgene-encoded anti-Ars clones and B cell maturation. In the first subaim of this section, the investigator will compare the transgene-encoded clonotype (high affinity to Ars) with endogenously emerging clones (low affinity to Ars) for their population of spatial sites of B cell maturation, AFC and GC. For this study an additional antibody reagent will be employed that is more specific for the transgene clonotype. In the second subaim of this section, using the same general methodologies, they will characterize the relationship between affinity for Ars by these two antibody types and the somatic mutation levels of these genes. In a third subaim they will determine whether there is a positive relationship between sites of apoptosis in a GC and the relative incidence of affinity maturation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023739-10
Application #
2671867
Study Section
Special Emphasis Panel (ZRG2-IVP (03))
Project Start
1986-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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
Alabyev, Boris; Manser, Tim (2002) Bcl-2 rescues the germinal center response but does not alter the V gene somatic hypermutation spectrum in MSH2-deficient mice. J Immunol 169:3819-24
Heltemes, Lynn M; Manser, Tim (2002) Level of B cell antigen receptor surface expression influences both positive and negative selection of B cells during primary development. J Immunol 169:1283-92
Lentz, V M; Manser, T (2001) Cutting edge: germinal centers can be induced in the absence of T cells. J Immunol 167:15-20
Vora, K A; Lentz, V M; Monsell, W et al. (2001) The T cell-dependent B cell immune response and germinal center reaction are intact in A-myb-deficient mice. J Immunol 166:3226-30
Tumas-Brundage, K M; Notidis, E; Heltemes, L et al. (2001) Predominance of a novel splenic B cell population in mice expressing a transgene that encodes multireactive antibodies: support for additional heterogeneity of the B cell compartment. Int Immunol 13:475-84
Lentz, V M; Manser, T (2000) Self-limiting systemic autoimmune disease during reconstitution of T cell-deficient mice with syngeneic T cells: support for a multifaceted role of T cells in the maintenance of peripheral B cell tolerance. Int Immunol 12:1483-97
Vora, K A; Tumas-Brundage, K M; Lentz, V M et al. (1999) Severe attenuation of the B cell immune response in Msh2-deficient mice. J Exp Med 189:471-82
Vora, K A; Tumas-Brundage, K; Manser, T (1999) Contrasting the in situ behavior of a memory B cell clone during primary and secondary immune responses. J Immunol 163:4315-27
Manser, T; Tumas-Brundage, K M; Casson, L P et al. (1998) The roles of antibody variable region hypermutation and selection in the development of the memory B-cell compartment. Immunol Rev 162:183-96

Showing the most recent 10 out of 33 publications