Abstract

To study the role of complement (C) and C receptors (CRs) in controlling B-cell development and the antibody repertoire, humoral immune responses, and spontaneous autoimmunity, we shall generate congenic lines of mice that are deficient for the classical and/or alternate C pathways and for specific combinations of CR ligands. These animals will be used to map genetically the separate and combined roles of Clq, C4, C3, and CR1 and -2 in selective clonal deletion, anergy, and secondary V(D)J rearrangement in developing B lymphocytes, germinal center and serum antibody responses, clearance of dead cells and cellular debris, and the promotion of autoimmunity. We propose that C and CR deficiencies promote self-reactivity by two distinct but mutually supportive pathways: alteration of central tolerance and the B-cell repertoire by the effects of CR1/2 and their ligands and impaired removal of immunogenic cellular debris and immune complexes by Clq and C3. Thus, we propose that the innate immune system controls both the frequency of peripheral, self-reactive B cells and their exposure to antigen.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049326-03
Application #
6632322
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Ridge, John P
Project Start
2001-03-15
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$308,000
Indirect Cost

  Institution

Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Richards, Stephanie L; Lord, Cynthia C; Pesko, Kendra et al. (2009) Environmental and biological factors influencing Culex pipiens quinquefasciatus Say (Diptera: Culicidae) vector competence for Saint Louis encephalitis virus. Am J Trop Med Hyg 81:264-72
Smartt, Chelsea T; Richards, Stephanie L; Anderson, Sheri L et al. (2009) West Nile virus infection alters midgut gene expression in Culex pipiens quinquefasciatus Say (Diptera: Culicidae). Am J Trop Med Hyg 81:258-63
Ueda, Yoshihiro; Liao, Dongmei; Yang, Kaiyong et al. (2007) T-independent activation-induced cytidine deaminase expression, class-switch recombination, and antibody production by immature/transitional 1 B cells. J Immunol 178:3593-601
Richards, Stephanie L; Pesko, Kendra; Alto, Barry W et al. (2007) Reduced infection in mosquitoes exposed to blood meals containing previously frozen flaviviruses. Virus Res 129:224-7
Richards, Stephanie L; Mores, Christopher N; Lord, Cynthia C et al. (2007) Impact of extrinsic incubation temperature and virus exposure on vector competence of Culex pipiens quinquefasciatus Say (Diptera: Culicidae) for West Nile virus. Vector Borne Zoonotic Dis 7:629-36
Ueda, Yoshihiro; Kondo, Motonari; Kelsoe, Garnett (2005) Inflammation and the reciprocal production of granulocytes and lymphocytes in bone marrow. J Exp Med 201:1771-80
Ueda, Yoshihiro; Yang, Kaiyong; Foster, Sandra J et al. (2004) Inflammation controls B lymphopoiesis by regulating chemokine CXCL12 expression. J Exp Med 199:47-58
Lee, Alfred Ian; Fugmann, Sebastian D; Cowell, Lindsay G et al. (2003) A functional analysis of the spacer of V(D)J recombination signal sequences. PLoS Biol 1:E1
Cowell, Lindsay G; Davila, Marco; Yang, Kaiyong et al. (2003) Prospective estimation of recombination signal efficiency and identification of functional cryptic signals in the genome by statistical modeling. J Exp Med 197:207-20
Cowell, Lindsay G; Davila, Marco; Kepler, Thomas B et al. (2002) Identification and utilization of arbitrary correlations in models of recombination signal sequences. Genome Biol 3:RESEARCH0072