This project focuses on two major aspects of B cell production and function in humans: virgin and memory B cell generation. The differentiation steps that hemopoietic progenitor cells must undergo to give rise to clonally diverse virgin B lymphocytes will be analyzed in these experiments with an eye toward possible clinical manipulation of B cell production. Studies are proposed to dissect the (i) precise order of B-lineage differentiation events, (ii) order of transcriptional activity of genes important in this progression and (iii) assembly, expression and function of antigen receptor units as a function of differentiation stage and age. Fresh leads suggesting that B cell production in the bone marrow can be regulated both positively and negatively via non-antigen-specific receptors (IL-7, IFNalpha/Beta and CDI9) will be explored in one series of experiments. The hypothesis that B cells can be generated by an alternative differentiation pathway, involving light chain gene rearrangement before the rearrangement of conventional heavy chain genes, will be tested. In these experiments, (i) 'surrogate' heavy chains (MC) that couple kappa light chains to the Igalpha/beta signal transduction units on two B-lineage cell lines will be isolated and characterized, (ii) the surrogate RC gene cloned, sequenced, and expressed, (iii) monoclonal antibodies produced against the surrogate HC, and (iv) these reagents used as probes to identify bone marrow cells in this pathway. Studies will be conducted to pursue preliminary data suggesting the antibody repertoire may differ in B cells generated via this alternative pathway. The phenotypic and functional characteristics of memory B cells will be examined as a function of age. In these experiments IgA1 and IgA2 B cells will be purified from adult and cord blood samples for analysis of their (i) cell surface antigenic profile and activation status, (ii) mechanism of the isotype switch, (iii) antibody repertoire, (iv) expression of developmentally-regulated genes, and (v) functional capabilities. These studies of virgin IgM B cells and their IgA1 and IgA2 memory B cell progeny should provide valuable information for the design of vaccine strategy in individuals of various ages.
| Reshetnikova, Evdokiya S; Mechetina, Ludmila V; Volkova, Olga Y et al. (2012) Differential expression of FCRLA in naïve and activated mouse B cells. Cell Immunol 272:182-92 |
| Gururajan, Murali; Haga, Christopher L; Das, Sabyasachi et al. (2010) MicroRNA 125b inhibition of B cell differentiation in germinal centers. Int Immunol 22:583-92 |
| Ehrhardt, Gotz R A; Hijikata, Atsushi; Kitamura, Hiroshi et al. (2008) Discriminating gene expression profiles of memory B cell subpopulations. J Exp Med 205:1807-17 |
| Goitsuka, Ryo; Chen, Chen-Lo H; Benyon, Lesley et al. (2007) Chicken cathelicidin-B1, an antimicrobial guardian at the mucosal M cell gateway. Proc Natl Acad Sci U S A 104:15063-8 |
| Munfus, Delicia L; Haga, Christopher L; Burrows, Peter D et al. (2007) A conserved gene family encodes transmembrane proteins with fibronectin, immunoglobulin and leucine-rich repeat domains (FIGLER). BMC Biol 5:36 |
| Haga, Christopher L; Ehrhardt, Gotz R A; Boohaker, Rebecca J et al. (2007) Fc receptor-like 5 inhibits B cell activation via SHP-1 tyrosine phosphatase recruitment. Proc Natl Acad Sci U S A 104:9770-5 |
| Hirano, Masayuki; Davis, Randall S; Fine, W David et al. (2007) IgEb immune complexes activate macrophages through FcgammaRIV binding. Nat Immunol 8:762-71 |
| Zhang, Zhixin; Espinoza, Celia R; Yu, Zhihong et al. (2006) Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes. Nat Immunol 7:616-24 |
| Fujiwara, Naruyoshi; Hidano, Shinya; Mamada, Hiroshi et al. (2006) A novel avian homologue of CD72, chB1r, down modulates BCR-mediated activation signals. Int Immunol 18:775-83 |
| Davis, Randall S; Ehrhardt, Goetz R A; Leu, Chuen-Miin et al. (2005) An extended family of Fc receptor relatives. Eur J Immunol 35:674-80 |
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