This proposal focuses on unresolved issues of early B lineage differentiation in mice and, especially, in humans.
(Aim 1) A novel model of human B cell development has been identified, the EU12 cell line, in which CD34+/|a heavy chain"""""""" pro-B cells spontaneously undergo step-wise differentiation to become IgM+/IgD+ B cells. This clone will be used to (i) test the hypothesis that intraclonal V(D)Jrecombinatorial diversification contributes to the efficient generation of a primary B cell repertoire, (ii) define the changes in gene expression profile during B lineage differentiation, (iii) test the effects of modifying newly-identified and previously-recognized B lineage genes in pro-B cells by sense, antisense and dominant-negative transgenes, and (iv) examine the effects of ligating cell surface receptors (preBCR, BCR, IL7R, CD19, CD32, and CD40) on growth and differentiation of these B lineage cells.
(Aim 2) A recently-developed, highly- amplified immunofluorescence method will be used to identify pro-B, pre-B and B cell receptor components on primary B lineage cells to define similarities and differences in the human and mouse B cell differentiation programs. After redefinition of when and where the i heavy chains, surrogate light chains, icA,light chains, and Igo/p are expressed during B lineage differentiation in both species, pro-B, pre-B, and B cell subpopulations will be isolated for comparative analysis of their gene expression profiles and differentiation potential. The latter experiments will incorporate new information obtained in the analysis of differentiation- related changes in the gene expression profile of EU12 cells.
(Aim 3) Complementary ex vivo models will be used to elaborate early B lineage differentiation events in mice and humans. An IL-7 producing stomal cell model will be employed to delineate early events in mouse B lineage differentiation. Mouse stromal cells, with and without modification by human stromal cell-derived factor 1 (SDF-1), IL-7 and Fey receptor transgenes, will be employed to evaluate the capacity of human lymphoid progenitors to undergo B lineage differentiation. This comparative analysis will define novel features of B cell differentiationthat are likely to have significant clinical implications.
| Nakahara, Hirotomo; Herrin, Brantley R; Alder, Matthew N et al. (2013) Chronic lymphocytic leukemia monitoring with a Lamprey idiotope-specific antibody. Cancer Immunol Res 1:223-8 |
| 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 |
Showing the most recent 10 out of 55 publications
