The murine CD21/Cr2 gene encodes two proteins implicated in the acquisition of an optimal immune response. The CD21 pathway includes signals for B cell survival and optimal activation, and presentation of native antigen by follicular dendritic cells (FDC) in the germinal centers of the spleen. The expression of murine CD21 is tightly controlled. The proteins are found on B cells during specific stages of differentiation and are expressed by FDC once they have taken up their position within the spleen. This competing application proposes to continue our analysis of the mechanism of CD21 gene control and the functions of the CD21 proteins in the generation of an appropriate immune response. We have demonstrated that promoter and intronic elements regulate the CD21 gene. We propose to continue our analysis of the transcriptional control of CD21, incorporating the comparative analysis of two other genes, CD19 and CD23, that are expressed at similar times of B cell differentiation. We will also continue our examination of a mutant mouse line with an engineered deletion of the CD21 intronic control region. These analyses also include the role of transcriptional activators from herpes virus that induce CD21 and CD23 expression, and the effect of such over expression on the immune response. Our analysis of the function of the CD21 proteins will focus upon the role of the CD21 proteins as complement receptors enhancing both the acquired and innate immune responses including the generation of the immunoglobulin isotypes. We will also analyze the role of various gene products whose expression is critically altered in CD21 deficient animals during immune activation. The generation of an appropriate immune response is critical to the health of the individual. The CD21 proteins straddle the fields of acquired and innate immune responses such that their manipulation could influence immediate responses to an infection as well as the more long term consequences of immunologic memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI024158-23S1
Application #
8526629
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Davidson, Wendy F
Project Start
1986-12-01
Project End
2013-06-30
Budget Start
2012-08-17
Budget End
2013-06-30
Support Year
23
Fiscal Year
2012
Total Cost
$71,634
Indirect Cost
$23,718
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Donius, Luke R; Orlando, Christopher M; Weis, Janis J et al. (2014) Generation of a novel Cr2 gene allele by homologous recombination that abrogates production of Cr2 but is sufficient for expression of Cr1. Immunobiology 219:53-63
Donius, Luke R; Weis, Janis J; Weis, John H (2014) Murine complement receptor 1 is required for germinal center B cell maintenance but not initiation. Immunobiology 219:440-9
Pioli, Peter D; Debnath, Irina; Weis, Janis J et al. (2014) Zfp318 regulates IgD expression by abrogating transcription termination within the Ighm/Ighd locus. J Immunol 193:2546-53
Pioli, Peter D; Weis, John H (2014) Snail transcription factors in hematopoietic cell development: a model of functional redundancy. Exp Hematol 42:425-30
Pioli, Peter D; Dahlem, Timothy J; Weis, Janis J et al. (2013) Deletion of Snai2 and Snai3 results in impaired physical development compounded by lymphocyte deficiency. PLoS One 8:e69216
Donius, Luke R; Handy, Jennifer M; Weis, Janis J et al. (2013) Optimal germinal center B cell activation and T-dependent antibody responses require expression of the mouse complement receptor Cr1. J Immunol 191:434-47
Debnath, Irina; Roundy, Kirstin M; Pioli, Peter D et al. (2013) Bone marrow-induced Mef2c deficiency delays B-cell development and alters the expression of key B-cell regulatory proteins. Int Immunol 25:99-115
Dahlem, Timothy; Cho, Scott; Spangrude, Gerald J et al. (2012) Overexpression of Snai3 suppresses lymphoid- and enhances myeloid-cell differentiation. Eur J Immunol 42:1038-43
Bramwell, Kenneth K C; Ma, Ying; Weis, John H et al. (2012) High-throughput genotyping of advanced congenic lines by high resolution melting analysis for identification of Bbaa2, a QTL controlling Lyme arthritis. Biotechniques 52:183-90
Lochhead, Robert B; Sonderegger, F Lynn; Ma, Ying et al. (2012) Endothelial cells and fibroblasts amplify the arthritogenic type I IFN response in murine Lyme disease and are major sources of chemokines in Borrelia burgdorferi-infected joint tissue. J Immunol 189:2488-501

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