Studies of the molecular basis of human severe combined immunodeficiency (SCID) have ushered in a new era of improved diagnosis and treatment of these rare, but serious genetic disorders and also contributed to the fields of immunology and lymphocyte development. While many disease genes for human SCID are now known, less is known about "leaky" or "partial" SCID, also called combined immunodeficiency (CID);both SCID and CID cases of unknown genotype provide opportunities for further discovery. In addition, the mouse offers the power to dissect lymphoid developmental pathways, and we have discovered a new form of mouse SCID, deficiency of a predicted transcription factor Zbtb1. Mice lacking Zbtb1 have no T cells, but B lineage development is only mildly impaired. This T-B+ SCID model is important because its phenotype resembles that of humans with cytokine signaling pathway defects in the common g chain (gc) receptor, the IL-7 receptor a chain (IL7Ra), and Janus kinase 3 (Jak3), whereas the mouse knockouts lacking these proteins differ from humans in having T cells, but lacking B cells (T-B+). We will combine resources from human patients and mouse models to address the pathogenesis of lymphocyte developmental and functional defects. Samples from patients with SCID/CID will be assessed for defects in known SCID genes, and the cases remaining without a genotype assignment will be studied for defects in new gene candidates. Meanwhile, we will define the specific developmental and functional lymphoid phenotype of Zbtb1 deficient mice to uncover the normal role of Zbtb1 in mouse T and NK cell development and B cell differentiation and function. Comparisons between the Zbtb1- mouse, humans with cytokine signaling defects, and normal human hematopoietic stem cells (HSC) in which ZBTB1 gene expression is knocked down by RNAi will provide new insight into lymphoid development. Thus the goals of this proposal are to (i) assemble samples from SCID and CID patients without known gene defects;(ii) explore SCID pathogenesis of B cell impairment in Zbtb1- mice;(iii) use parallel in vitro and in vivo strategies to compare lymphoid developmental potential of HSC from wild type vs. Zbtb1 knockout mice and normal vs. ZBTB1 knockdown cord blood stem cells;and (iv) find Zbtb1 interacting partners and gene targets, which (along with ZBTB1 itself) will be assessed for mutations that may cause human SCID.

Public Health Relevance

The development of lymphocytes from blood-forming stem cells is incompletely understood, but critically important for treating humans with severe combined immunodeficiency (SCID), other immune and blood diseases, and cancers. We study humans and mice with SCID to find their underlying gene defects and to learn about pathways essential for lymphocyte maturation. We discovered that mice lacking Zbtb1 (a previously unstudied zinc finger protein) cannot form T lymphocytes, though B lymphocytes are present. Zbtb1 is related to transcription factors that repress expression of their target genes. We will investigate how Zbtb1 and its targets function in developing mouse and human lymphoid cells and determine whether defects in Zbtb1 or the genes it acts upon cause human disorders of immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078248-04
Application #
8389652
Study Section
Special Emphasis Panel (ZRG1-IMM-C (52))
Program Officer
Johnson, David R
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$359,444
Indirect Cost
$126,794
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Dvorak, Christopher C; Horn, Biljana N; Puck, Jennifer M et al. (2014) A trial of plerixafor adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency. Pediatr Transplant 18:602-8
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Mallott, Jacob; Kwan, Antonia; Church, Joseph et al. (2013) Newborn screening for SCID identifies patients with ataxia telangiectasia. J Clin Immunol 33:540-9
Puck, Jennifer M (2012) Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol 129:607-16
Puck, Jennifer M (2011) The case for newborn screening for severe combined immunodeficiency and related disorders. Ann N Y Acad Sci 1246:108-17
Puck, Jennifer M (2011) Neonatal screening for severe combined immunodeficiency. Curr Opin Pediatr 23:667-73