Jennifer M. Puck, M.D.
Professor
Department of Pediatrics and Institute for Human Genetics

Contact Information:
University of California,
San Francisco
513 Parnassus Avenue, HSE 301A, Box 0519
San Francisco, CA
94143-0519

Tel:(415) 476-3181
Fax: (415) 476-3466
puckj@peds.ucsf.edu

Links:
Immunology

 

Genetic Basis of Human Immune Disorders

Dr. Puck’s program focuses on human primary immunodeficiencies, diseases that are pleiotropic and rare, but treatable. They are important because they illuminate generalizable mechanisms in human host defenses and autoimmunity that often differ from predictions based on targeted gene disruptions in mice. Projects include investigation of genetics, clinical and molecular characterization, and management of selected primary immunodeficiencies. Studies in humans are augmented with mouse models to advance basic understanding and develop therapies, including hematopoietic stem cell gene therapy. Documentation and scoring of clinical features of selected diseases has been a starting point for experiments to probe linkage and underlying molecular mechanisms. The overarching goal is to return to the clinic with new approaches for population screening, specific diagnosis, identification of genetic modifiers, and treatment.

Severe combined immunodeficiency (SCID) is a major topic of research in the laboratory. In 1993, Dr. Puck’s group was one of two that identified the X-linked SCID disease gene, accounting for 50% of human SCID, as the common gamma chain cytokine receptor; now 14 SCID genes are known, but details of pathogenesis and genotype/phenotype correlations remain to be fully worked out. Individuals with SCID are healthy at birth, but die of infections in infancy unless provided with a functional immune system. Bone marrow transplantation, enzyme replacement, and even gene therapy have changed this previously fatal disease to a treatable one. SCID infants identified by a prior family history and treated early in life have better survival, less morbidity and lower treatment costs than those recognized only after onset of serious infections. Unfortunately 80% of infants with SCID today are not identified in the pre-infectious period. Universal newborn screening could remedy this problem. T cell receptor excision circles (TRECs) can be quantitated in the dried blood spots already collected from all babies, and babies with SCID lack TRECs. TREC newborn screening is being pursued to identify SCID cases in time for pre-symptomatic treatment and also afford opportunities to (1) investigate all causes of absent TRECs; (2) learn the true incidence of SCID; (3) find additional SCID genes; and (4) discover correlations between clinical features and particular geneotypes. This information in turn could lead to optimization of treatment, including implementation of gene targeted therapies. Mouse models of SCID, also pursued in Dr. Puck’s laboratory, provide new information about the development of lymphocytes as well as suggesting new candidate genes which when defective can cause human immunologic diseases.

Dr. Puck has also worked to define other human primary immunodeficiencies, including autoimmune lymphoproliferative syndrome (ALPS), due to defects in lymphocyte apoptosis, and hyper-immunoglobulin E syndrome (HIES or Job syndrome, after the biblical character afflicted with boils). The variable expressivity and penetrance of these disorders provides a challenge to discover genetic modifiers using a genomic technologies in combination with rigorous clinical scoring of large patient and family cohorts.

Selected Publications

Ochs H, Smith CIE, Puck J, eds. Primary Immunodeficiency Diseases, A Molecular and Genetic Approach, Second edition .NY: Oxford Univ Press, 2006-7.

Vacek MM, Schäffer AA, Davis J, Fischer RE, Dale JK, Straus SE, Puck J. HLA B44 is associated with decreased severity of autoimmune lymphoproliferative syndrome in patients with CD95 mutations (ALPS Ia). Clin Immunol 118:59-65, 2006.

Zhu S, Hsu AP, Vacek MM, Zheng L-X, Schäffer AA, Dale JK, Davis J, Fischer RE, Straus SE, Boruchov D, Saulsbury FT, Lenardo MJ, Puck J. Genetic alterations in caspase-10 can be causative or protective in autoimmune lymphoproliferative syndrome. Hum Genet 119:284-294, 2006.

Chinen J, Davis J, deRavin S, Linton G, Hsu A, Naumann N, Nomicos E, Silvin C, Theobald-Whiting N, Ulrick J, Malech H, Puck J. Immunologic improvement aftrer gene therapy in 3 preadolescents with X-linked severe combined immunodeficiency (XSCID). Molecular Therapy 15(suppl):S312 (Plenary symposium abstract 806), 2006.

Chan K, Puck J. Development of population–based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol 115:391-398, 2005.