We are conducting a research program to find the causes and develop better treatments for inherited disorders of the immune system. These include immunodeficiencies, in which gene defects impair the ability of the immune system to fight infections and also disorders of immune cell regulation, in which autoimmunity may be seen. Current areas of investigation include severe combined immunodeficiency, mucocutaneous candidiasis, hyper-IgE syndrome (also known as Job syndrome after the biblical character who was stricken with boils), certain inherited autoimmune diseases, including variants of autoimmune lymphoproliferative disease, or ALPS, and genetic determinants of susceptibility to HIV/AIDS. Hyper-IgE syndrome is an enigmatic, rare condition that is characterized by recurrent skin infections, eczema, extreme elevations of serum IgE, and pneumonia with formation of lung cysts. The specific immune defect has not been discovered; therefore we have undertaken genetic studies to map the disease. We have collected samples and performed clinical and laboratory evaluations on many families with autosomal dominant and recessive forms of the syndrome. We have discovered that there are at least 3 loci in the human genome that can be associated with hyper-IgE syndrome. We have also mapped dominant mucocutaneous candidiasis to human chromosome 2p. Candidiasis is a significant problem in HIV/AIDS, and understanding the basis of the inherited condition is expected to lead us to better understanding and management of fungal infections in HIV/AIDS. Mouse models of immune deficiency are also under study, as they are likely to advance our understanding of human immune disorders. A new form of mouse SCID has been mapped in the mouse and the causative gene is being sought. Genes that determine level of immune functioning in the mouse and in inherited primary immunodeficiencies are likely candidates for genetic modifiers of susceptibility to HIV/AIDS and rapid progression of AIDS. Therefore genes we identify will be screened for variants in HIV populations characterized as to infection rate and short vs. long incubation time before developing. Part of this project involves developing and implementing sophisticated new tests of lymphocyte function. Beyond just counting lymphocytes and inducing cell activation in bulk cultures, it is important to define the range of cells that are capable of responding to infections. We have initiated new tests of T-cell excision circles (TRECs) as an indicator of newly formed T cells and spectratyping by PCR to examine the diversity of lymphocyte receptors. In addition, population screening for immune disorders is desirable to diagnose these conditions before serious or lethal infections occur. We are piloting newborn screening protocols for this application.
| Rao, V Koneti; Dugan, Faith; Dale, Janet K et al. (2005) Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol 129:534-8 |
| Maric, Irina; Pittaluga, Stefania; Dale, Janet K et al. (2005) Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome. Am J Surg Pathol 29:903-11 |
| Vogt, Guillaume; Chapgier, Ariane; Yang, Kun et al. (2005) Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nat Genet 37:692-700 |
| Grimbacher, Bodo; Holland, Steven M; Puck, Jennifer M (2005) Hyper-IgE syndromes. Immunol Rev 203:244-50 |
| Notarangelo, Luigi; Casanova, Jean-Laurent; Fischer, Alain et al. (2004) Primary immunodeficiency diseases: an update. J Allergy Clin Immunol 114:677-87 |
| Hay, Beverly N; Martin, Julie E; Karp, Barbara et al. (2004) Familial immunodeficiency with cutaneous vasculitis, myoclonus, and cognitive impairment. Am J Med Genet A 125:145-51 |
| Puck, Jennifer M; Straus, Stephen E (2004) Somatic mutations--not just for cancer anymore. N Engl J Med 351:1388-90 |
| Matsuzaki, Hajime; Loi, Halina; Dong, Shoulian et al. (2004) Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res 14:414-25 |
| Eberting, Cheryl Lee D; Davis, Joie; Puck, Jennifer M et al. (2004) Dermatitis and the newborn rash of hyper-IgE syndrome. Arch Dermatol 140:1119-25 |
| Legembre, Patrick; Barnhart, Bryan C; Zheng, Lixin et al. (2004) Induction of apoptosis and activation of NF-kappaB by CD95 require different signalling thresholds. EMBO Rep 5:1084-9 |
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