Inherited diseases are often uncommon in themselves, but a good source of insight for understanding common, complex diseases. We study 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 autoimmune lymphoproliferative syndrome (ALPS), severe combined immunodeficiency, mucocutaneous candidiasis, hyper-IgE syndrome (also known as Job syndrome after the biblical character who was stricken with boils), and other conditions. Patients with ALPS have large lymph nodes and spleens, increased numbers of a rare type of lymphocyte called CD4-/CD8- T cells, or double-negative T cells, and defects in programmed cell death, or apoptosis of their lymphocytes. We found that most patients with ALPS have inherited mutations in the apoptosis mediator Fas. Their lymphocytes do not die when they should. Instead, they accumulate and can attack the body's own tissues. Autoimmune diseases of the red blood cells, platelets and white blood cells are common in ALPS. We found some affected members of ALPS families who are more severely affected than others. Modifying genes that influence severity of ALPS are being sought. Some patients with no mutation in the Fas gene have defects in related genes such as caspase-10. During the past year we have started to investigate genetic modifiers of disease severity in ALPS. We first investigated the major histocompatibility locus (MHC) because it is known to be involved in susceptibility to many autoimmune conditions. By performing HLA typing in members of families with many cases of ALPS due to Fas gene defects, we have found that HLA B44 is protective, while HLA A31 may be a risk factor for severe disease in ALPS. We have started a genome-wide approach to finding additional modifier loci. Such genes might turn out to be important determinants for more common sporadic autoimmune diseases besides ALPS. Hyper-IgE syndrome is an enigmatic, rare condition 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 also mapped dominant mucocutaneous candidiasis to human chromosome 2p and we are evaluating a candidate gene. Mouse models of immune deficiency are also under study, as they are likely to advance our understanding of human immune disorders. 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.
| 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 |
| 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 |
| Renner, Eleonore D; Puck, Jennifer M; Holland, Steven M et al. (2004) Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr 144:93-9 |
| Tock, Christine L; Holland, Steven M; Puck, Jennifer M et al. (2004) A man with distinctive facial features and recurrent pyoderma, pneumonia, and skeletal fractures. J Am Acad Dermatol 50:627-9 |
| 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 |
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