GENETIC ANALYSIS OF HOST DEFENSE DISORDERS

Human Genome Research

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Abstract

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.