Autoimmune polyendocrine syndrome type II (APS-II) is characterized by the co-occurrence of two or more of various autoimmune disorders in individuals, and often also in their family members, most typically Addison's disease, autoimmune thyroid disease (Graves' disease and hypothyroidism), type I diabetes mellitus celiac disease, hypogonadism, vitiligo, alopecia, pernicious anemia, and myasthenia gravis, but in some families may also include lupus erythematosis, juvenile rheumatoid arthritis, multiple sclerosis, and other disorders. Our analyses strong indicate that autoimmunity in APS-II is controlled by a non-MHC gene in the context of a susceptible HLA genotype. We propose to map this non- MHC APS-II gene, determine its role in different clinical subtypes of APS-II, determine which autoimmune manifestations of APS-II are accounted for by this 2-locus model, and ultimately to identify the non- MHC APS-II gene. Our approach is to identify and analyze large APS-II pedigrees to define clerical heterogeneity that may reflect underlying genetic heterogeneity. We have carried out a series of large preliminary clinical surveys identifying three distinct groups of APS-II families in whom specific autoimmune disorders appear to occur as autosomal dominant traits; families with multiple cases of Addison's disease and other autoimmune disorders, families with multiple cases of vitiligo and other autoimmune disorders, and families with adult-onset type 1diabetes mellitus and other autoimmune disorders. In the multiplex Addison's disease families, we have identified specific HLA genotypes that appear to be necessary but not sufficient for the occurrence of disease. Given a susceptible HLA genotype, the occurrence of Addison's disease in these families appears to be determined by an autosomal dominantly inherited locus outside the MHC. We will map this non-MHC APS-II locus by an initial 10-cM genome screen to identify a candidate region of linkage, we will then refine this localization using additional families and additional markers, to the point of constructing a physical map of the region, and we will eventually identify the non-MHC APS-II susceptibility gene. We also plan to collect samples from vitiligo/APS-II and diabetes/APS-II families and to determine which of the various autoimmune manifestations in these families are accounted for by this gene. Definition of genes that predispose to various forms of APS-II will greatly enhance our understanding of the genetics and causation of autoimmunity in general. The occurrence of lupus erythematosis, juvenile rheumatoid arthritis, and multiple sclerosis in some families with APS-II suggests that the identification of APS-II genes may also shed light on the pathogenesis of these autoimmune disorders. In the long run, identification of genes and corresponding gene products that are involved in these autoimmune disorders will undoubtedly open up new avenues of approach to their treatment and even prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI046374-03
Application #
6494733
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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