(Taken from the investigator s abstract) Premature Ovarian Failure (POF) affects approximately 10 percent of amenorrheic women, and can be devastating because of the young age of onset, the presumed irreversible infertility, and the long-term consequences of estrogen deficiency. Although certain conditions, including chemo and radiation therapy, and X chromosomal deletions, are known to cause POF, the precise prevalence of the different etiologies is unknown. However, tests for organ specific serum antibody titers by the investigator and others, indicates that up to 50 percent of women with POF may have an underlying autoimmune abnormality. Recently, investigators have identified a functional defect in endogenous presentation of self-peptide fragments in the groove of major histocompatibility complex (MHC) class I molecules in patients with autoimmune disease with linkage to the HLA region. This defect results in decreased cell surface expression of conformationally correct class I antigens. Normally the complex of HLA class I and self peptide selects both positively and negatively T cells. Disruption of this process might explain the lack of self-antigen recognition and of self tolerance that leads to the autoimmune cell destruction in autoimmune diseases. The Tap-1 and Tap-2 intracellular peptide transporter genes, which map to the HLA class II region and control the delivery and association of endogenous peptides with class I molecules, may be responsible for the functional defect. Their preliminary data indicates that this same functional defect of class I antigen presentation is present in women with POF associated with the syndrome of Type II autoimmune polyglandular failure (PFG). Many autoimmune diseases are worse in women, presumably due to immunostimulatory effects of estrogen, but it is not known whether estrogen deficiency or estrogen replacement in women with POF affects the progression of their disease. In this proposal, they plan to capitalize on the collaborative expertise between clinical studies of women with POF in the Reproductive Endocrine Unit and the immunologic developments of the Immunobiology Laboratories. They wish to determine: 1) the prevalence of Tap controlled class I antigen presentation defects in women with POF; 2) the association of class I antigen defects with other manifestations of autoimmune diseases in POF; 3) the role of serum estrogen levels in the expression of autoimmune POF; 4) the efficacy of immunosuppressive therapy in those women with automimmune dysfunction; and 5) the presence and/or the prevalence of Tap-1 and Tap-2 gene defects as the basis of abnormal class I antigen presentation in women with autoimmune POF.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD032460-01A2
Application #
2025599
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1997-04-10
Project End
2000-03-31
Budget Start
1997-04-10
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Yan, G; Schoenfeld, D; Penney, C et al. (2000) Identification of premature ovarian failure patients with underlying autoimmunity. J Womens Health Gend Based Med 9:275-87