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Immunopathogenesis of Addison's disease and related disorders

Objective

1) identification of new autoantigens in adrenal gland and in the gonads 2) identification of B-cell epitopes in the autoantigens and subsequent development of diagnostic tests, 3) characterisation of the helper T-cell and cytotoxic T-cells responses toward adrenal and gonadal autoantigens and identification of the corresponding T-cell epitopes, 4) analysis of the HLA background of various forms of Addison's disease and the study of HLA T-cell peptide interaction with molecular modelling, 5) search for immunological cross reactivity between Candida albicans antigens and adrenal and gonadal autoantigens, 6) generation of animal models for Addison's disease for immunotherapeutic studies and 7) the study of 21-hydroxylase antibodies in related autoimmune diseases.

Autoimmune Addison's disease, the main course of adrenocortical failure in the developed world is characterised by an immune response against adrenal cortex and in some instances against other steroid hormone-producing cells as well. Recently, our groups have shown that the target antigens in the adrenal cortex and the gonads are members of the steroidogenic enzymes, notably 21-hydroxylase (P450c21), 17-hydroxylase (P450c17) and the side-chain cleavage enzyme (P450scc). These studies > will now be continued in a co-ordinated manner with the objectives stated above: 1) New autoantigens will be identified by screening adrenal or gonadal expression libraries 2) B-cell epitopes in the autoantigens are looked for by the Pepscan method 3) Helper T-cell and cytotoxic T-cells epitopes are identified using synthetic soluble peptides, 4) The HLA background of various forms of Addison's disease will be studied 5) Candida albicans expression libraries are screened with patient sera and with monoclonal antibodies to the identified autoantigens, 6) Animal models for Addison's disease are developed by immunization with cDNA expression vectors for the identified autoantigens 7) The presence of 21-hydroxylase antibodies in related autoimmune diseases is looked for. The priorities of the project are to provide new diagnostic tools, better understanding of mechanisms of pathogenesis along with genetic background, detection of high risk individuals by antibody and HLA typing, information exchange on basic and clinical level and public awareness in participating countries.

Funding Scheme

CON - Coordination of research actions

Coordinator

University of Tampere
Address
6,Lenkkeilijankatu
33101 Tampere
Finland