Midtveisevaluering - Øyvind Bruserud

ABSTRAKT
 

Exploring and redefining Autoimmune polyendocrine syndrome type-I

Autoimmune diseases are a group of about 80 disorders that can involve almost any organ of the body. Approximately ten per cent of the European population is affected, particularly women, in whom it ranks among the top ten causes of death. Health expenditure in autoimmune diseases is double of what is used for cancer treatment. Most autoimmune diseases are multifactorial, with both genetic and environmental factors at play; the exact mechanisms behind these disorders are therefore poorly understood.

Autoimmune polyendocrine syndrome type-I (APS-I) is a unique disorder where mutations in one single gene, encoding the Autoimmune Regulator (AIRE), cause multi-organ autoimmune disease. Studies of AIRE and APS-I have taught us the principles of central immunological tolerance and how it can be broken, resulting in autoimmune diseases. Thus, it is an important model disease for autoimmunity.

The overall aim of this PhD project is to use APS-1 as a model disease to study different mechanisms contributing in autoimmunity. In the first project we gather in-depth clinical information (phenotype and epidemiology) on all Norwegian patients with APS-I, patients included in our National Registry. Further, we describe and correlate the clinical features with autoantibody profiles and AIRE mutations. In the second project, we focus on one of the three major disease components of the disease, namely chronic candidiasis, and describe an altered immune activation in patients’ whole blood and specific immune cells (monocytes) when exposed to candida antigens. In the third project we assess the bacterial microbiota of whole saliva in APS-1 patients by using high throughput sequencing and assess the possible role of the oral microbiota in the pathogenesis and phenotypic expression. Finally, in the fourth project we do functional analyses of the AIRE mutation c.879+1G>A trying to find the molecular explanation for a milder phenotype and to gain insight in general mechanisms of mRNA splicing.

Hopefully, this project will have implications for diagnosis and clinical care of patients with APS-I and organ-specific autoimmune diseases, and give further insight into the mechanisms behind autoimmune disorders.