ÐÒÔË·Éͧ¼Æ»®

Secondary objectives:

1. Identification of novel monogenic causes of organ-specific autoimmunity.

Based on our recent findings of novel dominantly inherited forms of organ-specificÌýautoimmunity (), we hypothesize that monogenic organ-specificÌýautoimmune diseases are much more common than previously thought. OurÌýpreliminary findings from exome sequencing of patients with autoimmune Addison’s diseaseÌý(AAD) and autoimmune polyendocrine syndromes (APS) have identified several newÌýcandidate cases with possible disease-causing heterozygous mutations. We will:

• Compile extreme phenotypes and families with heavy aggregation of organ-specificÌýautoimmunity (from the National Registries for Organ-Specific Autoimmune DiseasesÌýin Norway ()Ìýand Sweden ().

• Perform DNA-sequencing using multiple strategies including hypothesis-drivenÌýtargeted panel sequencing, exome sequencing and whole genome sequencing.

• Analyze data by state-of-the-art bioinformatics analyses.
• Replicate findings using national cohorts (HUSK, MoBa and HUNT) and thoseÌýavailable through international collaborations (FP7EurAdrenal, FP6EurAPS).
Ìý

2. Delineate pathogenic mechanisms in organ-specific autoimmunity.

The autoimmunity-associated genetic mutations identified in secondary obj. 1 will be used to
identify key pathways and regulatory checkpoints involved in autoimmune pathogeneses.
We have established a number of advanced techniques for analyses of autoantibodies and
autoreactive B- and T-cells and have vast experience with animal models. We will:Use human samples (blood, tissue samples, organoids) for single cell analysis to
functionally characterize identified genes and their mutations in the context of their
pathways.
• Develop complementary mouse models generated by Crispr/Cas9 technique, which
is excellently suited for monogenic diseases.
• Implement array-based antibody screening and advanced T cell assays based on
flow cytometry (including Cytof) and HLA-multimers to study immune responses
related to these pathways.

3. Develop novel biomarkers for prediction, diagnostics and prognosis.

Autoantibody assays are currently used for diagnostic purposes and help determineÌýautoimmune aetiology, but can be hard to interpret in a prognostic clinical setting. ThusÌýadditional biomarkers and genetic traits that reflect various pathogenic pathways wouldÌýgive a more precise assessment of disease risk and can be used to monitor theÌýeffect of novel treatment modalities. We willÌý

• Use findings from secondary objective 1 to identify genetic risk biomarkers.Ìý

• Identify and functionally validate autoimmune biomarkers from pathogenicÌýpathways identified in secondary objective 2.

• Delineate genetic and immunological biomarker patterns and relate them to risk,Ìýdiagnostic utility, and prognosis for specific organ-specific diseases using theÌýresults from secondary objectives 1 and 2.

4. Establish novel immunotherapies for rare autoimmune organ-specificÌýdiseases.

Building on results from secondary obj 1-3 we will devise targeted therapies for selectedÌýorgan-specific diseases by repurposing already existing drugs and develop novelÌýmonoclonal antibodies specifically targeting the pathways involved in autoimmuneÌýdestruction. This could provide us with means to reverse and possibly prevent developmentÌýof organ-specific autoimmune diseases. Pre-clinical testing will start in the mouse modelsÌýgenerated under secondary objective 2.Ìý