Autoinflammatory Diseases: Epigenetics & Immunomics (INSAID)

Systemic autoinflammatory diseases (SAID) are a group of molecular disorders characterized by seemingly unprovoked inflammation. Currently, it is possible to give a definitive diagnosis by using molecular analysis techniques for some patients, but for others the analysis outcome can be inconclusive or even misleading. In daily clinical practice, it is still very common that patients show clear symptoms of autoinflammatory disease but cannot be characterized using molecular techniques (undefined SAID). It is therefore of great importance to improve the diagnosis of SAID to avoid wrong and apply correct treatment options. First, the presented project will establish an agreement among experts detailing how to interpret the outcome of genetic tests in accordance with clinical data. This will allow, in combination with proposed enhanced genetic tests, to improve the diagnosis of SAID patients. Furthermore, the effect of external or environmental factors (epigenetics) on the organism of defined SAID will be studied using Familial Mediterranean Fever (FMF) as an example. Finally, a new platform containing different kinds of heterogeneous data will be established to identify the causing mechanisms of undefined SAIDs. The pursuit of these goals in combination with existing well characterized patient samples makes a highly promising approach to improve molecular diagnosis and to shed light on undiagnosed SAID cases. This project is part of the international collaborative project INSAID. The AIT Molecular Diagnostics group will be an essential partner of the INSAID project by providing highly paralleled epigenetic, immunomics, and inflammatory analysis technologies and bioinformatics key expertise for analyses of patients serum and DNA. The findings of these experiments will be used to characterize undefined SAID on molecular levels for enabling and improving patient-therapy.

Systemic autoinflammatory diseases (SAID) are a highly heterogeneous group of molecular disorders characterized by seemingly unprovoked systemic inflammation and periodic fever attacks. Molecular analysis can provide a definitive diagnosis in some patients with inherited SAID, but the results can be inconclusive or even misleading in several other cases. In daily practice, the number of patients having a clinical picture highly consistent with an autoinflammatory disease but are orphan of a molecular characterization (undefined SAID) is still high. It is therefore of great importance to improve the diagnosis of SAID to avoid wrong and apply correct treatment options. This project was part of the international collaborative project INSAID. The main goals of the project were: i) to establish consensus among experts on the correct interpretation of genetic tests in accordance with available clinical criteria; ii) To improve the performance of genetic diagnosis; iii) to evaluate the impact of modifier factors in the phenotype of defined SAID, using the most common SAID Familial Mediterranean Fever (FMF) as a prototype; iv) to establish a multidimensional platform for the identification of new genes and conditions for orphan patients. To characterize the molecular pathology of SAID, the Austrian Institute of Technology (AIT) performed DNA methylation-, serum marker-, protein-microarray studies, and bioinformatics. The DNA methylation experiments were focused on FMF patients. A first genome wide methylation study with 72 samples was the base of a more detailed sequencing experiment. The validation sequencing experiment was performed using 126 patient DNA samples targeting 96 regions discovered in the preceding genome wide methylation study to define epigenetic marker for SAID. Autoantibody profiles of 356 samples covering patients from 6 different SAID groups and healthy controls were analyzed using high density protein-microarrays. Comparing the different groups against the controls enables further clarification of immunological processes in SAID. The serum marker analysis targeted 92 inflammatory proteins and focused on the SAID group systemic juvenile idiopathic arthritis (SJIA). The results validated known and identified new disease specific marker. In the course of the project new disease specific biomarker were identified. The outcome has the impact to help understanding the complex nature of different inflammatory disease and is a step towards future therapeutic developments. The findings derived from the project have the potential to be transferred into medical diagnostics are closer to the medical application and diagnostic market.