The Single Cell Disease Map of Autoinflammation in Blood

• Applicant: Dr. Thomas Ulas, since 3/2024
• Subject Area: Clinical Immunology and Allergology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458854699

Autoinflammation, a dysregulation in the innate arm of the immune system, can cause diverse clinical phenotypes, seen in primary immunodeficiencies with known mutations, but also in autoinflammatory syndromes without known cause. The introduction of next-generation sequencing into clinical practice in recent years has revealed a plethora of associated mutations, and genotype-phenotype relationships have been challenged. The field is debating on how to diagnose and group the various syndromes under the umbrella of autoinflammation.This project proposes to, for the first time, define complete molecular phenotypes of all immune cells in the circulation on the single-cell level in autoinflammatory disease.With a systems medicine approach, a comprehensive single-cell disease map of autoinflammation in the blood using single-cell transcriptomics will be generated and simultaneously the functional states of all immune cells present in the blood characterised. Patients diagnosed with FMF, HIDS and CGD as well as patients with autoinflammatory syndrome without underlying known genetic cause will be analysed and compared to control donors. Subgroups of this cohort will also be analysed after prospective SARS-CoV-2 vaccination and further a subgroup of samples will be analysed after stimulation with IL-1, both to evoking potential greater functional alterations in the system under two different types of challenge than in direct sampling.A deep, high-parameter characterisation of the circulating immune cells by scRNA-seq of non-activated and activated cells of different autoinflammatory syndromes will provide a novel resolution to the pathophysiological alterations in autoinflammatory disease on a cell population as well as on molecular level. Elucidation of the patient’s immune status by analysing all immune cell populations present in peripheral blood with regard to their numbers and functional state is necessary to obtain a more complete picture of the ongoing disturbances. A more detailed view on the correlation between clinical symptoms and the immune parameters is missing and will advance the understanding of disease pathology and possibly etiology, which in turn may help finding new diagnostic biomarkers as well as therapeutic avenues for treatment. The gained knowledge will directly translate to understanding of other diseases with autoinflammatory contribution and possible overreactions during vaccination; thus, there will be a direct medical and societal impact.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Anna Aschenbrenner, until 3/2024