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Functional analysis of a new genetic variant suspected to cause a novel form of primary immunodeficiency featuring frequent respiratory infections, a susceptibility to herpesviral infection and lymphoid malignancy in three individuals.

Subject Area Pediatric and Adolescent Medicine
Immunology
Rheumatology
Term from 2017 to 2020
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 389148238
 
Final Report Year 2020

Final Report Abstract

During my postdoc in the lab of Professor Sophie Hambleton at Newcastle University I have been working on paediatric patients suffering from inborn errors of immunity with a particular focus on immune cell signalling. We were fortunate to describe hypomorphic variants in the IL2RB gene encoding the β-subunit of the interleukin (IL)-2 and IL-15 receptor as a new cause of severe immune dysregulation. The missing IL-2 signal was observed to abolish survival of regulatory T cells in the periphery leading to severe autoimmunity. In addition, we could link impaired formation or survival of memory cytotoxic lymphocytes i.e. CD8+ T and NK cells to severe Cytomegalovirus infections. Downstream of many cytokine receptors, the group of STAT (signal transducer of activator of transcription) molecules transfers signals from the cell membrane into the nucleus and shapes transcriptional responses. The main transmitter of IL-2 and IL-15 signals is STAT5 and we described patients with new germline variants in this transcription factor to either cause immune dysregulation when its function is impaired or severe allergic manifestations when overactive. Most of the seven members of the STAT family can be activated by different cytokines and signal in various different combinations, only STAT2 is exclusively regulating responses to type-I interferons. We published the first cases of autosomal-recessive STAT2 gain-of-function mutations leading to severe autoinflammation particularly affecting the brain. This new type-I interferonopathy was found to result from the failure of the mutated STAT2 molecule to interact with its own negative regulator. In light of the increasing use of Janus kinase (JAK) inhibitors (e.g. Ruxolitinib), which target the kinases linking receptor and associated STAT molecules, it seems pivotal to expand our knowledge about function, regulation and kinetics of these signalling pathways. The study of rare patients with germline variants in these signalling molecules can inform our understanding of disease mechanisms and treatment complications.

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