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.
Immunology
Rheumatology
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.
Publications
- Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance. J Exp Med. 2019 Jun 3;216(6):1311-1327
Zhang Z, Gothe F, Pennamen P, James JR, McDonald D, Mata CP, Modis Y, Alazami AM, Acres M, Haller W, Bowen C, Döffinger R, Sinclair J, Brothers S, Zhang Y, Matthews HF, Naudion S, Pelluard F, Alajlan H, Yamazaki Y, Notarangelo LD, Thaventhiran JE, Engelhardt KR, Al-Mousa H, Hambleton S, Rooryck C, Smith KGC, Lenardo MJ
(See online at https://doi.org/10.1084/jem.20182304) - Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Sci Immunol. 2019 Dec 13;4(42)
Duncan CJA, Thompson B, Chen R, Rice GI, Gothe F, Young DF, Lovell SC, Shuttleworth VG, Brocklebank V, Corner B, Skelton AJ, Bondet V, Coxhead J, Duffy D, Fourrage C, Livingston JH, Pavaine J, Cheesman E, Bitetti S, Grainger A, Acres M, Innes BA, Mikulasova A, Sun R, Hussain R, Wright R, Wynn R, Zarhrate M, Zeef LAH, Wood K, Hughes SM, Harris CL, Engelhardt KR, Crow YJ, Randall RE, Kavanagh D, Hambleton S, Briggs TA
(See online at https://doi.org/10.1126/sciimmunol.aav7501) - Signal transducer and activator of transcription 5B deficiency due to a novel missense mutation in the coiled-coil domain. J Allergy Clin Immunol. 2019 Jan;143(1):413-416.e4
Acres MJ, Gothe F, Grainger A, Skelton AJ, Swan DJ, Willet JDP, Leech S, Galcheva S, Iotova V, Hambleton S, Engelhardt KR
(See online at https://doi.org/10.1016/j.jaci.2018.08.032)
