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Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

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Abstract

Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.

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Acknowledgments

We thank ImmunoQure AG for sharing antibodies used in the IFNα assay. The authors would like also to thank the data science platform of Imagine Institute (DrWareHouse).

Funding

Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002).

Author information

Authors and Affiliations

  1. Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, 24 boulevard du Montparnasse, 75015, Paris, France

    Lorenzo Lodi, Isabelle Melki, Luis Seabra, Alice Lepelley, Maria José Martin-Niclós, Yanick J. Crow & Marie-Louise Frémond

  2. Department of Health Sciences, University of Florence - Meyer Children’s University Hospital, Florence, Italy

    Lorenzo Lodi

  3. General Paediatrics- Infectious Diseases and Internal Medicine Department, Robert-Debré Hospital, AP-HP, Nord - Université de Paris, Paris, France

    Isabelle Melki, Camille Ducrocq, Cécile Dumaine & Marie Pouletty

  4. Paediatric Haematology-Immunology and Rheumatology Unit, Necker Hospital, AP-HP, Centre - Université de Paris, Paris, France

    Isabelle Melki, Brigitte Bader-Meunier, Romain Lévy, Pierre Quartier, Bénédicte Neven, Stéphane Blanche & Marie-Louise Frémond

  5. Translational Immunology Lab, Institut Pasteur, Paris, France

    Vincent Bondet & Darragh Duffy

  6. School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK

    Gillian I. Rice

  7. Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK

    Edwin Carter & Yanick J. Crow

  8. Department of Paediatric Rheumatology, Sidra Medicine, Doha, Qatar

    Buthaina Al Adba

  9. UMR CNRS 6015-INSERM U1083, MitoVasc Institute, University of Angers, Angers, France

    Magalie Barth

  10. Paediatric Neurosurgery Unit, Necker Hospital, AP-HP, Centre Université de Paris, Paris, France

    Thomas Blauwblomme

  11. Paediatric Dermatology Department, Necker Hospital, AP-HP, Centre Université de Paris, Paris, France

    Christine Bodemer

  12. Paediatric Neurology Department, Robert-Debré Hospital, AP-HP, Nord – Université de Paris, Paris, France

    Odile Boespflug-Tanguy & Sandrine Passemard

  13. Kids Neuroscience Centre, The Children’s Hospital at Westmead, University of Sydney, Westmead, NSW, Australia

    Russel C. Dale

  14. Paediatric Neurology Department, Necker Hospital, AP-HP, Centre Université de Paris, Paris, France

    Isabelle Desguerre & Marie Hully

  15. Paediatrics Department, Nice Hospitals, CHU LENVAL, Nice, France

    Fabienne Dulieu

  16. Department of Child and Adolescent Psychiatry, Robert-Debré Hospital, AP-HP, Nord – Université de Paris, Paris, France

    Pierre Ellul

  17. INSERM, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université, Paris, France

    Pierre Ellul

  18. Paediatric Pulmonology Department, Necker Hospital, AP-HP, Centre Université de Paris, Paris, France

    Alice Hadchouel

  19. Paediatrics Department, Versailles Hospital, Le Chesnay, France

    Véronique Hentgen

  20. French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d’Immunologie et des Maladies Infectieuses, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, Paris, France

    Miguel Hié

  21. Paediatrics Department, Centre Hospitalier Universitaire de Montpellier, Montpellier, France

    Eric Jeziorski

  22. National Reference Center for Neurometabolic Diseases, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, Paris, France

    Fanny Mochel

  23. Institut du Cerveau et de la Moelle épinière, INSERM U 1127, Sorbonne Université, Paris, France

    Fanny Mochel

  24. Child Neurology and Psychiatry Unit IRCCS Mondino Foundation, Pavia, Italy

    Simona Orcesi

  25. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy

    Simona Orcesi

  26. Paediatric Neurology Department, Trousseau Hospital, AP-HP, Sorbonne Université, Paris, France

    Florence Renaldo

  27. Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

    Rainer Seidl

  28. Department of Paediatric Neurosciences, Royal Hospital for Sick Children, Sciennes Road, Edinburgh, UK

    Jay Shetty

Authors
  1. Lorenzo Lodi
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  2. Isabelle Melki
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  3. Vincent Bondet
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  4. Luis Seabra
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  5. Gillian I. Rice
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  6. Edwin Carter
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  7. Alice Lepelley
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  8. Maria José Martin-Niclós
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  9. Buthaina Al Adba
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  10. Brigitte Bader-Meunier
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  11. Magalie Barth
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  12. Thomas Blauwblomme
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  13. Christine Bodemer
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  14. Odile Boespflug-Tanguy
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  15. Russel C. Dale
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  16. Isabelle Desguerre
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  17. Camille Ducrocq
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  18. Fabienne Dulieu
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  19. Cécile Dumaine
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  20. Pierre Ellul
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  21. Alice Hadchouel
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  22. Véronique Hentgen
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  23. Miguel Hié
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  24. Marie Hully
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  25. Eric Jeziorski
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  26. Romain Lévy
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  27. Fanny Mochel
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  28. Simona Orcesi
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  29. Sandrine Passemard
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  30. Marie Pouletty
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  31. Pierre Quartier
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  32. Florence Renaldo
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  33. Rainer Seidl
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  34. Jay Shetty
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  35. Bénédicte Neven
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  36. Stéphane Blanche
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  37. Darragh Duffy
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  38. Yanick J. Crow
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  39. Marie-Louise Frémond
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Contributions

L.L., I.M., Y.J.C., and M.L.F. designed the study. L.L. and I.M. collected clinical data. V.B., L.S., G.I.R., E.C., A.L., and M.J.M.M. performed the experiments and analyzed data. I.M., B.A.A., B.B.M., M.B., T.B., C.B., O.B.T., R.C.D., I.D., C.Duc, F.D., C.Dum, P.E., A.H., V.H., M.Hi, M.Hu, E.J., R.L., F.M., S.O., S.P., M.P., P.Q., F.R., R.S., J.S., B.N., S.B., Y.J.C., and M.L.F. participated in patient evaluation and provided resources. L.L. and M.L.F. performed statistical analyses. L.L. and M.L.F. wrote the paper. L.L., I.M., V.B., A.L., B.A.A., B.B.M., R.C.D., C.Dum, P.E., F.M., J.S., B.N., S.B., D.D., Y.J.C., and M.L.F. reviewed and edited the manuscript. Y.J.C. and M.L.F. supervised the study. All authors have read the final approval of the version published.

Corresponding authors

Correspondence to Yanick J. Crow or Marie-Louise Frémond.

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The authors declare that they have no conflict of interest.

Ethics Approval

The study was approved by the Comité de protection des personnes Ile de France II and the French advisory committee on data processing in medical research (ID-RCB: 2014-A01017-40).

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Lodi, L., Melki, I., Bondet, V. et al. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies. J Clin Immunol 41, 603–609 (2021). https://doi.org/10.1007/s10875-020-00952-x

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