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Natural killer cells and type II interferon in Ro/SSA and La/SSB autoantibody-exposed newborns at risk of congenital heart block
  1. Margarita Ivanchenko1,
  2. Gudny Ella Thorlacius1,
  3. Malin Hedlund1,
  4. Vijole Ottosson1,
  5. Lauro Meneghel1,
  6. Sophia Björkander2,
  7. Amina Ossoinak1,
  8. Joanna Tingström1,
  9. Katarina Bremme3,
  10. Eva Sverremark-Ekström2,
  11. Kristina Gemzell-Danielsson3,
  12. Sven-Erik Sonesson4,
  13. Karine Chemin1,
  14. Marie Wahren-Herlenius1,5
  1. 1 Division of Rheumatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  2. 2 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
  3. 3 Division of Obstetrics and Gynecology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  4. 4 Division of Pediatric Cardiology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  5. 5 Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Hordaland, Norway
  1. Correspondence to Professor Marie Wahren-Herlenius, Department of Medicine, Karolinska Institute, Stockholm, Sweden; marie.wahren{at}ki.se

Abstract

Objective Congenital heart block (CHB) with immune cell infiltration develops in the fetus after exposure to maternal Ro/La autoantibodies. CHB-related serology has been extensively studied, but reports on immune-cell profiles of anti-Ro/La-exposed neonates are lacking. In the current study, we characterised circulating immune-cell populations in anti-Ro/La+mothers and newborns, and explored potential downstream effects of skewed neonatal cell populations.

Methods In total, blood from mothers (n=43) and neonates (n=66) was sampled at birth from anti-Ro/La+ (n=36) and control (n=30) pregnancies with or without rheumatic disease and CHB. Flow cytometry, microarrays and ELISA were used for characterising cells and plasma.

Results Similar to non-pregnant systemic lupus erythematosus and Sjögren-patients, anti-Ro/La+mothers had altered B-cell subset frequencies, relative T-cell lymphopenia and lower natural killer (NK)-cell frequencies. Surprisingly, their anti-Ro/La exposed neonates presented higher frequencies of CD56dimCD16hi NK cells (p<0.01), but no other cell frequency differences compared with controls. Type I and II interferon (IFN) gene-signatures were revealed in neonates of anti-Ro/La+ pregnancy, and exposure of fetal cardiomyocytes to type I IFN induced upregulation of several NK-cell chemoattractants and activating ligands. Intracellular flow cytometry revealed IFNγ production by NK cells, CD8+ and CD4+ T cells in anti-Ro/La exposed neonates. IFNγ was also detectable in their plasma.

Conclusion Our study demonstrates an increased frequency of NK cells in anti-Ro/La exposed neonates, footprints of type I and II IFN and an upregulation of ligands activating NK cells in fetal cardiac cells after type I IFN exposure. These novel observations demonstrate innate immune activation in neonates of anti-Ro/La+pregnancy, which could contribute to the risk of CHB.

  • autoantibodies
  • autoimmunity
  • B cells
  • sjøgren's syndrome

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Footnotes

  • Handling editor Josef S Smolen

  • KC and MW-H contributed equally.

  • Contributors MI, MH, KC and MW-H conceived the study. MH, JT, SB, KB, ES-E, KG-D, S-ES recruited patients and provided biological material. MI, GET, MH, VO, AO, LM, KC and MW-H performed experiments and/or analysed data. MI, MH, GET generated figures and tables and MI wrote the first manuscript draft with input from MW-H, KC, GET and MH. All authors (MI, GET, MH, VO, LM, SB, AO, JT, KB, ES-E, KG-D, S-ES, KC, MW-H) participated in the editing of the manuscript until its final version.

  • Funding The study was supported by grants from the Swedish Research Council, the Heart-Lung Foundation, the Stockholm County Council, Karolinska Institutet, the Swedish Rheumatism association, the King Gustaf the V:the 80-year foundation and the Freemason’s in Stockholm Foundation for Children’s Welfare.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Regional Ethics Committee in Stockholm (Dnr 2013/2201-31).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information.

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