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Enhanced cytokine responsiveness in natural killer cells from a pilot cohort of uninfected seronegative women exposed to hepatitis C virus contaminated anti-D immunoglobulin

M. W. Robinson, C. Keane, M. Needham, G. Roche, E. Wallace, J. Connell, C. F. de Gascun, A. Naik, L. J. Fanning, C. Gardiner, D. D. Houlihan, View ORCID ProfileC. O’Farrelly
doi: https://doi.org/10.1101/747436
M. W. Robinson
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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C. Keane
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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M. Needham
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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G. Roche
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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E. Wallace
Department of Immunology, St. Vincent’s University Hospital, Dublin, Ireland
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J. Connell
UCD National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
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C. F. de Gascun
UCD National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
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A. Naik
Molecular Virology Diagnostic and Research Laboratory, Department of Medicine, University College Cork, Cork, Ireland
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L. J. Fanning
Molecular Virology Diagnostic and Research Laboratory, Department of Medicine, University College Cork, Cork, Ireland
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C. Gardiner
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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D. D. Houlihan
Liver Unit, St. Vincent’s University Hospital, Dublin, Ireland
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C. O’Farrelly
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, IrelandSchool of Medicine, Trinity College Dublin, Dublin, Ireland
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  • ORCID record for C. O’Farrelly
  • For correspondence: cliona.ofarrelly@tcd.ie
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Abstract

Background Some people exposed to hepatitis C virus (HCV) appear to be capable of preventing infection in the absence of detectable antibody responses. These ‘exposed seronegative (ESN)’ people appear naturally resistant to HCV infection. Here, we aimed to examine innate immune mechanisms in ESN individuals amongst rhesus negative Irish women exposed to HCV via contaminated anti-D immunoglobulin between 1977-79 and 1991-94.

Methods A total of 16 ESN individuals were recruited, along with 9 age- and gender-matched healthy controls. All tested negative for HCV-specific antibodies using conventional diagnostic assays. Peripheral blood cells were analysed for presence of adaptive immune response markers, innate immune responsiveness and natural killer cell phenotype and function.

Results The innate immune cell profile of ESN women in the present study was characterised by a significant decrease in monocyte frequency and elevated levels of interleukin-8 and -18 compared to age- and gender-matched healthy controls. NK cells from ESN women had normal expression of NK cell receptors but increased IFNγ-production upon cytokine and target cell stimulation as well as enhanced natural killer (NK) cell STAT3 phosphorylation in response to Type I IFN.

Conclusions We describe for the first time ESN individuals amongst Irish women with past exposure to HCV via contaminated anti-D immunoglobulin. NK cells from these ESN individuals are more responsive to cytokine signalling compared with age- and gender-matched controls. Human ESN cohorts can provide unique insights into the biological mechanisms associated with antigen-independent natural resistance to viral infection.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 28, 2019.
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Enhanced cytokine responsiveness in natural killer cells from a pilot cohort of uninfected seronegative women exposed to hepatitis C virus contaminated anti-D immunoglobulin
M. W. Robinson, C. Keane, M. Needham, G. Roche, E. Wallace, J. Connell, C. F. de Gascun, A. Naik, L. J. Fanning, C. Gardiner, D. D. Houlihan, C. O’Farrelly
bioRxiv 747436; doi: https://doi.org/10.1101/747436
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Enhanced cytokine responsiveness in natural killer cells from a pilot cohort of uninfected seronegative women exposed to hepatitis C virus contaminated anti-D immunoglobulin
M. W. Robinson, C. Keane, M. Needham, G. Roche, E. Wallace, J. Connell, C. F. de Gascun, A. Naik, L. J. Fanning, C. Gardiner, D. D. Houlihan, C. O’Farrelly
bioRxiv 747436; doi: https://doi.org/10.1101/747436

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