CD56bright Natural Killer Cells: A Possible Biomarker of Different Treatments in Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, which leads, in many cases, to irreversible disability. More than 15 disease-modifying treatments (DMTs) are available for the treatment of MS. Clinical activity or activity at magnetic resonance imaging (MRI) are now used to assess the efficacy of DMTs, but are negative prognostic factors per se. Therefore, a biomarker permitting us to identify patients who respond to treatment before they develop clinical/radiological signs of MS activity would be of high importance. The number of circulating CD56bright natural killer (NK) cells may be such a biomarker. CD56bright NK cells are a regulatory immune population belonging to the innate immune system. The number of CD56bright NK cells increases upon treatment with interferon-beta, alemtuzumab, dimethyl fumarate, after autologous hematopoietic stem cell transplantation, and is higher in those who respond to fingolimod. In some cases, an increased number of CD56bright NK cells is associated with an increase in their regulatory function. In the current review, we will evaluate the known effect on CD56bright NK cells of DMTs for MS, and will discuss their possible role as a biomarker for treatment response in MS.

[1]  What's happening in Neurology® Neuroimmunology & Neuroinflammation , 2020, Neurology.

[2]  G. Fink,et al.  Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis , 2020, Journal of Neurology.

[3]  A. Bar-Or,et al.  Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis , 2020, Scientific Reports.

[4]  W. Brück,et al.  Molecular biomarkers in multiple sclerosis , 2019, Journal of Neuroinflammation.

[5]  A. Zabalza,et al.  Adaptive Features of Natural Killer Cells in Multiple Sclerosis , 2019, Front. Immunol..

[6]  O. Ciccarelli,et al.  Daclizumab-induced encephalitis in multiple sclerosis , 2019, Multiple sclerosis.

[7]  Jeffrey S. Miller,et al.  Human NK Cell Development: One Road or Many? , 2019, Front. Immunol..

[8]  A. Buriani,et al.  Increased NK Cell Count in Multiple Sclerosis Patients Treated With Dimethyl Fumarate: A 2-Year Longitudinal Study , 2019, Front. Immunol..

[9]  L. Moretta,et al.  An Historical Overview: The Discovery of How NK Cells Can Kill Enemies, Recruit Defense Troops, and More , 2019, Front. Immunol..

[10]  A. Laroni.  Enhancing natural killer cells is beneficial in multiple sclerosis – Yes , 2018, Multiple sclerosis.

[11]  Chuanfeng Wu,et al.  Clonal expansion and compartmentalized maintenance of rhesus macaque NK cell subsets , 2018, Science Immunology.

[12]  A. Barla,et al.  New miRNA Signature Heralds Human NK Cell Subsets at Different Maturation Steps: Involvement of miR-146a-5p in the Regulation of KIR Expression , 2018, Front. Immunol..

[13]  J. Álvarez-cermeño,et al.  Optimal response to dimethyl fumarate associates in MS with a shift from an inflammatory to a tolerogenic blood cell profile , 2018, Multiple sclerosis.

[14]  G. Deniz,et al.  Dysfunction of CD3-CD16+CD56dim and CD3-CD16-CD56bright NK cell subsets in RR-MS patients. , 2018, Clinical immunology.

[15]  F. Al-Shahrour,et al.  Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study , 2018, Front. Immunol..

[16]  M. Freedman,et al.  The Shifting Landscape of Disease-Modifying Therapies for Relapsing Multiple Sclerosis , 2018, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[17]  R. Hupperts,et al.  Dimethyl fumarate induces a persistent change in the composition of the innate and adaptive immune system in multiple sclerosis patients , 2018, Scientific Reports.

[18]  H. Atkins,et al.  Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis , 2018, Front. Immunol..

[19]  Clare Baecher-Allan,et al.  Multiple Sclerosis: Mechanisms and Immunotherapy , 2018, Neuron.

[20]  P. Bhargava,et al.  Dimethyl fumarate treatment alters NK cell function in multiple sclerosis , 2018, European journal of immunology.

[21]  K. Schmierer,et al.  Alemtuzumab depletion failure can occur in multiple sclerosis , 2018, Immunology.

[22]  M. Hecker,et al.  Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine‐1‐phosphate receptor modulator , 2018, CNS neuroscience & therapeutics.

[23]  M. Schilham,et al.  Expansion of cytotoxic CD56bright natural killer cells during T-cell deficiency after allogeneic hematopoietic stem cell transplantation. , 2017, The Journal of allergy and clinical immunology.

[24]  J. Lechner-Scott,et al.  Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia , 2017, Multiple sclerosis.

[25]  Jeffrey A. Cohen,et al.  Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis , 2017, Neurotherapeutics.

[26]  M. Sormani,et al.  Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis , 2017, Nature Reviews Neurology.

[27]  M. Jordana,et al.  Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection , 2017, The Journal of experimental medicine.

[28]  G. Comi,et al.  Evolving concepts in the treatment of relapsing multiple sclerosis , 2017, The Lancet.

[29]  H. Wiendl,et al.  Regulatory Functions of Natural Killer Cells in Multiple Sclerosis , 2016, Front. Immunol..

[30]  F. Locatelli,et al.  Human innate lymphoid cells. , 2016, Immunology letters.

[31]  V. Arolt,et al.  Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis , 2016, Neurology: Neuroimmunology & Neuroinflammation.

[32]  Antonio Uccelli,et al.  Dysregulation of regulatory CD56(bright) NK cells/T cells interactions in multiple sclerosis. , 2016, Journal of autoimmunity.

[33]  G. Foster,et al.  Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo , 2016, PLoS pathogens.

[34]  R. Hohlfeld,et al.  Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation , 2016, Proceedings of the National Academy of Sciences.

[35]  M. Mehling,et al.  Tissue Distribution Dynamics of Human NK Cells Inferred from Peripheral Blood Depletion Kinetics after Sphingosine‐1‐Phosphate Receptor Blockade , 2015, Scandinavian journal of immunology.

[36]  F. Malavasi,et al.  CD56brightCD16− NK Cells Produce Adenosine through a CD38-Mediated Pathway and Act as Regulatory Cells Inhibiting Autologous CD4+ T Cell Proliferation , 2015, The Journal of Immunology.

[37]  K. Schmierer,et al.  Is it time to target no evident disease activity (NEDA) in multiple sclerosis? , 2015, Multiple sclerosis and related disorders.

[38]  H. Wiendl,et al.  Alemtuzumab in Multiple Sclerosis: Mechanism of Action and Beyond , 2015, International journal of molecular sciences.

[39]  D. Centonze,et al.  Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS , 2015, Acta Neuropathologica.

[40]  K. Selmaj,et al.  CD56bright natural killer cells and response to daclizumab HYP in relapsing-remitting MS , 2015, Neurology: Neuroimmunology & Neuroinflammation.

[41]  D. Hafler,et al.  Regulatory T cells in autoimmune neuroinflammation , 2014, Immunological reviews.

[42]  M. Mirabella,et al.  Circulating CD56dim NK cells expressing perforin are increased in progressive multiple sclerosis , 2013, Journal of Neuroimmunology.

[43]  A. Maghazachi,et al.  Effects of Vitamin D3, Calcipotriol and FTY720 on the Expression of Surface Molecules and Cytolytic Activities of Human Natural Killer Cells and Dendritic Cells , 2013, Toxins.

[44]  D. Arnold,et al.  Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. , 2012, The New England journal of medicine.

[45]  David H. Miller,et al.  Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. , 2012, The New England journal of medicine.

[46]  B. Engelhardt,et al.  T‐cell trafficking in the central nervous system , 2012, Immunological reviews.

[47]  B. Ursø,et al.  Cytotoxicity of CD56bright NK Cells towards Autologous Activated CD4+ T Cells Is Mediated through NKG2D, LFA-1 and TRAIL and Dampened via CD94/NKG2A , 2012, PloS one.

[48]  X. Montalban,et al.  Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis. , 2011, Clinical immunology.

[49]  H. Weiner,et al.  IL-27 Imparts Immunoregulatory Function to Human NK Cell Subsets , 2011, PloS one.

[50]  J. Sheridan,et al.  Intermediate-affinity interleukin-2 receptor expression predicts CD56bright natural killer cell expansion after daclizumab treatment in the CHOICE study of patients with multiple sclerosis , 2011, Multiple sclerosis.

[51]  D. Maric,et al.  Unexpected Role for Granzyme K in CD56bright NK Cell-Mediated Immunoregulation of Multiple Sclerosis , 2011, The Journal of Immunology.

[52]  A. Bar-Or,et al.  Reduction of the Peripheral Blood CD56bright NK Lymphocyte Subset in FTY720-Treated Multiple Sclerosis Patients , 2011, The Journal of Immunology.

[53]  S. Cepok,et al.  Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS , 2011, Neurology.

[54]  J. Passweg,et al.  CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells , 2010, European journal of immunology.

[55]  B. Bielekova,et al.  An IL-2 Paradox: Blocking CD25 on T Cells Induces IL-2–Driven Activation of CD56bright NK Cells , 2010, The Journal of Immunology.

[56]  L. Kappos,et al.  A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. , 2010, The New England journal of medicine.

[57]  F. Barkhof,et al.  Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. , 2010, The New England journal of medicine.

[58]  D. Bourdette,et al.  Interferon-beta-1a treatment increases CD56bright natural killer cells and CD4+CD25+ Foxp3 expression in subjects with multiple sclerosis , 2009, Journal of Neuroimmunology.

[59]  M. Robin,et al.  An Unusual CD56brightCD16low NK Cell Subset Dominates the Early Posttransplant Period following HLA-Matched Hematopoietic Stem Cell Transplantation1 , 2008, The Journal of Immunology.

[60]  L. Airas,et al.  Expansion of CD56Bright natural killer cells in the peripheral blood of multiple sclerosis patients treated with interferon-beta , 2007, Neurological Sciences.

[61]  R. Schreiber,et al.  Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function1 , 2007, The Journal of Immunology.

[62]  C. Markowitz.  Interferon-beta , 2007, Neurology.

[63]  A. Thiel,et al.  CD56brightCD16− Killer Ig-Like Receptor− NK Cells Display Longer Telomeres and Acquire Features of CD56dim NK Cells upon Activation1 , 2007, The Journal of Immunology.

[64]  J. Buer,et al.  Gene and protein characteristics reflect functional diversity of CD56dim and CD56bright NK cells , 2006, Journal of leukocyte biology.

[65]  T. Waldmann,et al.  Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[66]  T. Yamamura,et al.  The regulatory role of natural killer cells in multiple sclerosis. , 2004, Brain : a journal of neurology.

[67]  M. Caligiuri,et al.  CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. , 2003, Blood.

[68]  M. Caligiuri,et al.  The biology of human natural killer-cell subsets. , 2001, Trends in immunology.

[69]  M. Caligiuri,et al.  Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset , 2001 .

[70]  T. Yamamura,et al.  Natural killer type 2 bias in remission of multiple sclerosis. , 2001, The Journal of clinical investigation.

[71]  A. Compston,et al.  Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. , 1996, The Journal of clinical investigation.

[72]  Mitchell S. V. Elkind,et al.  : Intrathecal effects of daclizumab treatment of multiple sclerosis , 2012 .

[73]  M. Robin,et al.  An unusual CD56(bright) CD16(low) NK cell subset dominates the early posttransplant period following HLA-matched hematopoietic stem cell transplantation. , 2008, Journal of immunology.

[74]  T. Ghayur,et al.  Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. , 2001, Blood.

[75]  J. Sheridan,et al.  CD56 bright natural killer cells and response to daclizumab HYP in relapsing-remitting MS , 2022 .