BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system. The cause of MS is still unknown, and the role of innate immunity is still poorly understood. OBJECTIVE: The goal of this study was to understand whether, compared to healthy controls, the elements of innate immunity are altered in the blood of MS patients in the remitting phase. METHODS: A total of 77 naïve MS patients and 50 healthy controls were included in this cohort study. Peripheral blood samples were collected and analyzed. All the calculations were performed with the statistical system R (r-project.org). RESULTS: The results showed that MS patients had significantly lower relative representations of granulocytes than healthy controls, while the relative representations of monocytes remained unchanged. CD64- and PD-L1-positive granulocytes exhibited a nonsignificant decreasing trend, while granulocytes with other membrane markers remained noticeably unchanged. CONCLUSION: The results of this study suggest that studies of the causes of MS and its treatment should also be focused on the elements of the innate immune response.

Biomedical Research Center University Hospital Hradec Kralove Sokolská 581 500 05 Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Králové Rokitanského 62 500 03 Hradec Kralove Czech Republic

Department of Clinical Immunology and Allergology University Hospital Hradec Králové Sokolská 581 500 05 Hradec Kralove Czech Republic

Department of Neurology Faculty of Medicine and University Hospital Hradec Králové Charles University Prague Sokolská 581 500 05 Hradec Kralove Czech Republic

Memory Clinic Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital 5 Úvalu 84 150 06 Prague Czech Republic

See more in PubMed

Yamasaki R., Kira J.I. Multiple Sclerosis. Adv. Exp. Med. Biol. 2019;1190:217–247. PubMed

Macaron G., Ontaneda D. Diagnosis and Management of Progressive Multiple Sclerosis. Biomedicines. 2019;7:56. doi: 10.3390/biomedicines7030056. PubMed DOI PMC

Zandoná M.E., Kim S.H., Hyun J.W., Park B., Joo J., Kim H.J. The onset location of neuromyelitis optica spectrum disorder predicts the location of subsequent relapses. Mult. Scler. J. 2014;20:1908–1911. doi: 10.1177/1352458514528763. PubMed DOI

Katz Sand I. Classification, diagnosis, and differential diagnosis of multiple sclerosis. Curr. Opin. Neurol. 2015;28:193–205. doi: 10.1097/WCO.0000000000000206. PubMed DOI

Katz Sand I., Krieger S., Farrell C., Miller A.E. Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis. Mult. Scler. 2014;20:1654–1657. doi: 10.1177/1352458514521517. PubMed DOI

Ghasemi N., Razavi S., Nikzad E. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017;19:1–10. PubMed PMC

Olsson T., Barcellos L.F., Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat. Rev. Neurol. 2017;13:25–36. doi: 10.1038/nrneurol.2016.187. PubMed DOI

Perron H., Lang A. The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clin. Rev. Allergy Immunol. 2010;39:51–61. doi: 10.1007/s12016-009-8170-x. PubMed DOI

Wekerle H. Nature, nurture, and microbes: The development of multiple sclerosis. Acta Neurol. Scand. 2017;136(Suppl. 201):22–25. doi: 10.1111/ane.12843. PubMed DOI

Ellwardt E., Zipp F. Molecular mechanisms linking neuroinflammation and neurodegeneration in MS. Pt. AExp. Neurol. 2014;262:8–17. doi: 10.1016/j.expneurol.2014.02.006. PubMed DOI

Yadav S.K., Mindur J.E., Ito K., Dhib-Jalbut S. Advances in the immunopathogenesis of multiple sclerosis. Curr. Opin. Neurol. 2015;28:206–219. doi: 10.1097/WCO.0000000000000205. PubMed DOI

Canto E., Oksenberg J.R. Multiple sclerosis genetics. Mult. Scler. 2018;24:75–79. doi: 10.1177/1352458517737371. PubMed DOI

Patsopoulos N.A., Baranzini S.E., Santaniello A., Shoostari P., Cotsapas C., Wong G., Beecham A.H., James T., Replogle J., Vlachos I.S., et al. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019:365. PubMed PMC

Turvey S.E., Broide D.H. Innate immunity. J. Allergy Clin. Immunol. 2010;125(Suppl. 2):S24–S32. doi: 10.1016/j.jaci.2009.07.016. PubMed DOI PMC

Saferding V., Blüml S. Innate immunity as the trigger of systemic autoimmune diseases. J. Autoimmun. 2019;110:102382. doi: 10.1016/j.jaut.2019.102382. PubMed DOI

Hernández-Pedro N.Y., Espinosa-Ramirez G., de la Cruz V.P., Pineda B., Sotelo J. Initial immunopathogenesis of multiple sclerosis: Innate immune response. Clin. Dev. Immunol. 2013;2013:413465. doi: 10.1155/2013/413465. PubMed DOI PMC

Gandhi R., Laroni A., Weiner H.L. Role of the innate immune system in the pathogenesis of multiple sclerosis. J. Neuroimmunol. 2010;221:7–14. doi: 10.1016/j.jneuroim.2009.10.015. PubMed DOI PMC

Chu F., Shi M., Zheng C., Shen D., Zhu J., Zheng X., Cui L. The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis. J. Neuroimmunol. 2018;318:1–7. doi: 10.1016/j.jneuroim.2018.02.015. PubMed DOI

Ohl K., Tenbrock K., Kipp M. Oxidative stress in multiple sclerosis: Central and peripheral mode of action. Exp. Neurol. 2016;277:58–67. doi: 10.1016/j.expneurol.2015.11.010. PubMed DOI PMC

Nikić I., Merkler D., Sorbara C., Brinkoetter M., Kreutzfeldt M., Bareyre F.M., Brück W., Bishop D., Misgeld T., Kerschensteiner M. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 2011;17:495–499. doi: 10.1038/nm.2324. PubMed DOI

Haider L., Fischer M.T., Frischer J.M., Bauer J., Höftberger R., Botond G., Esterbauer H., Binder C.J., Witztum J.L., Lassmann H. Oxidative damage in multiple sclerosis lesions. Brain. 2011;134:1914–1924. doi: 10.1093/brain/awr128. PubMed DOI PMC

Fani Maleki A., Rivest S. Innate Immune Cells: Monocytes, Monocyte-Derived Macrophages and Microglia as Therapeutic Targets for Alzheimer’s Disease and Multiple Sclerosis. Front. Cell. Neurosci. 2019;13:355. doi: 10.3389/fncel.2019.00355. PubMed DOI PMC

Shemer A., Jung S. Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity. Semin. Immunopathol. 2015;37:613–623. doi: 10.1007/s00281-015-0519-z. PubMed DOI

Cadman E.T., Lawrence R.A. Granulocytes: Effector cells or immunomodulators in the immune response to helminth infection? Parasite Immunol. 2010;32:1–19. doi: 10.1111/j.1365-3024.2009.01147.x. PubMed DOI

Ueda Y., Kondo M., Kelsoe G. Inflammation and the reciprocal production of granulocytes and lymphocytes in bone marrow. J. Exp. Med. 2005;201:1771–1780. doi: 10.1084/jem.20041419. PubMed DOI PMC

Eyerich S., Metz M., Bossios A., Eyerich K. New biological treatments for asthma and skin allergies. Allergy. 2020;75:546–560. doi: 10.1111/all.14027. PubMed DOI

Thompson A.J., Banwell B.L., Barkhof F., Carroll W.M., Coetzee T., Comi G., Correale J., Fazekas F., Filippi M., Freedman M.S., et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–173. doi: 10.1016/S1474-4422(17)30470-2. PubMed DOI

Tsivgoulis G., Katsanos A.H., Grigoriadis N., Hadjigeorgiou G.M., Heliopoulos I., Kilidireas C., Voumvourakis K. The effect of disease modifying therapies on brain atrophy in patients with relapsing-remitting multiple sclerosis: A systematic review and meta-analysis. PLoS ONE. 2015;10:e0116511. doi: 10.1371/journal.pone.0116511. PubMed DOI PMC

Ho D.E., Imai K., King G., Stuart E.A. MatchIt: Nonparametric preprocessing for parametric causal inference. J. Stat. Softw. 2011;42:1–28. doi: 10.18637/jss.v042.i08. DOI

The R Project for Statistical Computing. [(accessed on 25 December 2019)]; Available online: http://r-project.org/

Lin A., Loré K. Granulocytes: New members of the antigen-presenting cell family. Front. Immunol. 2017;8:1781. doi: 10.3389/fimmu.2017.01781. PubMed DOI PMC

Gerrits J.H., McLaughlin P.M.J., Nienhuis B.N., Smit J.W., Loef B. Polymorphic mononuclear neutrophils CD64 index for diagnosis of sepsis in postoperative surgical patients and critically ill patients. Clin. Chem. Lab. Med. 2013;51:897–905. doi: 10.1515/cclm-2012-0279. PubMed DOI

Hussein O.A., El-Toukhy M.A., El-Rahman H.S. Neutrophil CD64 expression in inflammatory autoimmune diseases: Its value in distinguishing infection from disease flare. Immunol. Investig. 2010;39:699–712. doi: 10.3109/08820139.2010.491520. PubMed DOI

Annunziata P., Masi G., Cioni C. Association of circulating anti-CD64 IgM levels with favourable long-term clinical outcomes in multiple sclerosis patients. J. Neuroimmunol. 2019;330:130–135. doi: 10.1016/j.jneuroim.2019.03.005. PubMed DOI

Alsaab H.O., Sau S., Alzhrani R., Tatiparti K., Bhise K., Kashaw S.K., Iyer A.K. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front. Pharm. 2017;8:561. doi: 10.3389/fphar.2017.00561. PubMed DOI PMC

Luo Q., Huang Z., Ye J., Deng Y., Fang L., Li X., Guo Y., Jiang H., Ju B., Huang Q., et al. PD-L1-expressing neutrophils as a novel indicator to assess disease activity and severity of systemic lupus erythematosus. Arthr. Res. Ther. 2016;18:47. doi: 10.1186/s13075-016-0942-0. PubMed DOI PMC

Jayaraman A., Sharma M., Prabhakar B., Holterman M., Jayaraman S. Amelioration of progressive autoimmune encephalomyelitis by epigenetic regulation involves selective repression of mature neutrophils during the preclinical phase. Exp. Neurol. 2018;304:14–20. doi: 10.1016/j.expneurol.2018.02.008. PubMed DOI

Murdock B.J., Bender D.E., Kashlan S.R., Figueroa-Romero C., Backus C., Callaghan B.C., Goutman S.A., Feldman E.L. Increased ratio of circulating neutrophils to monocytes in amyotrophic lateral sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 2016;3:e242. doi: 10.1212/NXI.0000000000000242. PubMed DOI PMC

Rossi B., Constantin G., Zenaro E. The emerging role of neutrophils in neurodegeneration. Immunobiology. 2020;225:151865. doi: 10.1016/j.imbio.2019.10.014. PubMed DOI

Woodberry T., Bouffler S., Wilson A., Buckland R., Brüstle A. The Emerging Role of Neutrophil Granulocytes in Multiple Sclerosis. J. Clin. Med. 2018;7:511. doi: 10.3390/jcm7120511. PubMed DOI PMC

Croxford A.L., Kurschus F.C., Waisman A. Mouse models for multiple sclerosis: Historical facts and future implications. Biochim. Biophys. Acta Mol. Basis Dis. 2011;1812:177–183. doi: 10.1016/j.bbadis.2010.06.010. PubMed DOI

Pierson E.R., Wagner C.A., Goverman J.M. The contribution of neutrophils to CNS autoimmunity. Clin. Immunol. 2018;189:23–28. doi: 10.1016/j.clim.2016.06.017. PubMed DOI PMC

Aubé B., Lévesque S.A., Paré A., Chamma É., Kébir H., Gorina R., Lécuyer M.A., Alvarez J.I., De Koninck Y., Engelhardt B., et al. Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases. J. Immunol. 2014;193:2438–2454. doi: 10.4049/jimmunol.1400401. PubMed DOI

Kostic M., Dzopalic T., Zivanovic S., Zivkovic N., Cvetanovic A., Stojanovic I., Vojinovic S., Marjanovic G., Savic V., Colic M. IL-17 and Glutamate Excitotoxicity in the Pathogenesis of Multiple Sclerosis. Scand. J. Immunol. 2014;79:181–186. doi: 10.1111/sji.12147. PubMed DOI

Chabas D., Ness J., Belman A., Yeh E.A., Kuntz N., Gorman M.P., Strober J.B., De Kouchkovsky I., McCulloch C., Chitnis T., et al. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology. 2010;74:399–405. doi: 10.1212/WNL.0b013e3181ce5db0. PubMed DOI PMC

Bisgaard A.K., Pihl-Jensen G., Frederiksen J.L. The neutrophil-to-lymphocyte ratio as disease actvity marker in multiple sclerosis and optic neuritis. Mult. Scler. Relat. Disord. 2017;18:213–217. doi: 10.1016/j.msard.2017.10.009. PubMed DOI

Demirci S., Demirci S., Kutluhan S., Koyuncuoglu H.R., Yurekli V.A. The clinical significance of the neutrophil-to-lymphocyte ratio in multiple sclerosis. Int. J. Neurosci. 2016;126:700–706. doi: 10.3109/00207454.2015.1050492. PubMed DOI

Ortler S., Leder C., Mittelbronn M., Zozulya A.L., Knolle P.A., Chen L., Kroner A., Wiendl H. B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: Implications for the lesion pathogenesis of multiple sclerosis. Eur. J. Immunol. 2008;38:1734–1744. doi: 10.1002/eji.200738071. PubMed DOI

Javan M.R., Aslani S., Zamani M.R., Rostamnejad J., Asadi M., Farhoodi M., Nicknam M.H. Downregulation of immunosuppressive molecules, PD-1 and PD-L1 but not PD-L2, in the patients with multiple sclerosis. Iran. J. Allergy Asthma Immunol. 2016;15:296–302. PubMed