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Classical complement pathway factor alterations in narcolepsy

Published online by Cambridge University Press:  17 January 2022

Hande Yüceer Open the ORCID record for Hande Yüceer [Opens in a new window] ,
Duygu Gezen Ak ,
Gülçin Benbir Şenel ,
Erdinç Dursun ,
Vuslat Yılmaz ,
Derya Karadeniz ,
Erdem Tüzün  and
Cem İsmail Küçükali
Hande Yüceer
Affiliation:
Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
Duygu Gezen Ak
Affiliation:
Brain and Neurodegenerative Disorders Research Laboratories, Department of Medical Biology, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey
Gülçin Benbir Şenel
Affiliation:
Sleep Laboratory, Department of Neurology, Cerrahpaşa Faculty of Medicine, Istanbul University Cerrahpaşa, Istanbul, Turkey
Erdinç Dursun
Affiliation:
Brain and Neurodegenerative Disorders Research Laboratories, Department of Medical Biology, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey Department of Neuroscience, Institute of Neurological Sciences, Istanbul University-Cerrahpaşa, Istanbul, Turkey
Vuslat Yılmaz
Affiliation:
Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
Derya Karadeniz
Affiliation:
Sleep Laboratory, Department of Neurology, Cerrahpaşa Faculty of Medicine, Istanbul University Cerrahpaşa, Istanbul, Turkey
Erdem Tüzün
Affiliation:
Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
Cem İsmail Küçükali*
Affiliation:
Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
*
Author for correspondence: Cem İsmail Küçükali, Email: cemsmile@gmail.com
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Abstract

Objective:

Narcolepsy is a chronic sleep disorder long hypothesised to be an autoimmune disease. Complement-mediated immune mechanisms have not been investigated in detail in narcolepsy. Our aim was to establish the significance of classical pathway activation in narcolepsy.

Methods:

Sera of 42 narcolepsy patients and 26 healthy controls were screened with ELISA to determine the levels of C1q, C3a, C4d and complement component 4 binding protein (C4BP). A home-made ELISA method was developed to detect antibodies to C4BP-alpha (anti-C4BPA). The correlation between complement levels and clinical findings was examined.

Results:

C1q levels were significantly higher in narcolepsy patients while C4d and C4BP levels were significantly lower compared to healthy controls. C3a levels were comparable among patients and controls. Eleven narcolepsy patients showed serum anti-C4BPA levels. Total rapid eye movements (REM) time, sleep onset latency, REM sleep latency, sleep activity, percentage of wakefulness after sleep onset and Epworth sleepiness scale scores were correlated with levels of different complement factors.

Conclusion:

Complement-mediated immune mechanisms might partake in narcolepsy pathogenesis. The precise role of autoantibodies on complement level alterations needs to be investigated. Levels of complement factors and degradation products may potentially be utilised as biomarkers to predict the clinical severity of narcolepsy.

Keywords

autoimmunitycomplement C1qcomplement C4b-binding proteincomplement system proteinsnarcolepsy
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 34 , Issue 4 , August 2022 , pp. 212 - 219
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Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

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References

Abbas, AK, Lichtman, AH and Pillai, S (2017) Cellular and Molecular Immunology, 9th edn. Philadelphia: Saunders/Elsevier.Google Scholar
Agrawal, A, Shrive, AK, Greenhough, TJ and Volanakis, JE (2001) Topology and structure of the C1q-binding site on C-reactive protein. The Journal of Immunology 166(6), 3998–4004. doi: 10.4049/jimmunol.166.6.3998.CrossRefGoogle ScholarPubMed
Alexander, JJ, Anderson, AJ, Barnum, SR, Stevans, B and Tenner, AJ (2008) The complement cascade: Yin-Yang in neuroinflammation – neuro-protection and –degeneration. Journal of Neurochemistry 107(5), 1169–1187. doi: 10.1111/J.1471-4159.2008.05668.X.CrossRefGoogle ScholarPubMed
American Academy of Sleep Medicine (2005) The International Classification of Sleep Disorders : Diagnostic & Coding Manual, 2nd edn. Westchester IL: American Academy of Sleep Medicine. Available at https://www.worldcat.org/title/international-classification-of-sleep-disorders-diagnostic-coding-manual/oclc/67281425, 2 June 2019,Google Scholar
American Academy of Sleep Medicine (2014) International Classification of Sleep Disorders, 3rd edn. Darien, IL: American Academy of Sleep Medicine.Google Scholar
Bergamaschini, L, Miedico, A, Cicardi, M, Coppola, R, Faioni, EN and Agostoni, A (1999) Consumption of C4b-binding protein (C4BP) during in vivo activation of the classical complement pathway. Clinical and Experimental Immunology 116(2), 220–224. doi: 10.1046/j.1365-2249.1999.00874.x.CrossRefGoogle ScholarPubMed
Besedovsky, L, Lange, T and Haack, M (2019) The sleep-immune crosstalk in health and disease. Physiological Reviews 99(3), 1325–1380. doi: 10.1152/physrev.00010.2018.CrossRefGoogle ScholarPubMed
Blom, AM, Kask, L and Dahlbäck, B (2003) CCP1-4 of the C4b-binding protein α-chain are required for factor I mediated cleavage of complement factor C3b. Molecular Immunology 39(10), 547–556. doi: 10.1016/S0161-5890(02)00213-4.CrossRefGoogle ScholarPubMed
Chen, G, Tan, CS, Teh, BK and Lu, J (2011) Molecular mechanisms for synchronized transcription of three complement C1q subunit genes in dendritic cells and macrophages. Journal of Biological Chemistry 286(40), 34941–34950. doi: 10.1074/jbc.M111.286427.CrossRefGoogle ScholarPubMed
Coulthard, LG and Woodruff, TM (2015) Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. The Journal of Immunology 194(8), 3542–3548. doi: 10.4049/jimmunol.1403068.CrossRefGoogle ScholarPubMed
Dalakas, MC, Alexopoulos, H and Spaeth, PJ (2020) Complement in neurological disorders and emerging complement-targeted therapeutics. Nature Reviews Neurology 16(11), 601–617. doi: 10.1038/s41582-020-0400-0.CrossRefGoogle ScholarPubMed
Davies, ET, Nasaruddin, BA, Alhaq, A, Senaldi, G and Vergani, D (1988) Clinical application of new technique that measures Cd4 for assessment of activation of classical complement pathway. Journal of Clinical Pathology 41(2), 143–147. doi: 10.1136/jcp.41.2.143.CrossRefGoogle Scholar
Degn, M, Dauvilliers, Y, Dreisig, K, Lopez, R, Pfister, C, Pradervand, S, Kornum, BR and Tafti, M (2017) Rare missense mutations in P2RY11 in narcolepsy with cataplexy. Brain 140(6), 1657–1668. doi: 10.1093/brain/awx093.CrossRefGoogle ScholarPubMed
Deloumeau, A, Bayard, S, Coquerel, Q, Déchelotte, P, Bole-Feysot, C, Carlander, B, De Cock, VC, Fetissov, SO and Dauvilliers, Y (2010) Increased immune complexes of hypocretin autoantibodies in narcolepsy. PLoS ONE 5(10), e13320. doi: 10.1371/journal.pone.0013320.CrossRefGoogle ScholarPubMed
Druart, M and Le Magueresse, C (2019) Emerging roles of complement in psychiatric disorders. Frontiers in Psychiatry 10, 573. doi: 10.3389/FPSYT.2019.00573.CrossRefGoogle ScholarPubMed
Ekdahl, KN, Persson, B, Mohlin, C, Sandholm, K, Skattum, L and Nilsson, B (2018) Interpretation of serological complement biomarkers in disease. Frontiers in Immunology 9, 2237. doi: 10.3389/fimmu.2018.02237.CrossRefGoogle Scholar
Ermert, D and Blom, AM (2016) C4b-binding protein: the good, the bad and the deadly. Novel functions of an old friend. Immunology Letters 169(Pt 2), 82–92. doi: 10.1016/j.imlet.2015.11.014.CrossRefGoogle ScholarPubMed
Gordon, D (2006) Structural biology of the complement system. Immunology & Cell Biology 84(5), 486. doi: 10.1111/j.1440-1711.2006.01470.x.CrossRefGoogle Scholar
Hui, L, Hua, F, Diandong, H and Hong, Y (2007) Effects of sleep and sleep deprivation on immunoglobulins and complement in humans. Brain, Behavior, and Immunity 21(3), 308–310. doi: 10.1016/J.BBI.2006.09.005.CrossRefGoogle ScholarPubMed
Jennum, PJ, Sci, M, Pedersen, LØ, Maria, J, Bahl, C, Modvig, S, Fog, K, Holm, A, Kornum, BR, Gammeltoft, S (2017) Cerebrospinal fluid biomarkers of neurodegeneration are decreased or normal in narcolepsy. Sleep 40(1), zsw006. doi: 10.1093/sleep/zsw006.Google ScholarPubMed
Jurado-Gamez, B, Gomez-Chaparro, JL, Muñoz-Calero, M, Serna Sanz, A, Muñoz-Cabrera, L, Lopez-Barea, J and Gozal, D (2012) Serum proteomic changes in adults with obstructive sleep apnoea. Journal of Sleep Research 21(2), 139–146. doi: 10.1111/j.1365-2869.2011.00955.x.CrossRefGoogle ScholarPubMed
Kallenberg, CGM (2008) Anti-C1q autoantibodies. Autoimmunity Reviews 7(8), 612–615. doi: 10.1016/j.autrev.2008.06.006.CrossRefGoogle ScholarPubMed
Kornum, BR (2020) Narcolepsy type 1: what have we learned from immunology? Sleep 43(10), zsaa055. doi: 10.1093/sleep/zsaa055.CrossRefGoogle ScholarPubMed
Kornum, BR, Knudsen, S, Ollila, HM, Pizza, F, Jennum, PJ, Dauvilliers, Y and Overeem, S (2017) Narcolepsy. Nature Reviews Disease Primers 3, 16100. doi: 10.1038/nrdp.2016.100.CrossRefGoogle ScholarPubMed
Kusada-Funakoshi, M, Sasaki, J, Takada, Y, Soji, T and Arakawa, K (1991) Evidence that C4b-binding protein (proline-rich protein) is synthesized by hepatocytes. Biochemical Medicine and Metabolic Biology 45(3), 350–354. doi: 10.1016/0885-4505(91)90040-R.CrossRefGoogle ScholarPubMed
Latorre, D, Kallweit, U, Armentani, E, Foglierini, M, Mele, F, Cassotta, A, Jovic, S, Jarrossay, D, Mathis, J, Zellini, F, Becher, B, Lanzavecchia, A, Khatami, R, Manconi, M, Tafti, M, Bassetti, CL, Sallusto, F (2018) T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 562(7725), 63–68. doi: 10.1038/s41586-018-0540-1.CrossRefGoogle ScholarPubMed
Lechner, J, Chen, M, Hogg, RE, Toth, L, Silvestri, G, Chakravarthy, U and Xu, H (2016) Higher plasma levels of complement C3a, C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration. Immunity & Ageing 13(1), 1–9. doi: 10.1186/S12979-016-0060-5.CrossRefGoogle ScholarPubMed
Luo, G, Ambati, A, Lin, L, Bonvalet, M, Partinen, M, Ji, X, Maecker, HT and Mignot, EJM (2018) Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proceedings of the National Academy of Sciences of the United States of America 115(52), E12323–E12332. doi: 10.1073/pnas.1818150116.Google ScholarPubMed
Mahoney, CE, Cogswell, A, Koralnik, IJ and Scammell, TE (2019) The neurobiological basis of narcolepsy. Nature Reviews Neuroscience 20(2), 83–93. doi: 10.1038/s41583-018-0097-x.CrossRefGoogle ScholarPubMed
Manni, R, Capittini, C, Pasi, A, De Silvestri, A, Terzaghi, M, Martinetti, M, Tinelli, C, Rebuffi, C and Scotti, V (2018) Correlation between HLA-DQB1*06: 02 and narcolepsy with and without cataplexy: approving a safe and sensitive genetic test in four major ethnic groups. A systematic meta-analysis. Sleep Medicine 52(4), 150–157. doi: 10.1016/j.sleep.2018.08.024.Google Scholar
Matsuki, K, Honda, Y, Satake, M and Juji, T (1988) HLA in Narcolepsy in Japan. Berlin, Heidelberg: Springer, 58–75, 10.1007/978-3-642-83387-8_4 CrossRefGoogle Scholar
Mihlan, M, Blom, AM, Kupreishvili, K, Lauer, N, Stelzner, K, Bergström, F, Niessen, HWM and Zipfel, PF (2011) Monomeric C-reactive protein modulates classic complement activation on necrotic cells. The FASEB Journal 25(12), 4198–4210. doi: 10.1096/fj.11-186460.CrossRefGoogle ScholarPubMed
Miyagawa, T and Tokunaga, K (2019) Genetics of narcolepsy. Human Genome Variation 6(1), 273. doi: 10.1038/s41439-018-0033-7.CrossRefGoogle ScholarPubMed
Mohammadi, S, Mayeli, M, Saghazadeh, A and Rezaei, N (2020) Cytokines in narcolepsy: a systematic review and meta-analysis. Cytokine 131(1), 155103. doi: 10.1016/j.cyto.2020.155103.CrossRefGoogle ScholarPubMed
Nadjar, A, Wigren, HKM and Tremblay, ME (2017) Roles of microglial phagocytosis and inflammatory mediators in the pathophysiology of sleep disorders. Frontiers in Cellular Neuroscience 11, 250. doi: 10.3389/fncel.2017.00250.CrossRefGoogle ScholarPubMed
Nagura, H, Hasegawa, H, Yoshimura, S and Watanabe, K (1985) The third (C3) and fourth (C4) components of complement in human liver: immunocytochemical evidence for hepatocytes as the site of synthesis. Pathology International 35(1), 71–78. doi: 10.1111/j.1440-1827.1985.tb02206.x.CrossRefGoogle ScholarPubMed
Nixon, JP, Mavanji, V, Butterick, TA, Billington, CJ, Kotz, CM and Teske, JA (2015) Sleep disorders, obesity, and aging: the role of orexin. Ageing Research Reviews 20(Suppl. 1), 63–73. doi: 10.1016/j.arr.2014.11.001.CrossRefGoogle ScholarPubMed
Nordenfelt, P, Waldemarson, S, Linder, A, Mörgelin, M, Karlsson, C, Malmström, J and Björck, L (2012) Antibody orientation at bacterial surfaces is related to invasive infection. The Journal of Experimental Medicine 209(13), 2367–2381. doi: 10.1084/jem.20120325.CrossRefGoogle ScholarPubMed
Orbai, AM, Truedsson, L, Sturfelt, G, Nived, O, Fang, H, Alarcón, GS, Gordon, C, Merrill, JT, Fortin, PR, Bruce, IN, Isenberg, DA, Wallace, DJ, Ramsey-Goldman, R, Bae, SC, Hanly, JG, Sanchez-Guerrero, J, Clarke, AE, Aranow, CB, Manzi, S, Urowitz, MB, Gladman, DD, Kalunian, KC, Costner, MI, Werth, VP, Zoma, A, Bernatsky, S, Ruiz-Irastorza, G, Khamashta, MA, Jacobsen, S, Buyon, JP, Maddison, P, Dooley, MA, Van Vollenhoven, RF, Ginzler, E, Stoll, T, Peschken, C, Jorizzo, JL, Callen, JP, Lim, SS, Fessler, BJ, Inanc, M, Kamen, DL, Rahman, A, Steinsson, K, Franks, AG Jr, Sigler, L, Hameed, S, Pham, N, Brey, R, Weisman, MH, McGwin, G Jr, Magder, LS and Petri, M (2015) Anti-C1q antibodies in systemic lupus erythematosus. Lupus 24(1), 42–49. doi: 10.1177/0961203314547791.CrossRefGoogle ScholarPubMed
Pak, VM, Butts, B, Hertzberg, V, Collop, N, Quyyumi, AA, Cox, J, Rogers, A and Dunbar, SB (2020) Daytime sleepiness predicts inflammation and ambulatory blood pressure in sleep apnoea. ERJ Open Research 6(4), 00310–02019. doi: 10.1183/23120541.00310-2019.CrossRefGoogle ScholarPubMed
Pedersen, NW, Holm, A, Kristensen, NP, Bjerregaard, AM, Bentzen, AK, Marquard, AM, Tamhane, T, Burgdorf, KS, Ullum, H, Jennum, P, Knudsen, S, Hadrup, SR, Kornum, BR (2019) CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nature Communications 10(1), 499. doi: 10.1038/s41467-019-08774-1.CrossRefGoogle ScholarPubMed
Postiglione, E, Antelmi, E, Pizza, F, Vandi, S, la Morgia, C, Carelli, V, Nassetti, S, Seri, M and Plazzi, G (2020) Cataplexy and ataxia: red flags for the diagnosis of DNA methyltransferase 1 mutation. Journal of Clinical Sleep Medicine 16(1), 143–147. doi: 10.5664/JCSM.8140.CrossRefGoogle Scholar
Ramos-Sevillano, E, Urzainqui, A, Campuzano, S, Moscoso, M, González-Camacho, F, Domenech, M, de Córdoba, SR, Sánchez-Madrid, F, Brown, JS, García, E, Yuste, J (2015) Pleiotropic effects of cell wall amidase LytA on streptococcus pneumoniae sensitivity to the host immune response. Infection and Immunity 83(2), 591–603. doi: 10.1128/IAI.02811-14.CrossRefGoogle Scholar
Segawa, Y, Hisano, S, Matsushita, M, Fujita, T, Hirose, S, Takeshita, M and Iwasaki, H (2010) IgG subclasses and complement pathway in segmental and global membranous nephropathy. Pediatric Nephrology 25(6), 1091–1099. doi: 10.1007/s00467-009-1439-8.CrossRefGoogle ScholarPubMed
Shang, X, Ren, L, Sun, G, Yu, T, Yao, Y, Wang, L, Liu, F, Zhang, L, He, X, Liu, M (2021) Anti-dsDNA, anti-nucleosome, anti-C1q, and anti-histone antibodies as markers of active lupus nephritis and systemic lupus erythematosus disease activity. Immunity, Inflammation and Disease 9(2), 407–418. doi: 10.1002/iid3.401.CrossRefGoogle ScholarPubMed
Shiina, T, Hosomichi, K, Inoko, H and Kulski, JK (2009) The HLA genomic loci map: expression, interaction, diversity and disease. Journal of Human Genetics 54(1), 15–39. doi: 10.1038/jhg.2008.5.CrossRefGoogle ScholarPubMed
Shivshankar, P, Fekry, B, Eckel-Mahan, K and Wetsel, RA (2020) Circadian clock and complement immune system—Complementary control of physiology and pathology? Frontiers in Cellular and Infection Microbiology 10, 418. doi: 10.3389/FCIMB.2020.00418.CrossRefGoogle ScholarPubMed
Siegel, JM (1999) Narcolepsy: a key role for hypocretins (Orexins). Cell 98(4), 409–412, Available at: http://www.sciencedirect.com/science/article/pii/S0092867400819698 CrossRefGoogle Scholar
Singh, AK, Mahlios, J and Mignot, E (2013) Genetic association, seasonal infections and autoimmune basis of narcolepsy. Journal of Autoimmunity 43, 26–31. doi: 10.1016/j.jaut.2013.02.003.CrossRefGoogle ScholarPubMed
Sjöberg, AP, Trouw, LA and Blom, AM (2009) Complement activation and inhibition: a delicate balance. Trends in Immunology 30(2), 83–90. doi: 10.1016/J.IT.2008.11.003.CrossRefGoogle ScholarPubMed
Sjöberg, AP, Trouw, LA, McGrath, FDG, Hack, CE and Blom, AM (2006) Regulation of complement activation by C-reactive protein: targeting of the inhibitory activity of C4b-binding protein. The Journal of Immunology 176(12), 7612–7620. doi: 10.4049/jimmunol.176.12.7612.CrossRefGoogle ScholarPubMed
Stephan, AH, Barres, BA and Stevens, B (2012) The complement system: an unexpected role in synaptic pruning during development and disease. Annual Review of Neuroscience 35(1), 369–389. doi: 10.1146/annurev-neuro-061010-113810.CrossRefGoogle ScholarPubMed
Tanaka, S, Honda, Y, Honda, M, Yamada, H, Honda, K and Kodama, T (2017) Anti-tribbles pseudokinase 2 (TRIB2)-immunization modulates hypocretin/orexin neuronal functions. Sleep 40(1). doi:10.1093/sleep/zsw036.Google ScholarPubMed
Türkoğlu, R, Özyurt, S, Ulusoy, C, Erdağ, E and Tüzün, E (2016) Expression of switch-associated protein 70 is associated with lymphocyte activation and reduced disability in multiple sclerosis. Immunology Letters 177, 75–77. doi: 10.1016/j.imlet.2016.08.001.CrossRefGoogle ScholarPubMed
Tüzün, E, Saini, SS, Ghosh, S, Rowin, J, Meriggioli, MN and Christadoss, P (2006) Predictive value of serum anti-C1q antibody levels in experimental autoimmune myasthenia gravis. Neuromuscular Disorders 16(2), 137–143. doi: 10.1016/j.nmd.2005.11.005.CrossRefGoogle ScholarPubMed
Viste, R, Lie, BA, Viken, MK, Rootwelt, T, Knudsen-Heier, S and Kornum, BR (2021) Narcolepsy type 1 patients have lower levels of effector memory CD4+ T cells compared to their siblings when controlling for H1N1-(PandemrixTM)-vaccination and HLA DQB1*06: 02 status. Sleep Medicine 85, 271–279. doi: 10.1016/j.sleep.2021.07.024.CrossRefGoogle Scholar
Wang, G, Ren, X, Zhang, X, Wang, Q, Liu, T, Deng, N and Yan, D (2021) Proteomic profiling reveals the molecular changes of insomnia patients. BioMed Research International 2021, 6685929. doi:10.1155/2021/6685929.Google ScholarPubMed
Wang, S, Lu, H, Ni, J, Zhang, J, Tang, W, Lu, W, Cai, J and Zhang, C (2015) An evaluation of association between common variants in C4BPB/C4BPA genes and schizophrenia. Neuroscience Letters 590, 189–192. doi: 10.1016/j.neulet.2015.02.005.CrossRefGoogle ScholarPubMed