Advances of complement in the pathogenesis and targeted therapy of epilepsy_Journal of Epilepsy

Authors：

 HU Chunhui , LIN Binrong , ZHOU Youfeng

Department of Neurology, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), National Regional Medical Center, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350014, China;

Corresponding author：

HU Chunhui, Email: huchunhui1989@126.com

Keywords：

Epilepsy; Complement; Pathogenesis; Treatment

DOI：

10.7507/2096-0247.202308011

Video：

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There are more than 65 million patients with epilepsy in the world. The morbidity and mortality of epilepsy are high, and the social and psychological burden brought by this disease is serious. The etiology of epilepsy is complex and the seizure types are various. There are great heterogeneity in the clinical manifestations and etiology. At present, the etiology of epilepsy can be classified as six categories: structural, genetic, infectious, metabolic, immune, and neurodegenerative. More and more attention has been paid to the immune etiology of epilepsy. Complement, as an important part of the immune system, can participate in the development of epilepsy by promoting inflammatory response, affecting synaptic deletion and pruning imbalance, forming membrane attack complex and so on, which plays an important role in the pathogenesis of epilepsy. Intravenous immunoglobulin, human C1 esterase inhibitor (C1-Inh) and monoclonal antibody Eculizumab/Ravulizumab have been used for complement targeted therapy in epilepsy. However, the relationship between epilepsy and immunity is complex, and the role of complement in the epileptogenesis, development and treatment of epilepsy still needs to be further studied.

Citation： HU Chunhui, LIN Binrong, ZHOU Youfeng. Advances of complement in the pathogenesis and targeted therapy of epilepsy. Journal of Epilepsy, 2023, 9(6): 492-497. doi: 10.7507/2096-0247.202308011 Copy

1.	Balestrini S, Arzimanoglou A, Blümcke I, et al. The aetiologies of epilepsy. Epileptic Disord, 2021, 23 (1): 1-16.
2.	Flammer J, Neziraj T, Rüegg S, et al. Immune mechanisms in epileptogenesis: update on diagnosis and treatment of autoimmune epilepsy syndromes. Drugs, 2023, 83 (2): 135-158.
3.	Parker SE, Bellingham MC, Woodruff TM. Complement drives circuit modulation in the adult brain. Prog Neurobiol, 2022, 214: 102282.
4.	Dong X, Fan J, Lin D, et al. Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis. J Neuroinflammation, 2022, 19 (1): 226.
5.	Veremeyko T, Jiang R, He M, et al. Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes. Front Cell Neurosci, 2023, 17: 1170031.
6.	Rossini L, De Santis D, Cecchini E, et al. Dendritic spine loss in epileptogenic Type II focal cortical dysplasia: Role of enhanced classical complement pathway activation. Brain Pathol, 2023, 33 (3): e13141.
7.	Soyon Hong, Victoria F Beja-Glasser, Bianca M Nfonoyim, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 2016, 352 (6286): 712-716.
8.	Aronica E, Boer K, van Vliet EA, et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiology of Disease, 2007, 26 (3): 497-511.
9.	Coulthard LG, Hawksworth OA, Li R, et al. Complement C5aR1 signaling promotes polarization and proliferation of embryonic neural progenitor cells through PKC. The Journal of Neuroscience, 2017, 37 (22): 5395-5407.
10.	Nomaru H, Sakumi K, Katogi A, et al. Fosbgene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia. Glia, 2014, 62 (8): 1284-1298.
11.	Ding X, Wang J, Huang M, et al. Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration. Nat Commun, 2021, 12 (1): 2030.
12.	Stevens B, Allen NJ, Vazquez LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell, 2007, 131 (6): 1164-1178.
13.	Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature, 2016, 530 (7589): 177-183.
14.	Bialas AR, Stevens B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nature Neuroscience, 2013, 16 (12): 1773-1782.
15.	Chu Y, Jin X, Parada I, et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proceedings of the National Academy of Sciences, 2010, 107 (17): 7975-7980.
16.	Ma Y, Ramachandran A, Ford N, et al. Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy. Epilepsia, 2013, 54 (7): 1232-1239.
17.	Jamali S, Bartolomei F, Robaglia-Schlupp A, et al. Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex. Brain, 2006, 129 (3): 625-641.
18.	Bianca PB, Robert V, Esther CWB, et al. The pathology of multiple sclerosis is location-dependent no significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol, 2005, 64 (2): 147-55.
19.	Rus H, Cudrici C, Niculescu F. C5b-9 complement complex in autoimmune demyelination and multiple sclerosis: Dual role in neuroinflammation and neuroprotection. Annals of Medicine, 2009, 37 (2): 97-104.
20.	Tröscher AR, Mair KM, Verdú de Juan L, et al. Temporal lobe epilepsy with GAD antibodies: neurons killed by T cells not by complement membrane attack complex. Brain, 2023, 146 (4): 1436-1452.
21.	Leontariti M, Avgeris M, Katsarou MS, et al. Circulating miR-146a and miR-134 in predicting drug-resistant epilepsy in patients with focal impaired awareness seizures. Epilepsia, 2020, 61 (5): 959-970.
22.	Zhang HL, Lin YH, Qu Y, et al. The effect of miR-146a gene silencing on drug-resistance and expression of protein of P-gp and MRP1 in epilepsy. European Review for Medical and Pharmacological Sciences, 2018, 22: 2372-2379.
23.	Huang H, Cui G, Tang H, et al. Silencing of microRNA-146a alleviates the neural damage in temporal lobe epilepsy by down-regulating Notch-1. Molecular Brain, 2019, 12 (1): 102.
24.	Alexander JJ, Quigg RJ. The simple design of complement factor H: looks can be deceiving. Molecular Immunology, 2007, 44 (1-3): 123-132.
25.	De Córdoba SR, De Jorge EG. Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clinical & Experimental Immunology, 2007, 151 (1): 1-13.
26.	He F, Liu B, Meng Q, et al. Modulation of miR-146a/complement factor H-mediated inflammatory responses in a rat model of temporal lobe epilepsy. Bioscience Reports, 2016, 36 (6): e00433.
27.	Matsuda K, Budisantoso T, Mitakidis N, et al. Transsynaptic modulation of kainate receptor functions by C1q-like proteins. Neuron, 2016, 90 (4): 752-767.
28.	Palau F, Jamali S, Salzmann A, et al. Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures. PLoS ONE, 2010, 5 (9): e12740.
29.	Perez-Alcazar M, Daborg J, Stokowska A, et al. Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3. Experimental Neurology, 2014, 253: 154-164.
30.	Kopczynska M, Zelek WM, Vespa S, et al. Complement system biomarkers in epilepsy. Seizure, 2018, 60: 1-7.
31.	Segú-Vergés C, Caño S, Calderón-Gómez E, et al. Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system. Front Immunol, 2022, 13: 901872.
32.	Sinkovits G, Schnur J, Hurler L, Kiszel P, et al. Evidence, detailed characterization and clinical context of complement activation in acute multisystem inflammatory syndrome in children. Sci Rep, 2022, 12 (1): 19759.
33.	Mejia P, Lu F, Davis A. C1 inhibitor, a multi-functional serine protease inhibitor. Thrombosis and Haemostasis, 2017, 104 (11): 886-893.
34.	Chen M, Edwards SR, Reutens DC. Complement in the development of post-traumatic epilepsy: prospects for drug repurposing. Journal of Neurotrauma, 2020, 37 (5): 692-705.
35.	Alawieh A, Langley EF, Weber S, et al. Identifying the role of complement in triggering neuroinflammation after traumatic brain injury. The Journal of Neuroscience, 2018, 38 (10): 2519-2532.
36.	Fraser DA, Bohlson SS, Jasinskiene N, et al. C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. Journal of Leukocyte Biology, 2006, 80 (1): 107-116.
37.	Zelek WM, Xie L, Morgan BP, et al. Compendium of current complement therapeutics. Molecular Immunology, 2019, 114: 341-352.
38.	Brodsky RA, Peffault de Latour R, Rottinghaus ST, et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica, 2021, 106 (1): 230-237.
39.	Vanoli F, Mantegazza R. Ravulizumab for the treatment of myasthenia gravis. Expert Opin Biol Ther, 2023, 23 (3): 235-241.
40.	Fluiter K, Opperhuizen AL, Morgan BP, et al. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. The Journal of Immunology, 2014, 192 (5): 2339-2348.
41.	Lansita JA, Mease KM, Qiu H, et al. Nonclinical development of ANX005: a humanized anti-c1q antibody for treatment of autoimmune and neurodegenerative diseases. International Journal of Toxicology, 2017, 36 (6): 449-462.
42.	Jin Y, Zhao C, Chen L, et al. Identification of novel gene and pathway targets for human epilepsy treatment. Biological Research, 2016, 49 (1): 3.
43.	Lamers C, Mastellos DC, Ricklin D, et al. Compstatins: the dawn of clinical C3-targeted complement inhibition. Trends Pharmacol Sci, 2022, 43 (8): 629-640.
44.	Toutonji A, Krieg C, Borucki DM, et al. Mass cytometric analysis of the immune cell landscape after traumatic brain injury elucidates the role of complement and complement receptors in neurologic outcomes. Acta Neuropathol Commun, 2023, 11 (1): 92.
45.	Stokowska A, Aswendt M, Zucha D, et al. Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity. J Clin Invest, 2023, 133 (10): e162253.
46.	Brilland B, Garnier AS, Chevailler A, et al. Complement alternative pathway in ANCA-associated vasculitis: Two decades from bench to bedside. Autoimmunity Reviews, 2020, 19 (1): 102424.
47.	Osman M, Cohen Tervaert JW, Pagnoux C. Avacopan for the treatment of ANCA-associated vasculitis: an update. Expert Rev Clin Immunol, 2023, 19 (5): 461-471.
48.	Iacobaş DA, Chachua T, Iacobaş S, et al. ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms. Scientific Reports, 2018, 8 (1): 5722.

1. Balestrini S, Arzimanoglou A, Blümcke I, et al. The aetiologies of epilepsy. Epileptic Disord, 2021, 23 (1): 1-16.
2. Flammer J, Neziraj T, Rüegg S, et al. Immune mechanisms in epileptogenesis: update on diagnosis and treatment of autoimmune epilepsy syndromes. Drugs, 2023, 83 (2): 135-158.
3. Parker SE, Bellingham MC, Woodruff TM. Complement drives circuit modulation in the adult brain. Prog Neurobiol, 2022, 214: 102282.
4. Dong X, Fan J, Lin D, et al. Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis. J Neuroinflammation, 2022, 19 (1): 226.
5. Veremeyko T, Jiang R, He M, et al. Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes. Front Cell Neurosci, 2023, 17: 1170031.
6. Rossini L, De Santis D, Cecchini E, et al. Dendritic spine loss in epileptogenic Type II focal cortical dysplasia: Role of enhanced classical complement pathway activation. Brain Pathol, 2023, 33 (3): e13141.
7. Soyon Hong, Victoria F Beja-Glasser, Bianca M Nfonoyim, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 2016, 352 (6286): 712-716.
8. Aronica E, Boer K, van Vliet EA, et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiology of Disease, 2007, 26 (3): 497-511.
9. Coulthard LG, Hawksworth OA, Li R, et al. Complement C5aR1 signaling promotes polarization and proliferation of embryonic neural progenitor cells through PKC. The Journal of Neuroscience, 2017, 37 (22): 5395-5407.
10. Nomaru H, Sakumi K, Katogi A, et al. Fosbgene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia. Glia, 2014, 62 (8): 1284-1298.
11. Ding X, Wang J, Huang M, et al. Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration. Nat Commun, 2021, 12 (1): 2030.
12. Stevens B, Allen NJ, Vazquez LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell, 2007, 131 (6): 1164-1178.
13. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature, 2016, 530 (7589): 177-183.
14. Bialas AR, Stevens B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nature Neuroscience, 2013, 16 (12): 1773-1782.
15. Chu Y, Jin X, Parada I, et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proceedings of the National Academy of Sciences, 2010, 107 (17): 7975-7980.
16. Ma Y, Ramachandran A, Ford N, et al. Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy. Epilepsia, 2013, 54 (7): 1232-1239.
17. Jamali S, Bartolomei F, Robaglia-Schlupp A, et al. Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex. Brain, 2006, 129 (3): 625-641.
18. Bianca PB, Robert V, Esther CWB, et al. The pathology of multiple sclerosis is location-dependent no significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol, 2005, 64 (2): 147-55.
19. Rus H, Cudrici C, Niculescu F. C5b-9 complement complex in autoimmune demyelination and multiple sclerosis: Dual role in neuroinflammation and neuroprotection. Annals of Medicine, 2009, 37 (2): 97-104.
20. Tröscher AR, Mair KM, Verdú de Juan L, et al. Temporal lobe epilepsy with GAD antibodies: neurons killed by T cells not by complement membrane attack complex. Brain, 2023, 146 (4): 1436-1452.
21. Leontariti M, Avgeris M, Katsarou MS, et al. Circulating miR-146a and miR-134 in predicting drug-resistant epilepsy in patients with focal impaired awareness seizures. Epilepsia, 2020, 61 (5): 959-970.
22. Zhang HL, Lin YH, Qu Y, et al. The effect of miR-146a gene silencing on drug-resistance and expression of protein of P-gp and MRP1 in epilepsy. European Review for Medical and Pharmacological Sciences, 2018, 22: 2372-2379.
23. Huang H, Cui G, Tang H, et al. Silencing of microRNA-146a alleviates the neural damage in temporal lobe epilepsy by down-regulating Notch-1. Molecular Brain, 2019, 12 (1): 102.
24. Alexander JJ, Quigg RJ. The simple design of complement factor H: looks can be deceiving. Molecular Immunology, 2007, 44 (1-3): 123-132.
25. De Córdoba SR, De Jorge EG. Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clinical & Experimental Immunology, 2007, 151 (1): 1-13.
26. He F, Liu B, Meng Q, et al. Modulation of miR-146a/complement factor H-mediated inflammatory responses in a rat model of temporal lobe epilepsy. Bioscience Reports, 2016, 36 (6): e00433.
27. Matsuda K, Budisantoso T, Mitakidis N, et al. Transsynaptic modulation of kainate receptor functions by C1q-like proteins. Neuron, 2016, 90 (4): 752-767.
28. Palau F, Jamali S, Salzmann A, et al. Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures. PLoS ONE, 2010, 5 (9): e12740.
29. Perez-Alcazar M, Daborg J, Stokowska A, et al. Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3. Experimental Neurology, 2014, 253: 154-164.
30. Kopczynska M, Zelek WM, Vespa S, et al. Complement system biomarkers in epilepsy. Seizure, 2018, 60: 1-7.
31. Segú-Vergés C, Caño S, Calderón-Gómez E, et al. Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system. Front Immunol, 2022, 13: 901872.
32. Sinkovits G, Schnur J, Hurler L, Kiszel P, et al. Evidence, detailed characterization and clinical context of complement activation in acute multisystem inflammatory syndrome in children. Sci Rep, 2022, 12 (1): 19759.
33. Mejia P, Lu F, Davis A. C1 inhibitor, a multi-functional serine protease inhibitor. Thrombosis and Haemostasis, 2017, 104 (11): 886-893.
34. Chen M, Edwards SR, Reutens DC. Complement in the development of post-traumatic epilepsy: prospects for drug repurposing. Journal of Neurotrauma, 2020, 37 (5): 692-705.
35. Alawieh A, Langley EF, Weber S, et al. Identifying the role of complement in triggering neuroinflammation after traumatic brain injury. The Journal of Neuroscience, 2018, 38 (10): 2519-2532.
36. Fraser DA, Bohlson SS, Jasinskiene N, et al. C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. Journal of Leukocyte Biology, 2006, 80 (1): 107-116.
37. Zelek WM, Xie L, Morgan BP, et al. Compendium of current complement therapeutics. Molecular Immunology, 2019, 114: 341-352.
38. Brodsky RA, Peffault de Latour R, Rottinghaus ST, et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica, 2021, 106 (1): 230-237.
39. Vanoli F, Mantegazza R. Ravulizumab for the treatment of myasthenia gravis. Expert Opin Biol Ther, 2023, 23 (3): 235-241.
40. Fluiter K, Opperhuizen AL, Morgan BP, et al. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. The Journal of Immunology, 2014, 192 (5): 2339-2348.
41. Lansita JA, Mease KM, Qiu H, et al. Nonclinical development of ANX005: a humanized anti-c1q antibody for treatment of autoimmune and neurodegenerative diseases. International Journal of Toxicology, 2017, 36 (6): 449-462.
42. Jin Y, Zhao C, Chen L, et al. Identification of novel gene and pathway targets for human epilepsy treatment. Biological Research, 2016, 49 (1): 3.
43. Lamers C, Mastellos DC, Ricklin D, et al. Compstatins: the dawn of clinical C3-targeted complement inhibition. Trends Pharmacol Sci, 2022, 43 (8): 629-640.
44. Toutonji A, Krieg C, Borucki DM, et al. Mass cytometric analysis of the immune cell landscape after traumatic brain injury elucidates the role of complement and complement receptors in neurologic outcomes. Acta Neuropathol Commun, 2023, 11 (1): 92.
45. Stokowska A, Aswendt M, Zucha D, et al. Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity. J Clin Invest, 2023, 133 (10): e162253.
46. Brilland B, Garnier AS, Chevailler A, et al. Complement alternative pathway in ANCA-associated vasculitis: Two decades from bench to bedside. Autoimmunity Reviews, 2020, 19 (1): 102424.
47. Osman M, Cohen Tervaert JW, Pagnoux C. Avacopan for the treatment of ANCA-associated vasculitis: an update. Expert Rev Clin Immunol, 2023, 19 (5): 461-471.
48. Iacobaş DA, Chachua T, Iacobaş S, et al. ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms. Scientific Reports, 2018, 8 (1): 5722.

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