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Strategies for Inhibition of Complement Activation in the Treatment of Neurodegenerative Diseases

  • Chapter
Neuroinflammation

Part of the book series: Contemporary Neuroscience ((CNEURO))

Abstract

Complement is part of the humoral branch of the immune system involved in inflammation, opsonization, and cytolysis. Often, complement is the immune system’s first line of defense, with high levels of peripherally circulating complement proteins at the ready to encounter an invading pathogen. Thus, the complement system can provide the impetus for an immediate inflammatory response. The activation of complement can occur through interactions with antibodies or with other activating agents (e.g., bacteria and cell surfaces), leading to an inflammatory reaction. Its rather ubiquitous action in a variety of chronic inflammatory diseases in the periphery suggests that complement is one of the compelling forces behind the pathology. This also appears true for many diseases of the central nervous system (CNS). The activation of complement is detected in association with a variety of human neurodegenerative diseases, both acute and chronic. The temporal relation to disease onset and progression has prompted the hypothesis that complement activation is seminal to a variety of neuropathologies.

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References

  1. Biesecker, G. and Gomez, C. M. (1989) Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6. J. Immunol. 142, 2654–2659.

    PubMed  CAS  Google Scholar 

  2. Christados, P. (1988) C5 influences the development of murine myasthenia gravis. J. Immunol. 140, 2589–2592.

    Google Scholar 

  3. Piddlesden, S., Lassmann, H., Laffafian, I., Morgan, B. P., and Linington, C. (1991) Antibody-mediated demyelination in experimental allergic encephalomyelitis is independent of complement membrane attack complex formation. Clin. Exp. Immunol. 83, 245–250.

    Article  PubMed  CAS  Google Scholar 

  4. Piddlesden, S. J., Storch, M. K., Hibbs, M., Freeman, A. M., Lassmann, H., and Morgan, B. P. (1994) Soluble recombinant complement receptor 1 inhibits inflammation and demyelination in antibody-mediated demyelinating experimental allergic encephalomyelitis. J. Immunol. 152, 5477–5484.

    PubMed  CAS  Google Scholar 

  5. Rakonczay, Z. and Brimijoin, S. (1988) Monoclonal antibodies to human brain acetylcholinesterase: properties and applications. Cell Mol. Neurobiol. 8, 85–93.

    Article  PubMed  CAS  Google Scholar 

  6. Dagerlind, A., Pelto Huikko, M., Lundberg, J. M., Ubink, R., Verhofstad, A., Brimijoin, S., and Hokfelt, T. (1994) Immunologically induced sympathectomy of preganglionic nerves by antibodies against acetylcholinesterase: increased levels of peptides and their messenger RNAs in rat adrenal chromaffin cells. Neuroscience 62, 217–239.

    Article  PubMed  CAS  Google Scholar 

  7. Dagerlind, A., Zhang, X., Brimijoin, S., Lindh, B., and Hokfelt, T. (1994) Effects of preganglionic sympathectomy on peptides in the rat superior cervical ganglion. Neuroreport 5, 909–912.

    Article  PubMed  CAS  Google Scholar 

  8. Brimijoin, S., Hammond, P., Khraibi, A. A., and Tyce, G. M. (1994) Catecholamine release and excretion in rats with immunologically induced preganglionic sympathectomy. J. Neurochem. 62, 2195–2204.

    Article  PubMed  CAS  Google Scholar 

  9. Dagerlind, A., Brimijoin, S., Goldstein, M., and Hokfelt, T. (1993) Effects of antibodies against acetylcholinesterase on the expression of peptides and catecholamine synthesizing enzymes in the rat adrenal gland. Neuroscience 54, 1079–1090.

    Article  PubMed  CAS  Google Scholar 

  10. Brimijoin, S., Moser, V., Hammond, P., Oka, N., and Lennon, V. A. (1993) Death of intermediolateral spinal cord neurons follows selective, complement-mediated destruction of peripheral preganglionic sympathetic terminals by acetylcholinesterase antibodies. Neuroscience 54, 201–223.

    Article  PubMed  CAS  Google Scholar 

  11. Bean, A. J., Xu, Z., Chai, S. Y., Brimijoin, S., and Hokfelt, T. (1991) Effect of intracerebral injection of monoclonal acetylcholinesterase antibodies on cholinergic nerve terminals in the rat central nervous system. Neurosci. Lett. 133, 145–149.

    Article  PubMed  CAS  Google Scholar 

  12. Brimijoin, S., Balm, M., Hammond, P., and Lennon, V. A. (1990) Selective cornplexing of acetylcholinesterase in brain by intravenously administered monoclonal antibody. J. Neurochem. 54, 236–241.

    Article  PubMed  CAS  Google Scholar 

  13. Rozovsky, I., Morgan, T. E., Willoughby, D. A., Dugichi Djordjevich, M. M., Pasinetti, G. M., Johnson, S. A., and Finch, C. E. (1994) Selective expression of clusterin (SGP-2) and complement C1gB and C4 during responses to neurotoxins in vivo and in vitro. Neuroscience 62, 741–758.

    Article  PubMed  CAS  Google Scholar 

  14. Johnson, S. A., Lampert-Etchells, M., Pasinetti, G. M., Rozovsky, I., and Finch, C. E. (1992) Complement mRNA in the mammalian brain: Responses to Alzheimer’s disease and experimental brain lesioning. Neurobiol. Aging 13, 641–648.

    Article  PubMed  CAS  Google Scholar 

  15. Walker, D. G. and McGeer, P. L. (1992) Complement gene expression in human brain: comparison between normal and Alzheimer disease cases. Mol. Brain Res. 14, 109–116.

    Article  PubMed  CAS  Google Scholar 

  16. Pasinetti, G. M., Johnson, S. A., Rozovsky, I., Lampert-Etchells, M., Morgan, D. G., Gordon, M. N., Morgan, T. E., Willoughby, D., and Finch, C. E. (1992) Complement Clq and C4 mRNAs responses to lesioning in the rat brain. Exp. Neurol. 118, 117–125.

    Article  PubMed  CAS  Google Scholar 

  17. Muller-Eberhard, H.J. (1988) Molecular organization and function of the complement system. Ann. Rev. Biochem. 57, 321–347.

    Article  PubMed  CAS  Google Scholar 

  18. Volanakis, J. E. and Fearon, D. T. (1992) The molecular biology of the complement system, in Arthritis and Allied Conditions-A Textbook of Rheumatology ( McCarty, D. J. and Koopman, W. J., eds.), Lea and Febiger, Philadelphia, pp. 445–467.

    Google Scholar 

  19. Reid, K. M. B. and Porter, R. R. (1981) The proteolytic activation systems of complement. Ann. Rev. Biochem. 50, 433–464.

    Article  PubMed  CAS  Google Scholar 

  20. Cooper, N. R. (1985) The classical complement pathway: activation and regulation of the first component of complement. Adv. Immunol. 37, 151–216.

    Article  PubMed  CAS  Google Scholar 

  21. Reid, K. M. B. (1986) Activation and control of the complement system. Essays Biochem. 22, 27–68.

    PubMed  CAS  Google Scholar 

  22. Vanguri, P., Koski, C. L., Silverman, B., and Shin, M. L. (1982) Complement activation by isolated myelin: activation of the classical pathway in the absence of myelin-specific antibodies. Proc. Natl. Acad. Sci. USA 79, 3290–3294.

    Article  PubMed  CAS  Google Scholar 

  23. Vanguri, P. and Shin, M. L. (1986) Activation of complement by myelin: identification of Cl-binding proteins of human myelin from central nervous tissue. J. Neurochem. 46, 1535–1541.

    Article  PubMed  CAS  Google Scholar 

  24. Cyong, C.-J., Witkin, S. S., Rieger, B., Barbarese, E., Good, R. A., and Day, N. K. (1982) Antibody-independent complement activation by myelin via the classical complement pathway. J. Exp. Med. 155, 587–598.

    Article  PubMed  CAS  Google Scholar 

  25. Silverman, B. A., Carney, D. F., Johnston, C. A., Vanguri, P., and Shin, M. L. (1984) Isolation of membrane attack complex of complement from myelin membranes treated with serum complement. J. Neurochem. 42, 1024–1029.

    Article  PubMed  CAS  Google Scholar 

  26. Vanguri, P. and Shin, M. L. (1988) Hydrolysis of myelin basic protein in human myelin by terminal complement complexes. J. Biol. Chem. 263, 7228–7234.

    PubMed  CAS  Google Scholar 

  27. Eikelenboom, P., Hack, C. E., Rozemuller, J. M., and Stam, F. C. (1989) Complement activation in amyloid plaques in Alzheimer’s dementia. Virchows Arch. B Cell Pathol. 56, 259–262.

    CAS  Google Scholar 

  28. McGeer, P. L., Akiyama, H., Itagaki, S., and McGeer, E. G. (1989) Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci. Lett. 107, 341–346.

    Article  PubMed  CAS  Google Scholar 

  29. Rogers, J., Cooper, N. R., Webster, S., Schultz, J., McGeer, P. L., Styren, S. D., Civin, W. H., Brachova, L., Bradt, B., Ward, P., and Lieberburg, I. (1992) Complement activation by (3-amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 89, 10,016–10, 020.

    Google Scholar 

  30. Jiang, H., Burdick, D., Glabe, C. G., Cotman, C. W., and Tenner, A. J. (1994) ß-amyloid activates complement by binding to a specific region of the collagen-like domain of the Clq A chain. J. Immunol. 152, 5050–5059.

    PubMed  CAS  Google Scholar 

  31. Snyder, S. W., Wang, G. T., Barrett, L., Ladror, U. S., Causto, D., Lee, C. M., Krafft, G. A., Holzman, R. B., and Holzman, T. F. (1994) Complement Clq does not bind monomeric 0-amyloid. Exp. Neurol. 128, 136–142.

    Article  PubMed  CAS  Google Scholar 

  32. Mailler-Eberhard, H. J. and Schreiber, R.D. (1980) Molecular biology and chemistry chemistry of the alternative pathway of complement. Adv. Immunol. 29, 1–53.

    Article  Google Scholar 

  33. Pangburn, M. K. and Müller-Eberhard, H. J. (1984) The alternative pathway of corn-ment. Springer Semin. Immunopathol. 7, 163–192.

    Article  PubMed  CAS  Google Scholar 

  34. Silberberg, D. H., Manning, M. C., and Schreiber, A. D. (1984) Tissue culture demyelination by normal human serum. Ann. Neurol. 15, 575–580.

    Article  PubMed  CAS  Google Scholar 

  35. Koski, C. L., Vanguri, P., and Shin, M. L. (1985) Activation of the alternative pathway of complement by human peripheral nerve myelin. J. Immunol. 134, 1810–1818.

    PubMed  CAS  Google Scholar 

  36. Watson, M. D., Roher, A. E., Kim, K. S., Spiegel, K., and Emmerling, M. R. (1997) Complement Labelling of Aggregated Aß1–42 by Normal Human Serum Involves the Classical and Alternative Pathways. In Alzheimer’s Disease: Biology, Diagnosis and Therapeutics (Iqbal, K., Winblad, B., Nishimura, T., Takeda, M. and Wisniewski, H., eds.), John Wiley, Sussex, England.

    Google Scholar 

  37. Drickamer, K. (1988) Two distinct classes of carbohydrate-recognition domains in animal lectins. J. Biol. Chem. 263, 9557–9560.

    PubMed  CAS  Google Scholar 

  38. Malhotra, R., Lu, J., Holmskov, U., and Sim, R. B. (1994) Collectins, collectin receptors and the lectin pathway of complement activation. Clin. Exp. Immunol. 97, 4–9.

    Article  PubMed  CAS  Google Scholar 

  39. Holmskov, U. and Jensenius, J. C. (1993) Structure and function of collectins: humoral C-type lectins with collagenous regions. Behring Inst. Mitteilungen 93, 224–235.

    CAS  Google Scholar 

  40. Matsushita, M. and Fujita, T. J. (1992) Activation of the classical pathway by mannose-binding protein in association with a novel Cls-like serine protease. J. Exp. Med. 176, 1497–1502.

    Article  PubMed  CAS  Google Scholar 

  41. Colten, H. R. (1995) Biosynthesis of complement. Adv. Immunol. 22, 67–118.

    Article  Google Scholar 

  42. Barnum, S. R. (1995) Complement biosynthesis in the central nervous system. Crit. Rev. Oral Biol. Med. 6, 132–146.

    Article  PubMed  CAS  Google Scholar 

  43. Levi-Strauss, M. and Mallat, M. (1987) Primary cultures of murine astrocytes produce C3 and factor B, two components of the alternative pathway of complement activation. J. Immunol. 139, 2361–2366.

    PubMed  CAS  Google Scholar 

  44. May, P. C., Lampert-Etchells, M., Johnson, S. A., Poorer, J., Masters, J. N., and Finch, C. E. (1990) Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer’s disease and in response to experimental lesions in rat. Neuron 5, 831–839.

    Article  PubMed  CAS  Google Scholar 

  45. Nose, M., Katoh, W., and Okada, N. (1990) Tissue distribution of HRF20, a novel factor preventing the membrane attack of homologous complement, and its predominant expression on endothelial cells in vivo. Immunology 70, 145–149.

    PubMed  CAS  Google Scholar 

  46. McGeer, P. L., Walker, D. G., Akiyama, H., Kawamata, T., Guan, A. L., Parker, C. J., Okada, N., and McGeer, E. G. (1991) Detection of the membrane inhibitor of reactive lysis (CD59) in diseased neurons of Alzheimer brain. Brain Res. 544, 315–319.

    Article  PubMed  CAS  Google Scholar 

  47. Vedeler, C., Ulvestad, E., Bjorge, L., Conti, G., Williams, K., Mork, S., and Matre, R. (1994) The expression of CD59 in normal human nervous tissue. Immunol. 82, 2, 542–547.

    CAS  Google Scholar 

  48. Pasinetti, G. M., Johnson, S. A., Oda, T., Rozovsky, I., and Finch, C. E. (1994) Clusterin (SGP-2): a multifunctional glycoprotein with regional expression in astrocytes and neurons of the adult rat brain. J. Comp. Neurol. 339, 387–400.

    Article  PubMed  CAS  Google Scholar 

  49. Shen, Y., Halperin, J. A., and Lee, C. M. (1995) Complement-mediated neurotoxicity is regulated by homologous restriction. Brain Res. 671, 282–292.

    Article  PubMed  CAS  Google Scholar 

  50. Walker, D. G., Xiao, J., McGeer, E. G., and McGeer, P. L. (1995) Expression of complement inhibitors C1 inhibitor and protectin (CD59) by human neurons derived from NTERA2 teratocarcinoma cells. Soc. Neurosci. Abstracts 21, 395.

    Google Scholar 

  51. Vedeler, C. A., Matre, R., and Fischer, E. (1989) Isolation and characterization of complement receptors CR1 from human peripheral nerves. J. Neuroimmunol. 23, 215–221.

    Article  PubMed  CAS  Google Scholar 

  52. Vedeler, C.A. and Matre, R. (1990) Peripheral nerve CR1 express in situ cofactor activity for degradation of Cab. J. Neuroimmunol. 26, 51–66.

    Article  PubMed  CAS  Google Scholar 

  53. Koski, C. L., Estep, A. E., Sawant-Mane, S., Shin, M. L., Highbarger, L., and Hansch, G. M. (1996) Complement regulatory molecules on human myelin and glial cells: differential expression affects the deposition of activated complement proteins. J. Neurochem. 66, 303–312.

    Article  PubMed  CAS  Google Scholar 

  54. Zajicek, J., Wing, M., Skepper, J., and Compston, A. (1995) Human oligodendrocytes are not sensitive to complement: a study of CD59 expression in the human central nervous system. Lab. Invest. 73, 128–138.

    PubMed  CAS  Google Scholar 

  55. Wing, M. G., Zajicek, J. P., Seilly, D. J., Compston, D. A. S., and Lachmann, P. J. (1992) Oligodendrocytes lack glycolipid anchored proteins which protect them against complement lysis. Restoration of resistance to lysis by incorporation of CD59. Immunology 76, 140–145.

    PubMed  CAS  Google Scholar 

  56. Levison, S. W. and Goldman, J. E. (1993) Astrocyte origins, in Astrocytes: Pharmacology and Function. Academic, San Diego, pp. 1–22.

    Google Scholar 

  57. Bignami, A., Eng, L. F., Dahl, D., and Uyeda, C. T. (1972) Localization of the glial fibrillary acidic protein in astrocytes by immunofluoresence. Brain Res. 43, 429–435.

    Article  PubMed  CAS  Google Scholar 

  58. Del Bigio, M. R. (1995) The ependyma: a protective barrier between brain and cerebrospinal fluid. Glia 14, 1–13.

    Article  PubMed  Google Scholar 

  59. Sarnat, H. B. (1995) Ependymal reactions to injury. A review. J. Neuropathol. Exp. Neurol. 54, 1–15.

    Article  PubMed  CAS  Google Scholar 

  60. Barnum, S. R., Ishii, Y., Agrawal, A., and Volanakis, J. E. (1992) Production and interferon-gamma-mediated regulation of C2 and Factors B and D by the astroglioma cell line U105-MG. Biochem. J. 287, 595–601.

    PubMed  CAS  Google Scholar 

  61. Barnum, S. R., Jones, J. L., and Benveniste, E. N. (1992) Interferon-gamma regulation of C3 gene expression in human astroglioma cells. J. Neuroimmunol. 38, 275–282.

    Article  PubMed  CAS  Google Scholar 

  62. Gasque, P., Julen, N., Ischenko, A. M., Picot, C., Mauger, C., Chauzy, C., Ripoche, J., and Fontaine, M. (1992) Expression of complement components of the alternative pathway by glioma cell lines. J. Immunol. 149, 1381–1388.

    PubMed  CAS  Google Scholar 

  63. Gasque, P., Ischenko, A., Legoedec, J., Mauger, C., Schouft, M.-T., and Fontaine, M. (1993) Expression of complement classical pathway by human glioma in culture. J. Biol. Chem. 268, 25,068–25, 074.

    Google Scholar 

  64. Rus, H. G., Kim, L. M., Niculescu, F. I., and Shin, M. L. (1992) Induction of C3 expression in astrocytes is regulated by cytokines and New Castle disease virus. J. Immunol. 148, 928–933.

    PubMed  CAS  Google Scholar 

  65. Gasque, P., Fontaine, M., and Morgan, B. P. (1995) Complement expression in human brain. Biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. J. Immunol. 154, 4726–4733.

    PubMed  CAS  Google Scholar 

  66. Yang, C. Y., Jones, J. L., and Barnum, S. R. (1993) Expression of decay-accelerating factor (CD55), membrane cofactor protein (CD46) and CD59 in the human astroglioma cell line, D54-MG, and primary rat astrocytes. J. Neuroimmunol. 47, 123–132.

    Article  PubMed  CAS  Google Scholar 

  67. Gordon, D. L., Sadlon, T. A., Wesselingh, S. L., Russell, S. M., Johnstone, R. W., and Purcell, D. F. J. (1992) Human astrocytes express membrane cofactor protein (CD46), a regulator of complement activation. J. Neuroimmunol. 36, 199–208.

    Article  PubMed  CAS  Google Scholar 

  68. Gordon, D. L., Sadlon, T., Hefford, C., and Adriano, D. (1993) Expression of CD59, a regulator of the membrane attack complex of complement on human astrocytes. Brain Res. Mol. Brain Res. 18, 335–338.

    Article  PubMed  CAS  Google Scholar 

  69. Gasque, P., Chan, P., Fontaine, M., Ischenko, A., Lamacz, M., Gotze, O., and Morgan, B. P. (1995) Identification and characterization of the complement C5a anaphylatoxin receptor on human astrocytes. J. Immunol. 155, 4882–4889.

    PubMed  CAS  Google Scholar 

  70. Lacy, M., Whittemore, S. R., Haviland, D. L., Wetsel, R. A., and Barnum, S. R. (1995) Expression of the receptors for the C5a anaphylatoxin, interleukin-8 and fMLP by human astrocytes and microglia. J. Neuroimmunol. 61, 71–78.

    Article  PubMed  CAS  Google Scholar 

  71. Wetsel, R. A. (1995) Structure, function and cellular expression of complement anaphylatoxin receptors. Curr. Opinion Immunol. 7, 48–53.

    Article  CAS  Google Scholar 

  72. Haviland, D. L., McCoy, R. L., Whitehead, W. T., Akama, H., Molmenti, E. P., Brown, A., Parks, W. C., Perlmutter, D. H., and Wetsel, R. A. (1995) Cellular expression of the C5a anaphylatoxin receptor (C5a-R): demonstration of C5a-R on liver and lung cells. J. Immunol. 154, 1861–1869.

    PubMed  CAS  Google Scholar 

  73. Armstrong, R. C., Harvath, L., and Dubois-Daleq, M. E. (1990) Type 1 astrocytes and oligodendrocyte type- 2 astrocyte glial progenitors migrate toward distinct molecules. J. Neurosci. Res. 27, 400–407.

    Article  PubMed  CAS  Google Scholar 

  74. Muller-Ladner, U., Jones, J., S., G., Wetse, R. A., Raine, C., and Barnum, S. R. (1996) Enhanced expression of chemotactic receptors in multiple sclerosis lesions. J. Neurol. Sci. 144, 135–144.

    CAS  Google Scholar 

  75. Gasque, P., Chan, P., Mauger, C., Schouft, M. T., Singhrao, S., Dierich, M., Morgan, B. P., and Fontaine, M. (1996) Identification and characterization of complement C3 receptors on human astrocytes. J. Immunol. 156, 2247–2255.

    PubMed  CAS  Google Scholar 

  76. Fearon, D. T. and Carter, R. H. (1995) The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Ann. Rev. Immunol. 13, 127–149.

    Article  CAS  Google Scholar 

  77. Campbell, I. L., Abraham, C. R., Masliah, E., Kemper, P., Inglis, J. D., Oldstone, M. B. A., and Mucke, L. (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6 Proc. Natl. Acad. Sci. USA 90, 10,061–10, 065.

    Google Scholar 

  78. Barnum, S. R., Jones, J., Muller-Ladner, U., Samini, A., and Campbell, I. L. (1996) Chronic complement C3 expression in the CNS of transgenic mice with astrocyte-targeted interleukin 6 expression. Glia 18, 107–117.

    Google Scholar 

  79. Dujardin, B. C. G., Driedijk, P. C., Roijers, A. F. M., and Out, T. A. (1985) The determination of the complement components Clq, C4 and C3 in serum and cerebrospinal fluid by radioimmunoassay. J. Immunol. Methods 80, 227–237.

    Article  PubMed  CAS  Google Scholar 

  80. Gaillard, O., Meillet, D., Diemert, M. C., Musset, L., Delattre, J., Schuller, E., and Galli, J. (1993) Time-resolved immunofluorometric assay of complement C3: application to cerebrospinal fluid. Clin. Chem. 39, 309–312.

    PubMed  CAS  Google Scholar 

  81. Frydn, A., Forsberg, P., and Link, H. (1983) Synthesis of the complement factors C3 and C4 within the central nervous system over the course of aseptic meningitis. Acta Neurol. Scand. 68, 157–163.

    Google Scholar 

  82. Annunziata, P. and Volpi, N. (1985) High levels of C3c in the cerebrospinal fluid from amyotrophic lateral sclerosis patients. Acta Neurol. Scand. 72, 61–64.

    Article  PubMed  CAS  Google Scholar 

  83. Perry, V. H. and Gordon, S. (1988) Macrophages and microglia in the nervous system. Trends Neurosci. 11, 273–277.

    Article  PubMed  CAS  Google Scholar 

  84. Dickson, D. W., Mattiace, L.A., Kure, K., Hutchins, K., Lyman, W. D., and Brosnan, C. F. (1991) Biology of disease: microglia human disease, with an emphasis on acquired immune deficiency syndrome. Lab. Invest. 64, 135–156.

    PubMed  CAS  Google Scholar 

  85. Kreutzberg, G. W. (1995) Microglia, the first line of defense in brain pathologies. Arzneimittel-Forschung 45, 357–360.

    PubMed  CAS  Google Scholar 

  86. Ford, A. L., Goodsall, A. L., Hickey, W. F., and Sedgwick, J. D. (1995) Normal adult ramified microglia separated from other nervous system macrophages by flow cytometry. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD + T cells compared. J. Immunol. 154, 4309–4321.

    PubMed  CAS  Google Scholar 

  87. Rozemuller, J. M., Eikelenboom, P., Pals, S. T., and Stam, S. T. (1989) Microglial cells around amyloid plaques in Alzheimer’s disease express leucocyte adhesion molecules of the LFA-1 family. Neurosci. Lett. 101, 288–292.

    Article  PubMed  CAS  Google Scholar 

  88. Perry, V. H., Hume, D. A., and Gordon, S. (1985) Immunohistochemical localization of macrophages and microglia in adult and developing mouse brain. Neuroscience 15, 313–326.

    Article  PubMed  CAS  Google Scholar 

  89. Blasi, E., Barluzzi, R., Cocchini, V., Mazzolla, R., and Bistoni, F. (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J. Neuroimmunol. 27, 229–337.

    Article  PubMed  CAS  Google Scholar 

  90. Rozemuller, J. M., Stam, F. M., and Eikelenboom, P. (1990) Acute phase proteins are present in amorphous plaques in the cerebral but not in the cerebellar cortex of patients with Alzheimer’s disease. Neurosci. Lett. 119, 75–78.

    Article  PubMed  CAS  Google Scholar 

  91. Walker, D. G., Kim, S. U., and McGeer, P. L. (1995) Complement and cytokine gene expression in cultured microglia derived from postmortem human brains. J. Neurosci. Res. 40, 478–493.

    Article  PubMed  CAS  Google Scholar 

  92. Korotzer, A. R., Watt, J., Cribbs, D., Tenner, A. J., Burdick, D., Glabe, C., and Cotman, C. W. (1995) Cultured rat microglia express Clq and receptor for Clq: implications for amyloid effects on microglia. Exp. Neurol. 134, 214–221.

    Article  PubMed  CAS  Google Scholar 

  93. Akiyama, H., Tooyama, I., Konmdo, H., Ikeda, K., Kimura, H., McGeer, E. G., and McGeer, P. L. (1994) Early response of brain resident microglia to kainic acid-induced hippocampal lesions. Brain Res. 635, 257–268.

    Article  PubMed  CAS  Google Scholar 

  94. Walker, D. G., Yasushara, O., Patston, P. A., McGeer, E., and McGeer, P. L. (1995) Complement Cl inhibitor is produced by brain tissue and is cleaved in Alzheimer disease. Brain Res. 675, 75–82.

    Article  PubMed  CAS  Google Scholar 

  95. Dietzschold, B., Schwaeble, W., Schafer, M. K. H., Hooper, D. C., Zehng, Y. M., Petry, F., Sheng, H., Fink, T., Loos, M., Koprowski, H., and Weihe, E. (1995) Expression of Clq, a subcomponent of the rat complement system, is dramatically enhanced in brains of rats with either Borna disease or experimental allergic encephalomyelitis. J. Neurol. Sci. 130, 11–16.

    Article  PubMed  CAS  Google Scholar 

  96. Svensson, M., Lui, L., Mattsson, P., Morgan, B. P., and Aldskogius, H. (1995) Evidence for activation of the terminal pathway of complement and upregulation of sulfated glycoprotein (SGP)-2 in the hypoglossal nucleus following peripheral nerve injury. Mol. Chem. Neuropath. 24, 53–68.

    Article  CAS  Google Scholar 

  97. Michel, D., Chabot, J.-G., Moyse, E., Danik, M., and Quiron, T. (1992) Possible functions of a new genetic marker in the central nervous system: the sulfated glycoprotein-2 (SGP-2). Synapse 11, 105–111.

    Article  PubMed  CAS  Google Scholar 

  98. Giulian, G. and Baker, T. J. (1986) Characterization of ameboid microglia isolated from developing mammalian brain. J. Neurosci. 6, 2163–2178.

    PubMed  CAS  Google Scholar 

  99. Yao, J., Harvath, L., Gilbert, D. L., and Colton, C. A. (1990) Chemotaxis by a CNS macrophage, the microglia. J. Neurosci. Res. 27, 30–42.

    Article  Google Scholar 

  100. Morimura, T., Neurchrist, C., Kitz, K., Budka, H., Scheiner, O., Kraft, D., and Lassman, H. (1990) Monocyte subpopulations in human gliomas: expression of Fc and complement receptors and correlation with tumor proliferation. Acta Neuropathol. Berl. 80, 287–294.

    Article  PubMed  CAS  Google Scholar 

  101. Broadwell, R. D. and Sofroniew, M. V. (1993) Serum proteins bypass the blood-brain fluid barriers for extracellular entry to the central nervous system. Exp. Neurol. 120, 245–263.

    Article  PubMed  CAS  Google Scholar 

  102. Sanders, M. E., Koski, C. L., Robbins, D., Shin, M. L., Frank, M. M., and Somer, K. A. (1986) Activated terminal complement in CSF in Guillain-Barre syndrome and multiple sclerosis. J. Immunol. 136, 4456–4459.

    PubMed  CAS  Google Scholar 

  103. Smyth, M. D., Cribbs, D. H., Tenner, A. J., Shankle, W. R., Dick, M., Kesslak, J. P., and Cotman, C. W. (1994) Decreased levels of Clq in cerebrospinal fluid of living Alzheimer patients correlate with disease state. Neurobiol. Aging 15, 609–614.

    Article  PubMed  CAS  Google Scholar 

  104. Yam, P., Petz, L. D., Tourtellotte, W. W., and Ma, B. I. (1980) Measurement of complement components in cerebral spinal fluid by radioimmunoassay in patients with multiple sclerosis. Clin. Immunol. Immunopathol. 17, 492–505.

    Article  PubMed  CAS  Google Scholar 

  105. Terai, I., Kobayashi, K., Fujita, T., and Hagiwara, K. (1993) Human serum man-nose binding protein (MBP): development of an enzyme-linked immunosorbent assay (ELISA) and determination of levels in serum from 1085 normal Japanese and in some body fluids. Biochem. Med. Metab. Biol. 50, 111–119.

    Article  PubMed  CAS  Google Scholar 

  106. Roddy, J., Clark, I., Hazleman, B. L., Compston, D. A., and Scolding, N. J. (1994) Cerebrospinal fluid concentrations of the complement MAC inhibitor CD59 in multiple sclerosis and patients with other neurological disorders. J. Neurol. 241, 557–560.

    Article  PubMed  CAS  Google Scholar 

  107. Polihronis, M., Paizais, K., Carter, G., Sedal, G., and Murphy, B. (1993) Elevation of human cerebrospinal fluid clusterin concentration is associated with acute neuropathology. J. Neurol. Sci. 15, 230–233.

    Article  Google Scholar 

  108. Morgan, B. P., Campbell, A. K., and Compston, D. A. S. (1984) Terminal component of complement (C9) in cerebrospinal fluid of patients with multiple sclerosis. Lancet 2, 251–255.

    Article  PubMed  CAS  Google Scholar 

  109. Medof, M. E., Walter, E. I., Rutgers, J. L., Knowles, D. M., and Nussenzweig, V. (1987) Identification of the complement decay-accelerating factor (DAF) on epithelium and glandular cells and in body fluids. J. Exp. Med. 165, 848–864.

    Article  PubMed  CAS  Google Scholar 

  110. Choi-Miura, N. H., Ihara, Y., Fukuchi, K., Takeda, M., Nakano, Y., Tobe, T., and Tornita, M. (1992) SP40,40 is a constituent of Alzheimer’s amyloid. Acta Neuropathol. 83, 260–264.

    Article  PubMed  CAS  Google Scholar 

  111. Kossmann, T., Stahel, P. F., Morganti-Kossman, M. C., Jones, J., and Barnum, S. R. (1997) Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury. J. Neuroimmunol. 73, 63–69.

    Article  PubMed  CAS  Google Scholar 

  112. Barnum, S. R., Jones, J. L., and Benveniste, E. N. (1993) Interleukin-1 and tumor necrosis factor mediated-regulation of C3 gene expression in human astroglioma cells. Glia 7, 225–236.

    Article  PubMed  CAS  Google Scholar 

  113. Celada, A., Klemsz, M. J., and Maki, R. A. (1989) Interferon-y activates multiple pathways to regulate the expression of the genes for major histocompatibility class II-Aß, tumor necrosis factor and complement component C3 in mouse macrophages. Eur. J. Immunol. 19, 1103–1109.

    Article  PubMed  CAS  Google Scholar 

  114. Barnum, S. R. and Jones, J. (1995) Diffential regulation of C3 gene expression in human astroglioma cells by interferon-7 and interleukin-lß. Neurosci. Lett. 197, 121–124.

    Article  PubMed  CAS  Google Scholar 

  115. Morgan, T. E., Laping, N. J., Rozovsky, I., Oda, T., Hogan, T. H., Finch, C. E., and Pasinetti, G. M. (1995) Clusterin expression by astrocytes is influenced by transforming growth factor beta 1 and heterotypic cell interactions. J. Neuroimmunol. 58, 101–110.

    Article  PubMed  CAS  Google Scholar 

  116. Barnum, S. R. and Jones, J. L. (1994) Transforming growth factor-ßl inhibits inflammatory cytokine-induced C3 gene expression in astrocytes. J. Immunol. 152, 765–773.

    PubMed  CAS  Google Scholar 

  117. Haga, S., Ikeda, K., Sato, M., and Ishii, T. (1993) Synthetic Alzheimer amyloid ß/A4 peptides enhance production of complement C3 component by cultured micro-glial cells. Brain Res. 601, 88–94.

    Article  PubMed  CAS  Google Scholar 

  118. Rowe, P. 0., McLean, R. H., Wood, R. A., Leggiardo, R. J., and Winkelstein, J. A. (1989) Association of homozygous C4B deficiency with bacterial meningitis. J. Infect. Dis. 160, 448–451.

    CAS  Google Scholar 

  119. Swart, A. G., Fijen, C. A. P., Kuijper, E. J., Daha, M. R., and Dankert, J. (1991) Complement deficiencies in infections with neisseria meningitis. Complement In-flamm. 8, 227, 228.

    Google Scholar 

  120. Ross, S. C. and Densen, P. (1984) Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine 63, 243–273.

    Article  PubMed  CAS  Google Scholar 

  121. Fukumori, Y. and Yoshimura, K. (1989) A high incidence of C9 deficiency among healthy blood donors in Osaka, Japan. Int. Immunol. 1, 85–89.

    Article  PubMed  CAS  Google Scholar 

  122. Agnello, V. (1978) Complement deficiency states. Medicine 57, 1–23.

    Article  PubMed  CAS  Google Scholar 

  123. Nielsen, H. E., Koch, C., Magnussen, P., and Lind, I. (1989) Complement deficiency in selected groups of patients with meningococcal disease. Scand. J. Infect. Dis. 21, 389–396.

    Article  PubMed  CAS  Google Scholar 

  124. Monoco, S., Gehrmann, J., Raivich, G., and Kreutzberg, G. W. (1992) MHC-positive, ramified macrophages in the normal and injured rat peripheral nervous system. J. Neurocytol. 21, 623–634.

    Article  Google Scholar 

  125. Gehrmann, J., Schoen, S. W., and Kreutzberg, G. W. (1991) Lesion of the rat entorhinal cortex leads to a rapid microglial reaction in the dentate gyrus. A light and electron microscopical study. Acta Neuropathol. (Berl.) 82, 442–455.

    Article  CAS  Google Scholar 

  126. Arvidsson, J. (1986) Transganglionic degeneration in vibrissae innervating primary sensory neurons of the rat: a light and electron microscopic study. J. Comp. Neurol. 249, 392–403.

    Article  PubMed  CAS  Google Scholar 

  127. Johnson, S. A., Pasinetti, G. M., and Finch, C. E. (1994) Expression of complement C1gB and C4 mRNAs during rat brain development. Brain Res. Dev. 80, 163–174.

    Article  CAS  Google Scholar 

  128. O’Bryan, M. K., Cheema, S. S., Bartlett, P. F., Murphy, B. F., and Pearse, M. J. (1993) Clusterin levels increase during neuronal development. J. Neurobiol. 24, 421–432.

    Article  PubMed  Google Scholar 

  129. Pasinetti, G. M. (1996) Inflammatory mechanisms in neurodegeneration and Alzheimer’s disease: the role of the complement system. Neurobiol. Aging 17, 707–716.

    Article  PubMed  CAS  Google Scholar 

  130. Weiser, M. R., Williams, J. P., Moore, F. D., Jr., Kobzik, L., Ma, M., Hechtman, H. B., and Carroll, M. C. (1996) Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J. Exp. Med. 183, 2343–2348.

    Article  PubMed  CAS  Google Scholar 

  131. Wessels, M. R., Butko, P., Ma, M., Warren, H. B., Lage, A. L., and Carroll, M. C. (1995) Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity. Proc. Natl. Acad. Sci. USA 92, 11,490–11, 494.

    Google Scholar 

  132. Lumsden, C. E. (1970) The immunogenesis of the multiple sclerosis plaque. Brain Res. 28, 365–390.

    Article  Google Scholar 

  133. Penfield, W. and Cone, W. (1926) Acute swelling of oligodendroglia. A specific type of neuroglia change. Arch. Neurol. Psychiatr. 16, 131–153.

    Article  Google Scholar 

  134. Mollnes, T. E., Lea, T., Harboe, M., and Tschopp, J. (1985) Monoclonal antibodies recognising a neoantigen of poly (C9) detect the human terminal complement complex in tissue and plasma. Scand. J. Immunol. 22, 183–195.

    Article  PubMed  CAS  Google Scholar 

  135. Compston, D. A. S., Morgan, B. P., Campbell, A. K., Wilkins, P., Cole, G., Thomas, N. D., and Jasani, B. (1989) Immunocytochemical localization of the terminal complement complex in multiple sclerosis. Neuropath. Appl. Neurobiol. 15, 307–316.

    Article  CAS  Google Scholar 

  136. Compston, D. A. S., Morgan, B. P., Oleesky, D., Fifield, R., and Campbell, A. K. (1986) Cerebrospinal fluid C9 in demyelinating disease. Neurology 36, 1503–1506.

    Article  PubMed  CAS  Google Scholar 

  137. Scolding, N. J., Morgan, B. P., Houston, W. A. J., Linington, C., Campbell, A. K., and Compston, D. A. S. (1989) Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement. Nature 339, 620–622.

    Article  PubMed  CAS  Google Scholar 

  138. Morgan, B. P., Dankert, J. R., and Esser, A. F. (1987) Recovery of human neutrophils from complement attack: removal of the membrane attack complex by endocytosis and exocytosis. J. Immunol. 138, 246–253.

    PubMed  CAS  Google Scholar 

  139. Carney, D. F., Koski, C. L., and Shin, M. L. (1985) Elimination of terminal complement intermediates from the plasma membrane of nucleated cells: the rate of disappearance differs for cells carrying C5b-7 or C5b-8 or a mixture of C5b-8 with a limited number of C5b-9. J. Immunol. 134, 1804–1809.

    PubMed  CAS  Google Scholar 

  140. Campbell, A. K. and Morgan, B. P. (1985) Monoclonal antibodies demonstrate protection of polymorphonuclear leukocytes against complement attack. Nature 317, 164–166.

    Article  PubMed  CAS  Google Scholar 

  141. Cammer, W., Brosnan, C. F., Basile, C., Bloom, B. R., and Norton, W. T. (1986) Complement potentiates the degradation of myelin proteins by plasmin: implications for a mechanism of inflammatory demyelination. Brain Res. 364, 91–101.

    Article  PubMed  CAS  Google Scholar 

  142. Wren, D. R. and Noble, M. (1989) Oligodendrocytes and oligodendrocyte/type-2 astrocyte progenitor cells of adult rats are specifically susceptible to the lytic effects of complement in absence of antibody. Proc. Natl. Acad. Sci. USA 86, 9025–9029.

    Article  PubMed  CAS  Google Scholar 

  143. Scolding, N. J., Morgan, B. P., Houston, A., Campbell, A. K., Linington, C., and Compston, D. A. S. (1989) Normal rat serum cytotoxicity against syngeneic oligodendrocytes: complement activation and attack in the absence of anti-myelin antibodies. J. Neurol. Sci. 89, 289–300.

    Article  PubMed  CAS  Google Scholar 

  144. Piddlesden, S. J. and Morgan, B. P. (1993) Killing of rat glial cells by complement: deficiency of the rat analogue of CD59 is the cause of oligodendrocyte susceptibility to lysis. J. Neuroimmunol. 48, 169–176.

    Article  PubMed  CAS  Google Scholar 

  145. Ruijs, T. C. G., Freedman, M. S., Grenier, Y. G., Olivier, A., and Antel, J. P. (1990) Human oligodendrocytes are susceptible to cytolysis by major histocompatibility complex class I restricted lymphocytes. J. Neuroimmunol. 27, 89–97.

    Article  PubMed  CAS  Google Scholar 

  146. Yamada, T., Akiyama, H., and McGeer, P. L. (1990) Complement-activated oligodendroglia: a new pathogenic entity identified by immunostaining with antibodies to human complement proteins C3d and C4d. Neurosci. Lett. 112, 161–166.

    Article  PubMed  CAS  Google Scholar 

  147. Shirazi, Y., McMorris, F. A., and Shin, M. L. (1989) Arachidonic acid mobilization and phosphoinositide turnover by the terminal complement complex, C5b-9, in rat oligodendrocyte x C6 glioma cell hybrids. J. Immunol. 142, 4385–4391.

    PubMed  CAS  Google Scholar 

  148. Niculescu, F., Rus, H., and Shin, M. L. (1994) Receptor-independent activation of guanine nucleotide-binding regulatory proteins by terminal complement complexes. J. Biol. Chem. 269, 4417–4423.

    PubMed  CAS  Google Scholar 

  149. Nicholson-Weller, A. and Halperin, J. A. (1993) Membrane signaling by complement C5b-9, the membrane attack complex. Immunol. Res. 12, 244–257.

    Article  PubMed  CAS  Google Scholar 

  150. Cybulsky, A. V., Monge, J. C., Papillon, J., and McTavish, A. J. (1995) Complement C5b-9 activates cytosolic phospholipase A2 in glomerular epithelial cells. Am. J. Physiol. 269, F739–749.

    PubMed  CAS  Google Scholar 

  151. Shirazi, Y., Rus, H. G., Macklin, W. B., and Shin, M. L. (1993) Enhanced degradation of messenger RNA encoding myelin proteins by terminal complement complexes in oligodendrocytes. J. Immunol. 150, 4581–4590.

    PubMed  CAS  Google Scholar 

  152. Scolding, N. J., Houston, W. A. J., Morgan, B. P., Campbell, A. K., and Compston, D. A. S. (1989) Reversible injury of cultured rat oligodendrocytes by complement. Immunology 67, 441–446.

    PubMed  CAS  Google Scholar 

  153. Papadimitriou, J. C., Drachenberg, C. B., Shin, M. L., and Trump, B. F. (1994) Ultrastructural studies of complement mediated cell death: a biological reaction model to plasma membrane injury. Virchows Arch. 424, 677–685.

    Article  PubMed  CAS  Google Scholar 

  154. Niculescu, F., Rus, H., Shin, S., Lang, T., and Shin, M. S. (1993) Generation of diacylglycerol and ceramide during homologous complement activation. J. Immunol. 150, 214–224.

    PubMed  CAS  Google Scholar 

  155. Kolesnick, R. N., Haimovitz-Friedman, A., and Fuks, Z. (1994) The sphingomyelin signal transduction pathway mediates apoptosis for tumor necrosis factor, Fas, and ionizing radiation. fliochem. Cell. Biol. 72, 471–474.

    Article  CAS  Google Scholar 

  156. Cifone, M. G., De Maria, R., Roncaioli, P., Rippo, M. R., Azuma, M., Lanier, L. L., Santoni, A., and Testi, R. (1994) Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. J. Exp. Med. 180, 1547–1552.

    Article  PubMed  CAS  Google Scholar 

  157. Chen, M., Quintans, J., Fuks, Z., Thompson, C., Kufe, D. W., and Weichselbaum, R. R. (1995) Suppression of Bd-2 messenger RNA production may mediate apoptosis after ionizing radiation, tumor necrosis factor alpha, and ceramide. Cancer Res. 55, 991–994.

    PubMed  CAS  Google Scholar 

  158. Jones, J. and Morgan, B. P. (1995) Apoptosis is associated with reduced expression of complement regulatory molecules, adhesion molecules and other receptors on polymorphonuclear leucocytes: functional relevance and role in inflammation. Immunology 86, 651–660.

    PubMed  CAS  Google Scholar 

  159. Damerau, B., Grunefeld, E., and Vogt, W. (1978) Chemotactic effects of the complement-derived peptides C3a, C3ai, and C5a (classical anaphylatoxin) on rabbit and guinea-pig polymorphonuclear leukocytes. Naunyn-Schmiedeberg’s Arch. Pharmacol. 305, 181–184.

    Google Scholar 

  160. Damerau, B., Zimmermann, B., Grunefeld, E., Czorniak, K., and Vogt, W. (1980) Biological activities of C5a and C5adesArg from hog serum. Int. Arch. Allergy Appl. Immunol. 63, 408–414.

    Article  PubMed  Google Scholar 

  161. Gay, D. and Esiri, M. (1991) Blood-brain barrier damage in acute multiple sclerosis plaques. Brain 114, 557–572.

    Article  PubMed  Google Scholar 

  162. Ernst, J. D., Hartiala, K. T., Goldstein, I. M., and Sande, M. E. (1984) Complement (C5)-derived chemotactic activity accounts for accumulation of polymorphonuclear leukocytes in cerebrospinal fluid of rabbits with pneumococcal meningitis. Infect. Immunol. 46, 81–86.

    CAS  Google Scholar 

  163. Pender, M. P. (1987) Demyelination and neurological signs in experimental allergic encephalomyelitis. J. Neuroimmunol. 15, 11–24.

    Article  PubMed  CAS  Google Scholar 

  164. Raine, C. S. (1984) Analysis of autoimmune demyelination: its impact upon multiple sclerosis. Lab. Invest. 50, 608–635.

    PubMed  CAS  Google Scholar 

  165. Wisniewski, H. M. and Keith, A. B. (1977) Chronic relapsing experimental allergic encephalomyelitis: an experimental model of multipl sclerosis. Ann. Neurol. 1, 144–148.

    Article  PubMed  CAS  Google Scholar 

  166. Levine, S., Cochrane, C. G., and Carpenter, C. B. (1971) Allergic encephalomyelitis: effect of complement depletion with cobra venom. Proc. Soc. Exp. Biol. Med. 138, 285–289.

    PubMed  CAS  Google Scholar 

  167. Gordon, E. J., Myers, K. J., Dougherty, J. P., Rosen, H., and Ron, Y. (1995) Both anti-CD1la (LFA-1) and anti-CD1lb (MAC-1) therapy delay the onset and diminish the severity of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 62, 153–160.

    Article  PubMed  CAS  Google Scholar 

  168. Weisman, H. F., Bartow, T., Leppo, M. K., Marsh, H. C., Carson, G. R., Concino, M. F., Boyle, M. P., Roux, K. H., Weisfeldt, M. L., and Fearon, D. T. (1990) Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249, 146–151.

    Google Scholar 

  169. Prineas, J. W. (1981) Pathology of the Guillain-Barré syndrome. Ann. Neurol. 7, S6 - S9.

    Article  Google Scholar 

  170. Miyakawa, T., Murayama, E., Sumiyoshi, S., Deshimaru, M., and Kamano, A. (1971) A biopsy case of Landry-Guillain-Barré syndrome. Acta Neuropathol. (Berl.) 17, 181–187.

    Article  CAS  Google Scholar 

  171. Tonnessen, T. I., Nyland, H., and Aarli, J. A. (1982) Complement factors and acute phase reactants in the Guillain-Barré syndrome. Eur. Neurol. 21, 124–128.

    Article  PubMed  CAS  Google Scholar 

  172. Koski, C. L., Sanders, M. E., Swoveland, P. T., Lawley, T. J., Shin, M. L., Frank, M. M., and Joiner, K. A. (1987) Activation of terminal components of complement in patients with Guillain-Barré syndrome and other demyelinating neuropathies. J. Clin. Invest. 80, 1492–1497.

    Article  PubMed  CAS  Google Scholar 

  173. Hartung, H. P., Schwenke, C., Bitter-Suermann, D., and Toyka, K. V. (1987) Guillain-Barré syndrome: activated complement components C3a and C5a in CSF. Neurology 37, 1006–1009.

    Article  PubMed  CAS  Google Scholar 

  174. Nyland, H., Matre-R., and Mork, S. (1981) Immunological characterization of sural nerve biopsies from patients with Guillain-Barré syndrome. Ann. Neurol. 9, 80–86.

    Google Scholar 

  175. Dubois-Dalque, M., Buyse, M., Buyse, G., and Gorce, F. (1971) The action of Guillain-Barré syndrome serum on myelin: a tissue culture and electron microscopic analysis. J. Neurol. Sci. 13, 67–83.

    Article  Google Scholar 

  176. Hirano, A., Cook, S. D., Whitaker, J. N., Dowling, P. C., and Murray, M. R. (1971) Fine structural aspects of demyelination in vitro. The effects of Guillain-Barré serum. J. Neuropathol. Exp. 30, 249–265.

    Article  CAS  Google Scholar 

  177. Bradbury, K., Aparicio, S. R., Sumner, D. W., and Bird, C. C. (1984) Role of complement in demyelination in vitro by multiple sclerosis serum and other neurological disease sera. J. Neurol. Sci. 65, 293–305.

    Article  PubMed  CAS  Google Scholar 

  178. Sawant-Mane, S., Clark, M. B., and Koski, C. L. (1991) In vitro demyelination by serum antibody from patients with Guillain-Barré syndrome requires terminal complement complexes. Ann. Neurol. 29, 397–404.

    Article  PubMed  CAS  Google Scholar 

  179. Smith, M. E., Forno, L. S., and Hoffman, W. W. (1979) Experimental allergic neuritis in the Lewis rat. J. Neuropathol. Exp. Neurol. 38, 377–391.

    Article  PubMed  CAS  Google Scholar 

  180. Kadlubowski, M. and Hughes, R. A. C. (1979) Identification of the neuritogen for experimental allergic neuritis. Nature 277, 140–141.

    Article  PubMed  CAS  Google Scholar 

  181. Linington, C., Lassmann, H., Ozawa, K., Kosin, S., and Mongan, L. (1992) Cell adhesion molecules of the immunoglobulin supergene family as tissue-specific auto-antigens: induction of experimental allergic neuritis (EAN) by PO protein-specific T cell lines. Eur. J. Immunol. 22, 1813–1817.

    Article  PubMed  CAS  Google Scholar 

  182. Linington, C., Izumo, S., Suzuki, M., Uyemura, K., Meyermann, R., and Wekerle, H. (1984) A permanent rat T cell line that mediates experimental allergic neuritis in the Lewis rat in vivo. J. Immunol. 133, 1946–1950.

    PubMed  CAS  Google Scholar 

  183. Vriesendorp, F. J., Flynn, R. E., Pappolla, M. A., and Koski, C. L. (1995) Complement depletion affects demyelination and inflammation in experimental allergic neuritis. J. Neuroimmunol. 58, 157–165.

    Article  PubMed  CAS  Google Scholar 

  184. Feasby, T. E., Gilbert, J. J., Hahn, A. F., and Neilson, M. (1987) Complement depletion suppresses Lewis rat experimental allergic neuritis. Brain Res. 419, 97–103.

    Article  PubMed  CAS  Google Scholar 

  185. Jung, S., Toyka, K. V., and Hartung, H. P. (1995) Soluble complement receptor type 1 inhibits experimental autoimmune neuritis in Lewis rat. Neurosci. Lett. 200, 167–170.

    Article  PubMed  CAS  Google Scholar 

  186. Stoll, G., Schmidt, B., Jander, S., Toyka, K. V., and Hartung, H. P. (1991) Presence of the terminal complement complex (C5b-9) preceds myelin degradation in immune-mediated demyelination of the rat peripheral nervous system. Ann. Neurol. 30, 147–155.

    Article  PubMed  CAS  Google Scholar 

  187. Lindstrom, J. M., Lennon, V. A., Seybold, M. E., and Whittingham, S. (1976) Experimental autoimmune myasthenia gravis and myasthenia gravis: biochemical and immunochemical aspects. Ann. NY Acad. Sci. 274, 254–274.

    Article  PubMed  CAS  Google Scholar 

  188. Almon, R. R. and Appel, S. H. (1975) Interaction of myasthenic serum globulin with the acetylcholine receptor. Biochem. Biophys. Acta 393, 66–77.

    Article  PubMed  CAS  Google Scholar 

  189. Garlepp, M., Farrow, B., Kay, P., and Dawkins, R. L. (1979) Antibodies to the acetylcholine receptor in myasthenic dogs. Immunol. 37, 807–810.

    Google Scholar 

  190. Patrick, J. and Lindstrom, J. (1973) Autoimmune response to acetylcholine receptors. Science 180, 871–872.

    Article  PubMed  CAS  Google Scholar 

  191. Richman, D. P., Gomez, C. M., Berman, P. W., Burres, S. A., Fitch, F. W., and Arnason, B. G. (1980) Monoclonal anti-acetylcholine receptor antibodies can cause experimental myasthenia. Nature 286, 738, 739.

    Google Scholar 

  192. Lennon, V. A. and Lambert, E. H. (1980) Myasthenia gravis induced by monoclonal antibodies to acetylcholine receptors. Nature 285, 238–240.

    Article  PubMed  CAS  Google Scholar 

  193. Lindstrom, J. M., Engel, A. G., Seybold, M. E., Lennon, V. A., and Lambert, E. H. (1976) Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine receptor antibodies. J. Exp. Med. 144, 739–753.

    Article  PubMed  CAS  Google Scholar 

  194. Toyka, K. V., Drachman, D. B., Pestronk, A., and Kao, I. (1975) Myasthenia gravis: passive transfer from man to mouse. Science 190, 397–399.

    Article  PubMed  CAS  Google Scholar 

  195. Nastuk, W. L., Plescia, O. J., and Osserman, K. E. (1960) Changes in complement activity in patients with myasthenia gravis. Proc. Soc. Exp. Biol. Med. 105, 177–184.

    PubMed  CAS  Google Scholar 

  196. Engel, A. G., Lambert, E. H., and Howard, F. M. (1977) Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis. Ultrastrucutral and light microscopic localization and electrophysiologic correlations. Mayo Clin. Proc. 52, 267–280.

    PubMed  CAS  Google Scholar 

  197. Sahashi, K., Engel, A. G., Lindstrom, J. M., Lambert, E. H., and Lennon, V. A. (1978) Ultrastructural localization of immune complexes (IgG and C3) at the endplate in experimental autoimmune myasthenia gravis. J. Neurpathol. Exp. Neurol. 37, 213–223.

    Google Scholar 

  198. Sahashi, K., Engel, A. G., Lambert, E. H., and Howard, F. M. (1980) Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor endplate in myasthenia gravis. J. Neuropathol. Exp. Neurol. 39, 160–172.

    Article  PubMed  CAS  Google Scholar 

  199. Graus, Y. M. F., Verschuuren, J. J. G. M., Spaans, F., Jennekens, F., van Breda Vriesman, P. J. C., and De Baets, M. H. (1993) Age-related resistance to experimental autoimmune myasthenia gravis in rats. J. Immunol. 150, 4093–4103.

    PubMed  CAS  Google Scholar 

  200. Toyka, K. V., Drachman, D. B., Griffin, D. E., Pestronk, A., Winkelstein, J. A., Fishbeck, K. H., and Kao, I. (1977) Study of humoral immune mechanisms by passive transfer to mice. N. Engl. J. Med. 296, 125–131.

    Article  CAS  Google Scholar 

  201. Lennon, V. A., Seybold, M. E., Lindstrom, J. M., Cochrane, C., and Ulevitch, R. (1978) Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J. Exp. Med. 147, 973–983.

    Article  PubMed  CAS  Google Scholar 

  202. Kao, I. and Drachman, D. B. (1977) Myasthenic immunoglobulin acclerates acetylcholine receptor degradation. Science 196, 527–529.

    Article  PubMed  CAS  Google Scholar 

  203. Lennon, V. A. and Lambert, E. H. (1981) Monoclonal autoantibodies to acetylcholine receptors: evidence for a dominant idiotype and requirement of complement for pathogenicity. Ann. NY Acad. Sci. 377, 77–96.

    Article  PubMed  CAS  Google Scholar 

  204. Gaskin, F. (1992) Human antibodies to Alzheimer’s disease and normal neural elements, in Alzheimer’s Disease. New Treatment Strategies (Khachaturian, Z. S. and Blass, J. P., eds.), Marcel Dekker, New York, pp. 137–145.

    Google Scholar 

  205. Chapman, J., Bachar, O., Korczyn, A. D., Wertman, E., and Michaelson, D. M. (1988) Antibodies to cholinergic neurons in Alzheimer’s disease. J. Neurochem. 51, 479–485.

    Article  PubMed  CAS  Google Scholar 

  206. Fillit, H. M., Kemeny, E., Luine, V., Weksler, M. E., and Zabriskie, J. B. (1987) Antivascular antibodies in the sera of patients with senile dementia of the Alzheimer’s type. J. Gerontol. 42, 307–318.

    Article  Google Scholar 

  207. Gaskin, F. and Hart, M. A. (1988) Antibodies to cytoskeletal proteins in Alzheimer’s disease. J. Cell Biol. 107, 368a.

    Google Scholar 

  208. Kingsley, B. S., Gaskin, F., and Fu, S. M. (1988) Human antibodies to neurofibrillary tangles and astrocytes in Alzheimer’s disease. J. Neuroimmunol. 19, 89–99.

    Article  PubMed  CAS  Google Scholar 

  209. Eikelenboom, P. and Stam, F. C. (1982) Immunoglobulins and complement factors in senile plaques. Acta Neuropathol. (Berl.) 57, 239–242.

    Article  CAS  Google Scholar 

  210. Veerhuis, R., Janssen, I., Hack, C. E., and Eikelenboom, P. (1996) Early complement components in Alzheimer’s disease brains. Acta Neuropathol. 91, 53–60.

    Article  PubMed  CAS  Google Scholar 

  211. Veerhuis, R., vand der Valk, P., Janssen, I., Zhan, S. S., Van Nostrand, W. E., and Eikelenboom, P. (1995) Complement activation in amyloid plaques in Alzheimer’s disease brains does not proceed further than C3. Virchows Arch. 426, 603–610.

    Article  PubMed  CAS  Google Scholar 

  212. Ishii, T. and Haga, S. (1984) Immuno-electron-microscopic localization of complements in amyloid fibrils of senile plaques. Acta Neuropathol. (Berl.) 63, 296–300.

    Article  CAS  Google Scholar 

  213. Lampert-Etchells, M., Pasinetti, G. M., Finch, C. E., and Johnson, S. A. (1993) Regional localization of cells containing complement Clq and C4 mRNAs in the frontal cortex during Alzheimer’s disease. Neurodegeneration 2, 111–121.

    Google Scholar 

  214. Itagaki, S., Akiyama, H., Saito, H., and McGeer, P. L. (1994) Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer’s disease. Brain Res. 645, 78–84.

    Article  PubMed  CAS  Google Scholar 

  215. Lue, L.-F. and Rogers, J. (1992) Full complement activation fails in diffuse plaques of the Alzheimer’s disease cerebellum. Dementia 3, 308–313.

    Google Scholar 

  216. Eikelenboom, P., Rozemuller, J. M., Kraal, G., Stam, F. C., McBride, P. A., Bruce, M. E., and Fraser, H. (1991) Cerebral amyloid plaques in Alzheimer’s disease but not in scrapie-affected mice are closely associated with a local inflammatory process. Virchows Arch. B Cell Pathol. 60, 329–336.

    Article  CAS  Google Scholar 

  217. Afagh, A., Cummings, B. J., Cribbs, D. H., Cotman, C. W., and Tenner, A. J. (1996) Localization and cell association of Clq in Alzheimer’s disease brain. Exp. Neurol. 138, 22–32.

    Article  PubMed  CAS  Google Scholar 

  218. McGeer, P. L., Kawamata, T., and Walker, D. G. (1992) Distribution of clusterin in Alzheimer brain tissue. Brain Res. 579, 337–341.

    Article  PubMed  CAS  Google Scholar 

  219. Kawamata, T., Tooyama, I., Yamada, T., Walker, D. G., and McGeer, P. L. (1993) Lactotransferrin immunocytochemistry in Alzheimer and normal human brain. Am. J. Pathol. 142, 1574–1585.

    PubMed  CAS  Google Scholar 

  220. Kalaria, R. N. and Kroon, S. N. (1992) Complement inhibitor C4-binding protein in amyloid deposits containing serum amyloid P in Alzheimer’s disease. Biochem. Biophys. Res. Commun. 186, 461–466.

    Article  PubMed  CAS  Google Scholar 

  221. Webster, S., Glabe, C., and Rogers, J. (1995) Multivalent binding of complement protein Clq to the amyloid ß-peptide (Aß) promotes the nucleation phase of Aß aggregation. Biochem. Biophys. Res. Commun. 217, 869–875.

    Article  PubMed  CAS  Google Scholar 

  222. Kuo, Y. M., Emmerling, M. R., Vigo Pelfrey, C., Kasunic, T. C., Kirkpatrick, J. B., Murdoch, G. H., Ball, M. J., and Roher, A. E. (1996) Water-soluble Aß (N-40, N-42) oligomers in normal and Alzheimer disease brains. J. Biol. Chem. 271, 4077–4081.

    Article  PubMed  CAS  Google Scholar 

  223. Gravina, S. A., Ho, L., Eckman, C. B., Long, K. E., Otvos, L. J., Younkin, L. H., Suzuki, N., and Younkin, S. G. (1995) Amyloid beta protein (Aß) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at Aß 40 or Aß 42(43). J. Biol. Chem. 270, 7013–7016.

    Article  PubMed  CAS  Google Scholar 

  224. Loos, M. (1982) The classical complement pathway: mechanism of activation of the first component by antigen-antibody complexes. Prog. Allergy 30, 115–192.

    Google Scholar 

  225. Gewurz, H., Ying, S..C., Jiang, H., and Lint, T. F. (1993) Nonimmune activation of the classical complement pathway. Behring. Inst. Mitt. 93, 138–147.

    PubMed  CAS  Google Scholar 

  226. Jiang, H., Cooper, B., Robey, F. A., and Gewurz, H. (1992) DNA binds and activates complement via a specific sequence on the human Clq A chain. J. Biol. Chem. 267, 25,597–25, 601.

    Google Scholar 

  227. Jiang, H., Robey, F. A., and Gewurz, H. (1992) Localization of sites through which CRP binds and activates complement to residues 14–26 and 76–92 of the human Clq A chain. J. Exp. Med. 175, 1373–1379.

    Article  PubMed  CAS  Google Scholar 

  228. Ying, S.-C., Gewurz, A. T., Jiang, H., and Gewurz, H. (1993) Human serum amyloid P component oligomers bind and activate the classical complement pathway via residues 14–26 and 76–92 of the A chain collagen-like region of Clq. J. Immunol. 150, 169–176.

    PubMed  CAS  Google Scholar 

  229. Oda, T., Lehrer-Graiwer, J., Finch, C. E., and Pasinetti, G. M. (1995) Complement and ß-amyloid (Aß) neurotoxicity in vitro: a model for Alzheimer’s disease. Alzheimer’s Res. 1, 29–34.

    Google Scholar 

  230. Schultz, J., Schaller, J., McKinley, M., Bradt, B., Cooper, N., May, P., and Rogers, J. (1994) Enhanced cytotoxicity of amyloid beta-peptide by a complement dependent mechanism. Neurosci. Lett. 175, 99–102.

    Article  PubMed  CAS  Google Scholar 

  231. Klegeris, A., Walker, D. G., and McGeer, P. L. (1994) Activation of macrophages by Alzheimer ß amyloid peptide. Biochem. Biophys. Res. Commun. 199, 984–991.

    Article  PubMed  CAS  Google Scholar 

  232. Kawamata, T., Akiyama, H., Yamada, T., and McGeer, P. L. (1992) Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am. J. Pathol. 140, 691–707.

    PubMed  CAS  Google Scholar 

  233. Schwab, C., Steele, J. C., and McGeer, P. L. (1996) Neurofibrillary tangles of Guam parkinson-dementia are associated with reactive microglia and complement proteins. Brain Res. 707, 196–205.

    Article  PubMed  CAS  Google Scholar 

  234. Yamada, T., McGeer, P. L., and McGeer, E. G. (1992) Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol. 84, 100–104.

    Article  PubMed  CAS  Google Scholar 

  235. Yamada, T., Moroo, I., Koguchi, Y., Asahina, M., and Hirayama, K. (1994) Increased concentration of C4d complement protein in the cerebrospinal fluids in progressive supranuclear palsy. Acta Neurol. Scand. 89, 42–46.

    Article  PubMed  CAS  Google Scholar 

  236. Apostolski, S., Nikolic, J., Bugarski-Prokopljevic, C., Miletic, V., Pavlovic, S., and Filipovic, S. (1991) Serum and CSF immunological findings in ALS. Acta Neurol. Scand. 83, 96–98.

    Article  PubMed  CAS  Google Scholar 

  237. Tsuboi, Y., and Yamada, T. (1994) Increased concentration of C4d complement protein in CSF in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 57, 859–861.

    Article  PubMed  CAS  Google Scholar 

  238. Singhrao, S. K., Neal, J. W. Gasque P., Morgan, B. P., Newman G. R. (1996) Role of complement in the aetiology of Pick’s disease? J. Neuropathol. Exp. Neurol. 55, 578–593.

    Article  PubMed  CAS  Google Scholar 

  239. Yasuhara, O., Aimi, Y., McGeer, E. G., and McGeer, P. L. (1994) Expression of the complement membrane attack complex and its inhibitors in Pick disease brain. Brain Res. 652, 346–349.

    Article  PubMed  CAS  Google Scholar 

  240. McGeer, P. L., McGeer, E. G., Kawamata, T., Yamada, T., and Akiyama, H. (1991) Reactions of the immune system in chronic degenerative neurological diseases. Can. J. Neurol. Sci. 18, 376–379.

    PubMed  CAS  Google Scholar 

  241. Luchessi, B. R. (1993) Complement activation, neutrophils, and oxygen radicals in reperfusion injury. Stroke 24, I41–149.

    Google Scholar 

  242. Kasuya, H. and Shimizu, T. (1989) Activated complement components C3a and C4a in cerebrospinal fluid and plasma following subarachinoid hemorrhage. J. Neurosurg. 71, 741–746.

    Article  PubMed  CAS  Google Scholar 

  243. Xu, Y. B., Shu, J. S., and Zhang, G. P. (1994) Activation and free radical formation of leukocytes in patients with acute ischemic stroke. Chung Hua Nei Ko Tsa Chih. 33, 799–802.

    PubMed  CAS  Google Scholar 

  244. Zhang, Z. G., Chopp, M., Tang, W. X., Jiang, N., and Zhang, R. L. (1995) Postischemic treatment (2–4 h) with anti-CD 1 lb and anti-CD18 monoclonal antibodies are neuroprotective after transient (2 h) focal cerebral ischemia in the rat. Brain Res. 698, 79–85.

    Article  PubMed  CAS  Google Scholar 

  245. Asghar, S. S. (1984) Pharmacological manipulation of complement system. Pharmacol. Rev. 36, 223–244.

    PubMed  CAS  Google Scholar 

  246. Busby, T. F. and Ingham, K. C. (1990) NH2-terminal calcium-binding domain of human complement Cls-mediates the interaction of Clr-with Clq. Biochemistry 29, 4613–4618.

    Article  PubMed  CAS  Google Scholar 

  247. Villiers, C. L., Arlaud, G. J., Painter, R. H., and Colomb, M. G. (1980) Calcium binding properties of the Cl subcomponents Clq, C1r and Cls. FEBS. Lett. 117, 289–294.

    Article  PubMed  CAS  Google Scholar 

  248. Thielens, N. M., Illy, C., Bally, I. M., and Arlaud, G. J. (1994) Activation of human complement serine-proteinase Clr is down-regulated by a Ca(2+)-dependent intramolecular control that is released in the Cl complex through a signal transmitted by Clq. Biochem. J. 301, 509–516.

    PubMed  CAS  Google Scholar 

  249. Zapf, S. and Loos, M. (1985) Effect of EDTA and citrate on the functional activity of the first component of complement, Cl, and the Clq subcomponent. Immunobiology 170, 123–132.

    Article  PubMed  CAS  Google Scholar 

  250. Ziccardi, R. J. (1983) Nature of the metal ion requirement for assembly and function of the first component of human complement. J. Biol. Chem. 258, 6187–6192.

    PubMed  CAS  Google Scholar 

  251. Ziccardi, R. J. and Cooper, N. R. (1976) Activation of Clr by proteolytic cleavage. J. Immunol. 116, 504–509.

    PubMed  CAS  Google Scholar 

  252. Colomb, M. G., Arlaud, G. J., and Villiers, C. L. (1984) Activation of Cl. Phil. Trans. R. Soc. Lond. B. Biol. Sci. 306, 283–292.

    Article  CAS  Google Scholar 

  253. Schumaker, V. N., Zavodszky, P., and Poon, P. H. (1987) Activation of the first component of complement. Annu. Rev. Immunol. 5, 21–42.

    Article  PubMed  CAS  Google Scholar 

  254. Arlaud, G. J., Thielens, N. M., and Aude, C. A. (1989) Structure and function of Clr and Cls: current concepts. Behring. Inst. Mitt. 84, 56–64.

    PubMed  CAS  Google Scholar 

  255. Sim, R. B., Porter, R. R., Reid, K. B. M., and Gigli, I. (1977) The structure and enzymic activities of the Clr and Cls subcomponents of Cl, the first component of human serum complement. Biochemistry 163, 219–227.

    CAS  Google Scholar 

  256. Schasteen, C. S., Levine, R. P., McLafferty, S. A., Finn, R. F., Bullock, L. D., Mayden, J. C., and Glover, G. I. (1991) Synthetic peptide inhibitors of complement serine proteases-III. Significant increase in inhibitor potency provides further support for the functional equivalence hypothesis. Mol. Immunol. 28, 17–26.

    Article  PubMed  CAS  Google Scholar 

  257. Bing, D. H. (1969) Nature of the active site of a subunit of the first component of human complement. Biochemistry 8, 4503–4510.

    Article  PubMed  CAS  Google Scholar 

  258. Nagaki, K. and Stroud, R. M. (1969) The relationship of the hemolytic activity of active C’ 1 s to its TAMe esterase action: a new method of purification and assay. J. Immunol. 102, 421–430.

    PubMed  CAS  Google Scholar 

  259. Naff, G. B. and Ratnoff, O. S. (1968) The enzymatic nature of C’lr. Conversion of C’ls to C’1 esterase and digestion of amino acid esters by C’lr. J. Exp. Med. 128, 571–593.

    Article  PubMed  CAS  Google Scholar 

  260. Volanakis, J. E., Schrohenloher, R. E., and Stroud, R. M. (1977) Human factor D of the alternative complement pathway: purification and characterization. J. Immunol. 119, 337–342.

    PubMed  CAS  Google Scholar 

  261. Andrews, J. M. and Baillie, R. D. (1979) The enzymatic nature of human clr: a subcomponent of the first component of complement. J. Immunol. 123, 1403–1408.

    PubMed  CAS  Google Scholar 

  262. McRae, B. J., Lin, T. Y., and Powers, J. C. (1981) Mapping the substrate binding site of human Clr and Cls with peptide thioesters. Development of new sensitive substrates. J. Biol. Chem. 256, 12,362–12, 366.

    Google Scholar 

  263. Gal, P., Cseh, S., Schumaker, V. N., and Zavodszky, P. (1994) The structure and function of the first component of complement: genetic engineering approach (a review). Acta Microbiol. Immunol. Hung. 41, 361–380.

    PubMed  CAS  Google Scholar 

  264. Arlaud, G. J., Thielens, N. M., and Illy, C. (1993) Assembly of the Cl complex. Behring Inst. Mitt. 93, 189–195.

    PubMed  CAS  Google Scholar 

  265. Zavodszky, P., Cseh, S., Lorincz, Z., and Gal, P. (1996) The role of regulatory modules in the specificity and function of complement serine proteases Clr and Cls. Mol. Immunol. 33, 18S.

    Google Scholar 

  266. Gorski, J. P., Hugli, T. E., and Muller Eberhard, H. J. (1979) C4a: the third anaphylatoxin of the human complement system. Proc. Natl. Acad. Sci. USA 76, 5299–5302.

    Article  PubMed  CAS  Google Scholar 

  267. Kerr, M. A. (1979) Limited proteolysis of complement components C2 and factor B. Structural analogy and limited sequence homology. Biochem. J. 183, 615–622.

    PubMed  CAS  Google Scholar 

  268. Cooper, N. R. (1975) Enzymatic activity of the second component of complement. Biochemistry 14, 4245–4251.

    Article  PubMed  CAS  Google Scholar 

  269. Perkin, S. J. and Smith, K. F. (1993) Identity of the putative serine-proteinase fold in proteins of the complement system with nine relevant crystal structures. Biochem. J. 295, 109–114.

    Google Scholar 

  270. Yaegashi, T., Nunomura, S., Okutome, T., Nakayama, T., Kurumi, M., Sakurai, Y., Aoyama, T., and Fujii, S. (1984) Synthesis and structure-activity study of protease inhibitors. III. Amidinophenols and their benzoyl esters. Chem. Pharm. Bull. Tokyo 32, 4466–4477.

    Article  PubMed  CAS  Google Scholar 

  271. Haupt, H. and Baudner, S. (1981) Isolierung und kristallisation der huamcomplement-subkomponente Clr des CI-komplexes. Hoppe-Seyler’s Z. Physiol. Chem. 362, 1147–1150.

    Article  CAS  Google Scholar 

  272. Asghar, S. S., Pondman, K. W., and Cormane, R. H. (1973) Inhibition of Clr, Cls and generation of Cls by amidino compounds. Biochim. Biophys. Acta 317, 539–548.

    Article  PubMed  CAS  Google Scholar 

  273. Andrews, J. M., Roman, D. P., Jr., and Bing, D. H. (1978) Inhibition of four human serine proteases by substituted benzamidines. J. Med. Chem. 21, 1202–1207.

    Article  PubMed  CAS  Google Scholar 

  274. Bing, D. H., Cory, M., and Doll, M. (1974) The inactivation of human Cl by benzamidine and pyridinium sulfonylfluorides. J. Immunol. 113, 584–590.

    PubMed  CAS  Google Scholar 

  275. Kam, C. M., Oglesby, T. J., Pangburn, M. K., Volanakis, J. E., and Powers, J. C. (1992) Substituted isocoumarins as inhibitors of complement serine proteases. J. Immunol. 149, 163–168.

    PubMed  CAS  Google Scholar 

  276. Fujii, S. and Hitomi, Y. (1981) New synthetic inhibitors of Clr, Cl esterase, thrombin, plasmin, kallikrein and trypsin. Biochim. Biophys. Acta 661, 342–345.

    Article  PubMed  CAS  Google Scholar 

  277. Issekutz, A. C., Roland, D. M., and Patrick, R. A. (1990) The effect of FUT-175 (Nafamstat Mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo. Int. J. Immunopharmacol. 12, 1–9.

    Article  PubMed  CAS  Google Scholar 

  278. Oda, M., Ino, Y., Nakamura, K., Kuramoto, S., Shimamura, K., Iwaki, M., and Fujii, S. (1990) Pharmacological studies on 6-amidino-2-naphthyl[4-(4,5-dihydro1H-imidazol-2-yl)amino] benzoate dimethane sulfonate (FUT-187). I: inhibitory activities on various kinds of enzymes in vitro and anticomplement activity in vivo. Jpn. J. Pharmacol. 52, 23–34.

    Article  PubMed  CAS  Google Scholar 

  279. Nakayama, T., Taira, S., Ikeda, M., Ashizawa, H., Oda, M., Arakawa, K., and Fujii, S. (1993) Synthesis and structure-activity study of protease inhibitors. V. Chemical modification of 6-amidino-2-naphthyl 4-guanidinobenzoate. Chem. Pharm. Bull. Tokyo 41, 117–125.

    Article  PubMed  CAS  Google Scholar 

  280. Yanamoto, H., Kikuchi, H., Okamoto, S., and Nozaki, K. (1992) Preventive effect of synthetic serine protease inhibitor, FUT-175, on cerebral vasospasm in rabbits. Neurosurgery 30, 351–356; discussion 356–357.

    Google Scholar 

  281. Yanamoto, H., Kikuchi, H., Okamoto, S., and Nozaki, K. (1994) Cerebral vaso-spasm caused by cisternal injection of polystyrene latex beads in rabbits is inhibited by a serine protease inhibitor. Surg. Neurol. 42, 374–381.

    Article  PubMed  CAS  Google Scholar 

  282. Yanamoto, H., Kikuchi, H., Ishikawa, J., Shimizu, Y., Sato, M., Tokuriki, Y., Okamoto, S., Matsumoto, M., Matsumoto, K., and Nakamura, M. (1993) Intravenous FUT-175 inhibits complement activation in the cerebrospinal fluid and vasospasm-related delayed ischemic neurological deficit following subarachinoid hemorrhage, in Cerebral Vasospasm ( Findlay, J. M., ed.), Elsevier Science, Essex, pp. 431–433.

    Google Scholar 

  283. Gilmore, J. L., Hays, S. J., Caprathe, B. W., Lee, C., Emmerling, M. R., Michael, W., and Jaen, J. C. (1996) Synthesis and evaluation of 2-aryl-4H-3,1-benzoxazin-4ones as Clr serine protease inhibitors. Bioorg. Med. Chem. Lett. 5, 679–682.

    Article  Google Scholar 

  284. Teshima, T., Griffin, J. C., and Powers, J. C. (1982) A new class of heterocyclic serine protease inhibitors. Inhibition of human leukocyte elastase, porcine pancreatic elastase, cathepsin G, and bovine chymotrypsin A alpha with substituted benzoxazinones, quinazolines, and anthranilates. J. Biol. Chem. 257, 5085–5091.

    PubMed  CAS  Google Scholar 

  285. Brown, A.D. and Powers, J. C. (1995) Rates of thrombin acylation and deacylation upon reaction with low molecular weight acylating agents, carbamylating agents and carbonylating agents. Bioorg. Med. Chem. 3, 1091–1097.

    Article  PubMed  CAS  Google Scholar 

  286. Chow, M. M., Meyer E. F., Jr., Bode, W., Kam, C.-M., Radhakrishnan, R., Vijayalakshmi, J., and Powers, J. C. (1990) The 2.2-A resolution x-ray cruystal structure of the complex of trypsin inhibited by 4-chloro-3-ethoxy-7-guanidinoisocoumarin: a proposed model of the thrombin-inhibitor complex. J. Am. Chem. Soc. 112, 7783–7789.

    Google Scholar 

  287. Kam, C. M., Fujikawa, K., and Powers, J. C. (1988) Mechanism-based isocoumarin inhibitors for trypsin and blood coagulation serine proteases: new anticoagulants. Biochemistry 27, 2547–2557.

    Article  PubMed  CAS  Google Scholar 

  288. Roher, A. E., Lowenson, J. D., Clarke, S., Woods, A. S., Cotter, R. J., Gowing, E., and Ball, M. J. (1993) ß-Amyloid-(1–42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 10,836–10, 840.

    Google Scholar 

  289. Hugli, T. E. Human anaphylatoxin (C3a) from the third component of complement. Primary structure. J. Biol. Chem. 250, 8293–8301.

    Google Scholar 

  290. Fernandez, H. N. and Hugli, T. E. (1978) Primary structural analysis of the polypeptide portion of human C5a anaphylatoxin. Polypeptide sequence determination and assignment of the oligosaccharide attachment site in C5a. J. Biol. Chem. 253, 6955–6964.

    PubMed  CAS  Google Scholar 

  291. Tack, B. F., Morris, S. C., and Prahl, J. W. (1979) Third component of human complement: structural analysis of the polypeptide chains of C3 and C3b. Biochemistry 18, 1497–1503.

    Article  PubMed  CAS  Google Scholar 

  292. Piddlesden, S. J., Jiang, S., Vincent, A., and Morgan, B. P. (1996) Soluble complement receptor 1 (SCR1; TP10) protects against experimental allergic myasthenia gravis (EAMG). Mol. Immunol. 33, 76S.

    Google Scholar 

  293. Andreatta, R. H., Rahuel, J., Wesp, M., and Dukor, P. (1981) Attempts at specific inhibition of C3-convertase, in Enzyme Inhibitors ( Brodbeck, U., ed.), Verlag, Chemie, Basel, pp. 261–272.

    Google Scholar 

  294. Miyazaki, W., Izawa, T., Nakano, Y., Shinohara, M., Hing, K., Kinoshita, T., and Inoue, K. (1984) Effects of K-76 monocarboxylic acid, an anticomplementary agent, on various in vivo immunological reactions and on experimental glomerulonephritis. Complement 1, 134–146.

    PubMed  CAS  Google Scholar 

  295. Hong, K., Kinoshita, T., Miyazaki, W., Izawa, T., and Inoue, K. (1979) An anti-complementary agent, K-76 monocarboxylic acid: its site and mechanism of inhibition of the complement activation cascade. J. Immunol. 122, 2418–2423.

    PubMed  CAS  Google Scholar 

  296. Hong, K., Kinoshita, T., Kitajima, H., and Inoue, K. (1981) Inhibitory effect of K-76 monocarboxylic acid, an anticomplementary agent, on the C3b inactivator system. J. Immunol. 127, 104–108.

    PubMed  CAS  Google Scholar 

  297. Kaufman, T. S., Srivastava, R. P., Sindelar, R. D., Scesney, S. M., and Marsh, H. C., Jr. (1995) Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors. J. Med. Chem. 38, 1437–1445.

    Article  PubMed  CAS  Google Scholar 

  298. Peake, P. W., Pussell, B. A., Martyn, P., Timmermans, V., and Charlesworth, J. A. (1991) The inhibitory effect of rosmarinic acid on complement involves the CS convertase. Int. J. Immunopharmacol. 13, 853–857.

    Article  PubMed  CAS  Google Scholar 

  299. Inagi, R., Miyata, T., Maeda, K., Sugiyama, S., Miyama, A., and Nakashima, I. (1991) FUT-175 as a potent inhibitor of C5/C3 convertase activity for production of C5a and C3a. Immunol. Lett. 27, 49–52.

    Article  PubMed  CAS  Google Scholar 

  300. Wang, Y., Rollins, S. A., Madri, J. A., and Matis, L. A. (1995) Anti-CS monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. Proc. Natl. Acad. Sci. USA 92, 8955–8959.

    Article  PubMed  CAS  Google Scholar 

  301. Wang, Y., Hu, Q., Madri, J. A., Rollins, S. A., Chodera, A., and Matis, L. A. (1996) Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc. Natl. Acad. Sci. USA 93, 8563–8568.

    Article  PubMed  CAS  Google Scholar 

  302. Evans, M. J., Rollins, S. A., Wolff, D. W., Rother, R. P., Norin, A. J., Therrien, D. M., Grijalva, G. A., Mueller, J. P., Nye, S. H., Squinto, S. P., et al. (1995) In vitro and in vivo inhibition of complement activity by a single-chain Fv fragment recognizing human C5. Mol. Immunol. 32, 1183–1195.

    Google Scholar 

  303. Gerard, C. and Gerard, N.P. (1994) CSA anaphylatoxin and its seven transmembrane-segment receptor. Annu. Rev. Immunol. 12, 775–808.

    Article  PubMed  CAS  Google Scholar 

  304. Ames, R. S., Li, Y., Sarau, H. M., Nuthulaganti, P., Foley, J. J., Ellis, C., Zeng, Z., Su, K., Jurewicz, A. J., Hertzberg, R. P., Bergsma, D. J., and Kumar, C. (1996) Molecular cloning and characterization of the human anaphylatoxin C3a receptor. J. Biol. Chem. 271, 20,231–20, 234.

    Google Scholar 

  305. Buhl, A. M., Avdi, N., Worthen, G. S., and Johnson, G. L. (1994) Mapping of the C5a receptor signal transduction network in human neutrophils. Proc. Natl. Acad. Sci. USA 91, 9190–9194.

    Article  PubMed  CAS  Google Scholar 

  306. Buhl, A. M., Osawa, S., and Johnson, G. L. (1995) Mitogen-activated protein kinase activation requires two signal inputs from the human anaphylatoxin C5a receptor. J. Biol. Chem. 270, 19,828–19, 832.

    Google Scholar 

  307. Gerard, N. P. and Gerard, C. (1991) The chemotactic receptor for human C5a anaphylatoxin. Nature 349, 614–617.

    Article  PubMed  CAS  Google Scholar 

  308. Buckley, T. L., Brain, S. D., Rampart, M., and Williams, T. J. (1991) Time-dependent synergistic interactions between the vasodilator neuropeptide, calcitonin gene-related peptide (CGRP) and mediators of inflammation. Br. J. Pharmacol. 103, 1515–1519.

    Article  PubMed  CAS  Google Scholar 

  309. Bozic, C. R., Lu, B., Hopken, U. E., Gerard, C., and Gerard, N. P. (1996) Neuro-genic amplification of immune complex inflammation. Science 273, 1722–1725.

    Article  PubMed  CAS  Google Scholar 

  310. Brain, S. D. and Williams, T. J. (1985) Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability. Br. J. Pharmacol. 86, 855–860.

    Article  PubMed  CAS  Google Scholar 

  311. Schupf, N. and Williams, C. A. (1987) Psychopharmacological activity of immune complexes in rat brain is complement dependent. J. Neuroimmunol. 13, 293–303.

    Article  PubMed  CAS  Google Scholar 

  312. Schupf, N., Williams, C. A., Berkman, A., Cattell, W. S., and Kerper, L. (1989) Binding specificity and presynaptic action of anaphylatoxin C5a in rat brain. Brain Behay. Immunol. 3, 28–38.

    Article  CAS  Google Scholar 

  313. Morgan, E. L., Ember, J. A., Sanderson, S. D., Scholz, W., Buchner, R., Ye, R. D., and Hugli, T. E. (1993) Anti-05a receptor antibodies. Characterization of neutralizing antibodies specific for a peptide, C5aR-(9–29), derived from the predicted amino-terminal sequence of the human C5a receptor. J. Immunol. 151, 377–388.

    PubMed  CAS  Google Scholar 

  314. Morgan, E. L., Sanderson, S., Scholz, W., Noonan, D. J., Weigle, W. O., and Hugh, T. E. (1992) Identification and characterization of the effector region within human C5a responsible for stimulation of IL-6 synthesis. J. Immunol. 148, 3937–3942.

    PubMed  CAS  Google Scholar 

  315. Scholz, W., McClurg, M. R., Cardenas, G. J., Smith, M., Noonan, D. J., Hugh, T. E., and Morgan, E. L. (1990) C5a-mediated release of interleukin 6 by human monocytes. Clin. Immunol. Immunopathol. 57, 297–307.

    Article  PubMed  CAS  Google Scholar 

  316. Carter, W. O. (1996) Ischemia/reperfusion animal models: the effects of C5 depletion. Controlling the Complement System for Novel Drug Development. International Business Communications, Southborough, MA.

    Google Scholar 

  317. Kawai, M., Quincy, D. A., Lane, B., Mollison, K. W., Luly, J. R., and Carter, G. W. (1991) Identification and synthesis of a receptor binding site of human anaphylatoxin C5a. J. Med. Chem. 34, 2068–2071.

    Article  PubMed  CAS  Google Scholar 

  318. Kawai, M., Quincy, D. A., Lane, B., Mollison, K. W., Or, Y. S., Luly, J. R., and Carter, G. W. (1992) Structure-function studies in a series of carboxyl-terminal octapeptide analogues of anaphylatoxin C5a. J. Med. Chem. 35, 220–223.

    Article  PubMed  CAS  Google Scholar 

  319. Kawatsu, R., Sanderson, S. D., Blanco, I., Kendall, N., Finch, A. M., Taylor, S. M., and Colcher, D. (1996) Conformationally biased analogs of human C5a mediate changes in vascular permeability. J. Pharmacol. Exp. Ther. 278, 432–440.

    PubMed  CAS  Google Scholar 

  320. Sanderson, S. D., Kirnarsky, L., Sherman, S. A., Vogen, S. M., Prakash, O., Ember, J. A., Finch, A. M., and Taylor, S. M. (1995) Decapeptide agonists of human C5a: the relationship between conformation and neutrophil response. J. Med. Chem. 38, 3669–3675.

    Article  PubMed  CAS  Google Scholar 

  321. Ember, J. A., Sanderson, S. D., Taylor, S. M., Kawahara, M., and Hugh, T. E. (1992) Biologic activity of synthetic analogues of C5a anaphylatoxin. J. Immunol. 148, 3165–3173.

    PubMed  CAS  Google Scholar 

  322. Konteatis, Z. D., Siciliano, S. J., Van Riper, G., Molineaux, C. J., Pandya, S., Fischer, P., Rosen, H., Mumford, R. A., and Springer, M. S. (1994) Development of C5a receptor antagonists. Differential loss of functional responses. J. Immunol. 153, 4200–4205.

    PubMed  CAS  Google Scholar 

  323. Lanza, T. J., Durette, P. L., Rollins, T., Siciliano, S., Cianciarulo, D. N., Kobayashi, S. V., Caldwell, C. G., Springer, M. S., and Hagmann, W. K. (1992) Substituted 4,6-diaminoquinolines as inhibitors of C5a receptor binding. J. Med. Chem. 35, 252–258.

    Article  PubMed  CAS  Google Scholar 

  324. Chen, S., Frederickson, R. C. A., and Brunden, K. R. (1996) Neuroglial-mediated immunoinflammatory responses in Alzheimer’s Disease: complement activation and therapeutic approaches. Neurobiol. Aging 17, 781–787.

    Article  PubMed  CAS  Google Scholar 

  325. Tenner, A. J., Velazquez, P., and Cribbs, D. H. (1996) Structural features of the complement activation domain of ß-amyloid. Soc. Neurosci. Abstracts 22, 487.

    Google Scholar 

  326. Iversen, L. L., Mortishire-Smith, R. J., M.-S., Pollack, S. J., and Shearman, M. S. (1995) The toxicity in vitro of ß-amyloid protein. Biochem. J. 311, 1–16.

    CAS  Google Scholar 

  327. Hays, S. J. (1996) Alzheimer’s disease and ß-amyloid: patent activity between May 1995 and July 1996. Exp. Opinion Ther. Patents 6, 1035–1046.

    Article  CAS  Google Scholar 

  328. LeVine, H. (1996) ß-amyloid as a therapeutic target in Alzheimer’s Disease. Alzheimers Disease ID Res. Alert 1, 1–7.

    Google Scholar 

  329. Emmerling, M. R., Roher, A. E., Kim, K. S., Spiegel, K., and Watson, M. D. (1997) Complement interactions with aggregated Aß1–42: a nidus for inflammation in Alzheimer brains. Keystone Symposium: Molecular Mechanisms in Alzheimer’s Disease. Keystone Conf., Feb. 1–6, Tamarron, CO.

    Google Scholar 

  330. Carter, D. B. and Chou, K. C. (1996) A model for structure dependent binding of congo red to Alzheimer ß-amyloid fibrils. Soc. Neurosci. Abstracts 22, 1171.

    Google Scholar 

  331. Breitner, J. C. (1996) The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease. Annu. Rev. Med. 47, 401–411.

    Article  PubMed  CAS  Google Scholar 

  332. Rogers, J. (1996) Inflammation and Alzheimer’s Disease pathogenesis. Neurobiol. Aging 17, 681–686.

    Article  PubMed  CAS  Google Scholar 

  333. Weissmann, G., Korchak, H., Ludewig, R., Edelson, H., Haines, K., Levin, R. I., Herman, R., Rider, L., Kimmel, S., and Abramson, S. (1987) Non-steroidal anti-inflammatory drugs: how do they work? Eur. J. Rheumatol. Inflamm. 8, 6–17.

    PubMed  CAS  Google Scholar 

  334. Werns, S. W. and Lucchesi, B. R. (1989) Myocardial ischemia and reperfusion: the role of oxygen radicals in tissue injury. Cardiovasc. Drugs Ther. 2, 761–769.

    Article  PubMed  CAS  Google Scholar 

  335. Sato, T., Ino, Y., Koshiyama, Y., Motoyoshi, A., Oda, M., and Iwaki, M. (1986) Inhibitory effects of a novel synthetic protease inhibitor, FUT-175, on the paw edema in rats and zymosan-induced complement activation in vitro. Jpn. J. Pharmacol. 42, 587–589.

    Article  PubMed  CAS  Google Scholar 

  336. Crowell, R. E. and Van Epps, D. E. (1990) Nonsteroidal antiinflammatory agents inhibit upregulation of CD11b, CD11c, and CD35 in neutrophils stimulated by formyl-methionine-leucine-phenylalanine. Inflammation 14, 163–171.

    Article  PubMed  CAS  Google Scholar 

  337. Reder, E. T., Thapar, M., Sapugay, A. M., and Jensen, M. A. (1994) Prostaglandins and inhibitors of arachidonate metabolism suppress experimetnal allergic encephalomyelitis. J. Neuroimmunol. 54, 117–127.

    Article  PubMed  CAS  Google Scholar 

  338. Aisen, P. S., Marin, D. B., and Davis, K. L. (1996) Inflammatory processes—antiinflammatory therapy, in Alzheimer’s Disease: from Molecular Biology to Therapy (Becker, R. and Giacobini, E., eds.), Birkhauser, Boston, pp. 349–353.

    Google Scholar 

  339. Aisen, P. S. and Davis, K. L. (1994) Inflammatory mechanisms in Alzheimer’s disease: implications for therapy. Am. J. Psychiatry 151, 1105–1113.

    PubMed  CAS  Google Scholar 

  340. Rothwell, N. J. and Strijbos, P. J. (1995) Cytokines in neurodegeneration and repair. Int. J. Dev. Neurosci. 13, 179–185.

    Article  PubMed  CAS  Google Scholar 

  341. Elford, P. R., Heng, R., Revesz, L., and MacKenzie, A. R. (1995) Reduction of inflammation and pyrexia in the rat by oral administration of SDZ 224–015, an inhibitor of the interleukin-10 converting enzyme. Br. J. Pharmacol. 115, 601–606.

    Article  PubMed  CAS  Google Scholar 

  342. Thornberry, N. A. and Molineaux, S. M. (1995) Interleukin-1ß converting enzyme: a novel cysteine protease required for IL-10 production and implicated in programmed cell death. Protein Sci. 4, 3–12.

    Article  PubMed  CAS  Google Scholar 

  343. Shiosake, K. and Puttfarcken, P. (1995) Emerging opportunities in neuroinflammatory mechanisms of neurodegeneration. Ann. Rep. Med. Chem. 30, 31–39.

    Article  Google Scholar 

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  1. Katharyn Spiegel
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  2. Mark R. Emmerling
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  3. Scott R. Barnum
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Spiegel, K., Emmerling, M.R., Barnum, S.R. (1998). Strategies for Inhibition of Complement Activation in the Treatment of Neurodegenerative Diseases. In: Wood, P.L. (eds) Neuroinflammation. Contemporary Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-473-3_5

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