Blood Lymphocytes And Demyelination

The classic example of demyelination of the CNS is multiple sclerosis (MS), in which a chronic inflammatory lesion is characterised by a sharply demarcated plaque containing preserved axons denuded of myelin. Demyelination also occurs in infectious diseases such as progressive multifocal leucoencephalopathy and acute disseminated leucoencephalitis, but it is the disseminated focal form of MS that will be addressed in this review article.

Multiple sclerosis is often considered to be an immune-mediated disease because cellular and soluble components of the immune system are found within lesional areas, abnormal distributions of lymphocyte subsets, cytokines, and immunoglobu-lins occur in the blood and cerebrospinal fluid, and because it has pathological and clinical similarities to experimental allergic encephalomyelitis (see below). Com-promisation of the blood-brain barrier leads to an increased permeability that produces extensive local tissue oedema and passage of blood mononuclear leucocytes into the CNS.103 Such manifestations may result from an abnormal immune response initiated within the CNS or from a systemic immunoregulatory disturbance that permits the entry of autoreactive T cells directed against myelin antigens. At present it is unclear as to whether myelin loss is due to its "stripping" from the myelin sheath itself or dysfunction of myelin production by the oligodendrocyte.

4.4.1 Pathological Features of MS Lesions

Cellular plaques or lesions are distributed throughout the CNS and range in size from a few millimetres in diameter to confluent areas involving most of the cross section of the spinal cord, brain stem, or large areas of the cerebral hemispheres.104 The lesions usually encircle a venule or small vein and extend for considerable distances along the course of individual vessels.105 An early lesion appears as a perivascular area of hypercellularity with infiltrating lymphocytes and monocytes and activated microglia expressing MHC class II molecules.104 106 At this stage, there is no ingestion of myelin by phagocytic cells as judged by staining of conversion products (neutral lipids) with oil red-O (ORO). When demyelination occurs, the lesion is termed "active"; it develops centripetally and macrophages with internalised myelin debris acquire a characteristic "foamy" morphology. Activated lymphocytes and macrophages expressing MHC class II molecules abound in the lesion and they are often surrounded by deposits of immunoglobulins (including oligoclonal IgG) and complement. At the centre of the active lesion there is a loss of oligodendrocytes as the activated microglia and macrophages complete the phagocytosis of myelin debris. Even when the inflammation subsides, the peripheral rim of lesions retain MHC class II macrophages that are positive for ORO. The inactive lesion is comprised of a sharply demarcated area of demyelinated axons accompanied by local astrocytosis, little evidence of lipid destruction, and a few HLA-DR-positive macrophages and microglia.107

The majority of small lymphocytes in early MS lesions and in the hypercellular edge of plaques extending into normal white matter are CD4-positive T lympho-cytes.108-110 T lymphocytes of the CD8 phenotype are present in early lesions but this population predominates in later lesions.111 Examination of the distribution of T-lymphocyte subsets in MS plaques of different activity has led to the proposal that CD4-positive cells are responsible for the development and expansion of lesions, whilst the CD8-positive subset controls their local activity.110112

4.4.2 Experimental Allergic Encephalomyelitis (EAE)

Unravelling the contribution of T lymphocytes to the demyelinating process has benefited from the study of the animal model of MS: experimental allergic encephalomyelitis (EAE).113114 The model is induced by myelin proteins and their immunogenic peptides or by adoptive transfer of sensitized CD4-positive T lymphocytes to naive, syngeneic animals.115 Depending upon the species and strain of the animal, a monophasic, acute or spontaneous relapsing-remitting form of the disease is induced. Disease progression is inhibited by treatment with antibodies to MHC class II molecules,116 to CD4-positive cells,117 and by "vaccination" with disease-producing T lymphocytes.118

4.4.3 T Lymphocytes and Recognition of CNS Autoantigens

Organ-specific autoimmune diseases are triggered either by loss of self-tolerance to a tissue antigen or by sensitisation to self-antigen following an encounter with an infective microorganism (e.g., molecular mimicry and cross-reactivity, release of sequestered autoantigens, or T-cell activation by superantigens).119 Since T cells that recognise myelin-specific proteins (e.g., myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein) circulate in MS patients and healthy subjects, it appears that lymphocytes which recognise CNS autoantigens belong to the "normal" T-cell repertoire.120 In MS blood there is an increased prevalence of myelin-specific CD4-positive lymphocytes121 which, upon entering the CNS, could be activated by myelin products released as a consequence of CNS inflammation, viral infection, or by the recognition of epitopes common to pathogens and autoantigens.122 Sequence homology exists between myelin proteins and several viruses,123 124 but T lymphocytes that recognise both viral and myelin epitopes have yet to be demonstrated. Lymphocyte reactivity against myelin proteins is often confined to selective immunodominant determinants in EAE,119 and shifts in epitope recognition by clones of T cells in MS could contribute to the relapsing-remitting phase of the disease.

The T-cell receptor (TCR) binds antigen in association with an MHC class II molecule. Extensive heterogenicity exists in the structure of such receptors on different lymphocytes so as to accommodate the vast array of potential antigens that the immune system is capable of recognising. In T lymphocytes that infiltrate the CNS of animals with EAE, there is considerable conservation of the genes (known as V region genes) that encode for the specific regions of the ap TCR suggesting that they might be reactive against CNS antigens. Indeed, EAE is inhibited by the administration of antibodies directed against TCR VP variable sequences125 and by DNA vaccines encoding variable regions of the TCR.126 However, evidence for restricted V region gene usage in MS is controversial127 128 despite the beneficial application of specific TCR blocking peptides to patients with this disease.129

Regardless of antigen specificity, it is activated lymphocytes that cross the blood-brain barrier, but only T lymphocytes that recognise CNS antigens persist in the parenchyma and induce inflammation.130 An increase in the number of lymphocytes entering the CNS, therefore, is more likely to depend upon activation events in the periphery rather than infection and injury in the brain. Demyelination may arise from the direct or indirect activity of T lymphocytes. Multiple sclerosis plaques in areas of acute demyelination131 and at margins of chronic lesions132 contain T cells which express y§ TCRs. These unusual T cells recognise peptides of prokaryotic origin including heat shock proteins and attack and destroy oligodendrocytes in vitro.133 Oligodendrocytes are also susceptible to "bystandef damage during T-cell-mediated reactions within the local microenvironment. Cultured oligodendrocytes are lysed by T-lymphocyte-derived TNF-P134 (also known as lymphotoxin), and by perforins, produced by activated cytotoxic T cells.135 The generation of pore formation by perforins leads to intracellular calcium influx and cell death that resembles the cytopathic effects of the membrane attack complex of complement.136 These observations suggest that it is the oligodendrocyte rather than the myelin sheath which is particularly susceptible to T-lymphocyte-mediated damage.

4.4.4 T Lymphocytes, Cytokines, and Macrophages

Recognition of neuroantigens by sensitised T lymphocytes within the CNS could result in the release of cytokines and the activation of resident cells such as microglia which then induce demyelination. Based upon the profile of secretory cytokines, CD4-positive lymphocytes are subdivided into the TH1 and TH2 populations. Cyto-kines characteristic of TH1 cells include IL-2, IFN-y, TNF-P, and hence these cells are deemed to be proinflammatory. Interleukin 2 is vital for the survival of activated T cells, IFN-y enhances the phagocytic, cytotoxic, and antigen-presenting properties of macrophages and microglia,137 and TFN-a lyses oligodendrocytes,138 induces demyelination in vivo139 and, at the level of the blood-brain barrier, it may recruit and activate leucocytes. All three cytokines are readily identifiable within inflammatory cell infiltrates in MS lesions140 and it is the TH1 cells that are responsible for the passive transfer of EAE.141 On the other hand, TH2 cells secrete TGF-0 and interleukin 10 (IL-10) and are assigned an antiinflammatory function. Interleukin 10 impairs indirectly the activities of TH1 cells,142 TGF-0 promotes the healing phase of inflammation,143 and both suppress the proinflammatory activities of macrophages.144145 Disease remission in EAE is associated with an expansion of TH2 cells146 and an inability to switch from a predominantly TH1 to TH2 response may underlie the demyelinating events of EAE. No doubt, information will shortly be forthcoming concerning the distribution and function of TH1 and TH2 cells in MS.

Macrophage-mediated demyelination is implicated in both early and late MS lesions. The initial stages of myelin destruction are rapid147 and the oligodendrocyte or myelin sheath or both may be targeted in the primary disease process.148 Macrophages are held responsible for the majority of demyelination by releasing toxic factors such as TNF-a, proteinases, free radicals, and nitric oxide.149 150 The cells appear to lyse and then internalise myelin lamellae around myelinated axons until they become engorged with myelin debris.115 This debris becomes attached to clathi-rin-coated pits on the macrophage surface before internalisation in a process termed "receptor-mediated phagocytosis."151

In summary, considerable evidence implicates the T lymphocyte as occupying a pivotal role in the pathogenesis of demyelination in MS. Following recognition of myelin antigens, it is most likely that these cells release cytokines which trigger a cascade of events that results in leucocyte extravasation, activation of infiltrating inflammatory cells and resident macrophages, and loss of myelin. As the lesion ages, recruitment of y§ T cells could result in further myelin destruction. It is therefore understandable that considerable efforts are in progress to devise methods that will antagonise either the entry of T lymphocytes across the blood-brain barrier or their recognition of myelin antigens.

references

1. Widner, H. and Brundin, P., Immunological aspects of neural grafting in the mammalian central nervous system. A review and speculative synthesis, Brain Res., 472, 287, 1988.

2. Doherty, P. C., Allan, J. E., Lynch, F. E., and Ceredig, R., Dissection of an inflammatory process induced by CD8+ T cells, Immunol. Today, 11, 55, 1990.

3. Wekerle, H., Linington, C., Lassmann, H., and Meyermann, R., Cellular immune reactivity within the CNS, Trends Neurosci., 9, 271, 1986.

4. Adams, J. H. and Graham, D. I., The nervous system, in Muir's Textbook of Pathology, 13th ed., McSween, R. N. M. and Whaley, K., Eds., Edward Arnold, London, 1992, 817.

5. Hallenbeck, J. M. and Dutka, A. J., Background review and current concepts of reperfusion injury, Arch. Neurol., 47, 1245, 1990.

6. Granger, D. N. and Kvietys, P. R., Leukocyte-endothelial cell adhesion induced by ischaemia and reperfusion, Can. J. Physiol. Pharmacol., 71, 61, 1993.

Suzuki, S., Kelley, R. E., Reyes-Iglesias, Y., Alfonso, V. M., and Dietrich, W. D., Cerebrospinal fluid and peripheral white blood cell response to acute cerebral ischaemia, South. Med. J., 88, 819, 1995.

Hallenbeck, J. M., Dutka, A. J., Tanishima, T., Kochanek, P. M., Kumaroo, K. K., Thompson, C. B., Obrenovitch, T. P., and Contreras, T. J., Polymorphonuclear leucocyte accumulation in brain regions with low blood flow during the early post ischaemic period, Stroke, 17, 246, 1986.

Matsuo, Y., Onodera, H., Shiga, Y., Nakomura, M., Ninomija, M., Kihora, T., and Kogure, K., Correlation between myeloperoxidase-quantified neutrophil accumulation and ischaemic brain injury in the rat, Stroke, 25, 1469, 1994. Shiga, Y., Onodera, H., Kogure, K., Yamasaki, Y., Yashima, Y., Syozuhara, H., and Sendo, F., Neutrophil as a mediator of ischaemic oedema formation in the brain, Neurosci. Lett., 125, 110, 1991.

Hayward, N. J., Elliott, P. J., Sawyer, S. D., Bronson, R. T., and Bartus, R. T., Lack of evidence for neutrophil participation during infarct formation following focal cerebral ischaemia in the rat, Exp. Neurol., 139, 188, 1996. Jiang, N., Moyle, M., Soule, H. R., Rote, W. E., and Chopp, M., Neutrophil inhibitory factor is neuroprotective after focal ischaemia in rats, Ann. Neurol., 38, 935, 1995. Del Zoppo, G., Schmid-Schonbein, G., Mori, E., Copeland, B. C., and Chang, C., Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons, Stroke, 22, 1276, 1991. Schmid-Schonbein, G. and Engler, R., Granulocytes as active participators in acute myocardial ischaemia and infarction, Am. J. Cardiovasc. Pathol., 1, 15, 1986. Springer, T. A., Traffic signals for lymphocyte recirculation and leucocyte emigration: the multistep paradigm, Cell, 76, 301, 1994.

Bevilacqua, M. P., Endothelial-leucocyte adhesion molecules, Annu. Rev. Immunol., 11, 767, 1993.

Okada, Y., Copeland, B. R., More, E., Tung, M.-M., Thomas, W. S., and del Zoppo, G. J., P-selectin and intercellular adhesion molecule-1 expression after focal brain ischaemia and reperfusion, Stroke, 25, 202, 1994.

Matsuo, Y., Onodera, H., Shiga, Y., Shozuhara, H., Ninomiya, M., Kihara, T., Tama-tani, T., Miyasaka, M., and Kogure, K., Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat, Brain Res., 656, 344, 1994.

Wang, X., Siren, A. L., Liu, Y., Yue, T.-L., Barone, F. C., and Feuerstein, G. Z., Upregulation of intercellular adhesion molecule 1 (ICAM-1) on brain microvascular endothelial cells in rat ischaemic cortex, Brain Res. Mol. Brain Res., 26, 61, 1994. Liu, T., Clark, R. K., McDonnel, P. C., Young, P. R., White, R. F., Barone, F. C., and Fenerstein, G. Z., Tumour necrosis factor-alpha expression in ischemic neurons, Stroke, 25, 1481, 1994.

Wang, X., Yue, T.-L., Young, P. R., Barone, F. C., and Feuerstein, G. Z., Expression of interleukin-6, c-fos and zif268 mRNAs in rat ischaemic cortex, J. Cereb. Blood Flow Metab., 15, 166, 1995.

Hess, D. C., Zhao, W., Carroll, J., McEachin, M., and Buchanan, K., Increased expression of ICAM-1 during reoxygenation in brain endothelial cells, Stroke, 25, 1463, 1994.

Wang, X., Yue, T.-L., Barone, F. C., and Feuerstein, G. Z., Demonstration of increased endothelial-leukocyte adhesion molecule-1 mRNA expression in rat ischaemic cortex, Stroke, 26, 1665, 1995.

Barkalow, F. J., Goodman, M. J., and Mayadas, T. N., Cultured murine cerebral microvascular endothelial cells contain von Willebrand factor-positive Weibel-Palade bodies and support rapid cytokine-induced neutrophil adhesion, Microcirculation, 3, 19, 1996.

Chen, H., Chopp, M., Zhang, R. L., Bodzin, G., Chen, Q., Rusche, J. R., and Todd, R. F., III, Anti-CD11b monoclonal antibody reduces ischaemic cell damage after transient focal cerebral ischaemia in rat, Ann. Neurol., 35, 458, 1994. Lindsberg, P. J., Siren, A. L., Feuerstein, G. Z., and Hallenbeck, J. M., Antagonism of neutrophil adherence in the deteriorating stroke model in rabbits, J. Neurosurg., 82, 269, 1995.

Bowes, M. P., Zivin, J. A., and Rothlein, R., Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model, Exp. Neurol., 119, 215, 1993.

Zhang, R. L., Chapp, M., Jiang, N., Tang, W. X., Prostak, J., Manning, A. M., and Anderson, D. C., Anti-intercellular adhesion molecule-1 antibody reduces ischaemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat, Stroke, 26, 1438, 1995.

Connolly, E. S., Jr., Winfree, C. J., Springer, T. A., Naka, Y., Liao, H., Yan, S. D., Stern, D. M., Solomon, R. A., Gutierrez-Ramons, J. C., and Pinsky, D. J., Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke, J. Clin. Invest., 97, 209, 1996.

Seko, Y., Enokawa, Y., Nakao, T., Yagita, H., Okumura, K., and Yazaki, Y., Reduction of rat myocardial ischaemia/reperfusion injury by a synthetic selectin oligopeptide, J. Pathol., 178, 335, 1996.

Murohara, T., Margiotta, J., Phillips, L. M., Paulson, J. C., DeFres, S., Zalipsky, S., Guo, L. S., and Lefer, A. M., Cardioprotection by liposome-conjugated sialyl Lewis x-oligosaccharide in myocardial ischaemia and reperfusion injury, Cardiovasc. Res., 30, 965, 1995.

Feuerstein, G. Z. and Barone, F. C., Editorial comment, Stroke, 26, 1443, 1995. Buttini, M., Sauter, A., and Boddeke, H. W., Induction of interleukin-1 beta mRNA after focal cerebral ischaemia in the rat, Mol. Brain Res., 23, 126, 1994. Yamasaki, Y., Matsuura, N., Shozuhara, H., Itoyama, Y., and Kogure, K., Interleukin-1 as a pathogenic mediator of ischaemic brain damage in rats, Stroke, 26, 676, 1995. Loddick, S. A. and Rothwell, N. J., Neuroprotective effects of human recombinant interleukin-1 receptor antagonist on focal cerebral ischaemia in the rat, J. Cereb. Blood Flow Metab., 16, 932, 1996.

Yamasaki, Y., Matsuo, Y., Matsuura, N., Onodera, H., Itoyama, Y., and Kogure, K., Transient increase of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, in ischaemic brain areas after focal ischaemia in rats, Stroke, 26, 318, 1995.

Lindsberg, P. J., Hallenbeck, J. M., and Feuerstein, G., Platelet-activating factor in stroke and brain injury, Ann. Neurol., 30, 117, 1991.

Barone, F. C., Hillegass, L. M., Tzimas, M. N., Schmidt, D. B., Foley, J. J., White, R. F., Price, W. J., Feuerstein, G. Z., Clark, R. K., Griswold, D. E., et al., Time-related changes in myeloperoxidase activity and leukotriene B4 receptor binding reflect leucocyte influx in cerebral focal stroke, Mol. Chem. Neuropathol., 24, 13, 1995. Bell, M. D., Taub, D. D., and Perry, V. H., Overriding ME brains intrinsic resistance to leucocyte recruitment with intraparenchymal injections of recombinant chemo-kines, Neuroscience, 74(l), 285-292, 1996.

Bell, M. D., Taub, D. D., and Perry, V. H., Overriding the brain's intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemo-kines, Neuroscience, 74, 1, 1996.

Tani, M., Fuentes, M. E., Peterson, J. W., Trapp, B. D., Durham, S. K., Loy, J. K., Bravo, R., Ransohoff, R. M., and Lira, S. A., Neutrophil infiltration, glial reaction and neurological disease in transgenic mice expressing the chemokine N51/KC in oligodendrocytes, J. Clin. Invest., 98, 529, 1996.

Sacks, T., Moldow, C. F., Craddock, P. R., Bowers, T. K., and Jacob, H. A., Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes, J. Clin. Invest., 61, 1161, 1978.

Martin, W. J., Neutrophils kill pulmonary endothelial cells by a hydrogen peroxide-dependent pathway. An in vitro model of neutrophil-mediated injury, Am. Rev. Respir. Dis., 68, 1394, 1981.

Weiss, S. J., Young, J., Lobuglio, F., Slivka, A., and Nimeh, N. F., Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells, J. Clin. Invest., 68, 714, 1978.

Steinbeck, M. J., Khan, A. U., and Karnovsky, M. J., Intracellular singlet oxygen generation by phagocytosing neutrophils in response to particles coated with a chemical trap, J. Biol. Chem, 267, 13425, 1992.

Noris, M., Ruggenenti, P., Todeschini, M., Figliuzzi, M., Macconi, D., Zoja, C., Gaspari, F., and Remuzzi, G., Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury, Am. J. Kidney Dis., 27, 790, 1996.

Iadecola, C., Zhang, F., Zu, S., Casey, R., and Ross, M. E., Inducible nitric oxide synthase gene expression in brain following cerebral ischaemia, J. Cereb. Blood Flow Metab., 15, 378, 1995.

Clark, R. S., Kochanek, P. M., Schwarz, M. A., Schiding, J. K., Turner, D. S., Chen, M., Carlos, T. M., and Watkins, S. C., Inducible nitric oxide synthase expression in cerebrovascular smooth muscle and neutrophils after traumatic brain injury in immature rats, Paediatr. Res., 39, 784, 1996.

Pryor, W. A., and Squadrito, G. L., The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide, Am. J. Physiol., 268, L699, 1995. Zhang, F., Zu, S., and Iadecola, C., Time dependence of nitric oxide synthase inhibition on cerebral ischaemic damage, J. Cereb. Blood Flow Metab., 15, 595, 1995. Iadecola, C., Zhang, F., and Zu, S., Inhibition of inducible nitric oxide synthase ameliorates cerebral ischaemic damage, Am. J. Physiol., 268, R286, 1995. Riesenberg, K., Schlaeffer, F., Katz, A., and Levy, R., Inhibition of superoxide production in human neutrophils by combinations of heparin and thrombolytic agents, Br. Heart J, 73, 14, 1995.

Janoff, A., Elastase in tissue injury, Annu. Rev. Med., 36, 207, 1985. Matsumara, T., Kugiyama, K., Sugiyama, S., Ohgushi, M., Amanaka, K., Suzuki, M., and Yasua, H., Neutral endopeptidase 24.11 in neutrophils modulates protective effects of natriuretic peptides against neutrophil-induced endothelial cytotoxicity, J. Clin. Invest., 97, 2192, 1996.

Rodell, T. C., Cheronis, J. C., Ohnemus, C. L., Piermattei, D. J., and Repine, J. E., Xanthine oxidase mediates elastase induced injury to isolated lungs and endothelium, J. Appl. Physiol., 63, 2159, 1987.

Ginsburg, I., Gibbs, D. F., Schuger, L., Johnson, K. J., Ryan, U.S., Ward, P. A., and Varani, J., Vascular endothelial cell killing by combination of membrane-active agents and hydrogen peroxide, Free Radicals Biol. Med., 7, 369, 1989.

57. Varani, J., Ginsburg, I., Schuger, L., Gibbs, D. F., Bromberg, J., Johnson, K. J., Ryan, U. S., and Ward, P. A., Endothelial cell killing by neutrophils: synergistic interaction of oxygen products and proteases, Am. J. Pathol., 135, 435, 1989.

58. Perry, V. H. and Simon, G., Macrophages and microglia in the nervous system, Trends Neurosci., 11, 237, 1988.

59. Lassmann, H., Zimprich, F., Vass, K., and Hickey, W. F., Microglial cells are a component of the perivascular glia limitans, J. Neurol. Sci. Res., 28, 236, 1990.

60. Perry, V. H. and Gordon, S., Macrophages and the nervous system, Int. Rev. Cytol., 125, 203, 1991.

61. Dickson, D. W., Sunkee, D. L, Mattiace, L. A., Yen, S. H. C., and Brosnan, C., Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease, Glia, 7, 75, 1993.

62. McGeer, P. L., Kawamata, T., Walker, D. G., Akiyama, H., Tooyama, I., and McGeer, E. G., Microglia in degenerative neurological disease, Glia, 7, 84, 1993.

63. Andersson, P.-B., Perry, V. H., and Gordon, S., The acute inflammatory response to lipopolysaccharide in CNS parenchymas differs from that in other body tissues, Neuroscience, 42, 169, 1992.

64. Leibovich, S. J. and Ross, R., The role of the macrophage in normal repair, Am. J. Pathol., 78, 71, 1975.

65. Guilian, D., Chen, J., Ingeman, J. E., George, J. K., and Nopomen, M., The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain, J. Neurosci., 9, 4416, 1989.

66. Gehrmann, J., Shoen, S. W., and Kreutzberg, G. W., Lesion of the rat entorhinal cortex leads to a rapid microglial reaction in the deafferented dentate gyrus. A light and electron microscopical study, Acta Neuropathol., 82, 442, 1991.

67. Gehrmann, J., Bonnekoh, P., Miyazawa, T., Hossmann, K.-A., and Kreutzberg, G. W., Immunocytochemical study of an early microglial activation in ischemia, J. Cereb. Blood Flow Metab., 12, 257, 1992.

68. Gehrmann, J., Monaco, S., and Kreutzberg, G. W., Spinal cord microglia and DRG satellite cells rapidly respond to transection of the rat sciatic nerve, Restor. Neurol. Neurosci., 2, 181, 1991.

69. Gehrmann, J., Gold, R., Linigton, C., Lannes-Vieira, J., Wekerle, H., and Kreutzberg, G. W., The microglial involvement in experimental autoimmune inflammation of the central and peripheral nervous system, Glia, 7, 50, 1993.

70. Lotan, M. and Schwartz, M., Cross talk between the immune system and the nervous system in response to injury: implications for regeneration, FASEB J., 8, 1026, 1994.

71. Lunn, E. R., Perry, V. H., Brown, M. C., Rosen, H., and Gordon, S., Absence of Wallerian degeneration does not hinder regeneration in peripheral nerve, Eur. J. Neurosci., 1, 27, 1989.

72. Rappolee, D. A., Mark, D., Banda, M. J., and Werb, Z., Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping, Science, 241, 708, 1989.

73. Shimojo, M., Nakajima, K., Takei, N., Hamanoue, M., and Kohsaka, S., Production of basic fibroblast growth factor in cultured brain microglia, Neurosci. Lett., 123, 229, 1991.

74. Elkabes, S., Di Cicco-Bloom, E. M., and Black, I. B., Brain microglia macrophages express neutrophils that selectively regulate microglial proliferation and function, J. Neurosci., 16, 2508, 1996.

75. Raivich, G., Gehrmann, J., and Kreutzberg, G. W., Increase of macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor receptors in the regenerating rat facial nucleus, J. Neurosci. Res., 30, 682, 1991.

76. Suzumura, A., Sawada, M., Tanouchi, R., and Yamomoto, H., Proliferation of microglia by IL-4, Neuroimmunology, 1, 122, 1993.

77. Suzumura, A., Sawada, M., Yamomoto, H., and Marunouchi, T., Effect of colony stimulating factors on isolated microglia in vitro, J. Neuroimmunol., 30, 111, 1990.

78. Guilian, D. and Ingeman, J. E., Colony-stimulating factors as promoters of ameboid microglia, J. Neurosci., 8, 4707, 1988.

79. Guilian, D., Baker, T. J., Shih, L. N., and Luckman, L. B., IL-1 of the central nervous system is produced by ameboid microglia, J. Exp. Med., 164, 594, 1986.

80. Woodroofe, M. N., Sarna, G. S., Wadhwa, M., Hayes, G. M., Loughlin, A. J., Tinker, A., and Cuzner, M. L., Detection of IL-1 and IL-6 in adult rat brain following mechanical injury in vitro microdialysis. Evidence of a role for microglia in cytokine production, J. Neuroimmunol., 33, 227, 1991.

81. Guilian, D., Woodward, J., Young, D. G., Krebs, J. F., and Lachman, L. F., Interleu-kin-1 injected into mammalian brain stimulates astrogliosis and neovascularization, J. Neurosci., 8, 2485, 1988.

82. Loughlin, A. J., Woodroofe, M. N., and Cuzner, M. L., Regulation of Fc receptor and major histocompatibility complex antigen expression on isolated rat microglia by tumour necrosis factor, interleukin-1 and lipopolysaccharide: effects on interferon-gamma induced activation, Immunology, 75, 170, 1992.

83. Hayes, G. M., Woodroofe, M. N., and Cuzner, M. L., Characterization of microglia isolated from adult human and rat brain, J. Neuroimmunol., 19, 177, 1988.

84. Pow, D. V., Perry, V. H., Morris, J. F., and Gordon, S., Microglia in the neurohypophysis associate with and endocytose terminal portions of neurosecreting neurons, Neuroscience, 33, 567, 1989.

85. Akiyama, H., Itagaki, S., and McGeer, P. L., Major histocompatibility antigen expression on rat microglia following epidural kainic acid lesions, J. Neurosci. Res., 20, 147, 1988.

86. Kiefer, R., Lindholm, D., and Kreutzberg, G. W., Interleukin-6 and transforming growth factor-P1 mRNAs are induced in the rat facial nucleus following motoneuron axotomy, Eur. J. Neurosci., 5, 775, 1993.

87. Frei, K., Siepl, C., Groscusth, P., Bodmer, S., Schwardel, C., and Fontana, A., Antigen presentation of tumour cytotoxicity by interferon-y-treated microglial cells, Eur. J. Immunol., 17, 1271, 1987.

88. Woodroofe, M. N., Hayes, G. M., and Cuzner, M. L., Fc receptor density, MHC antigen expression and superoxide production are increased in interferon-gamma-treated microglia isolated from adult rat brain, Immunology, 68, 421, 1989.

89. Frei, K., Siepl, C., Groscurth, P., Bodmer, S., and Fontana, A., Immunology of microglial cells, Ann. N.Y. Acad. Sci., 540, 218, 1988.

90. Montgomery, D. L., Astrocytes: form, functions and roles in disease. (Review), Vet. Pathol., 31, 145, 1994.

91. Banati, R. B., Gehrmann, J., Schubert, P., and Kreutzberg, G. W., Cytotoxicity of microglia, Glia, 7, 111, 1993.

92. Zielasek, J., Tausch, M., Toyka, K. W., and Hartung, H. P., Production of nitrite by neonatal rat microglial cells/brain macrophages, Cell. Immunol., 141, 111, 1992.

93. Colton, C. A., Microglial oxyradical production: causes and consequences, Neuro-pathol. Appl. Neurobiol., 20, 208, 1994.

Wisniewski, H. M., Bancher, C., Barcikowska, M., Gen, G. Y., and Currie, J., Spectrum of morphological appearance of amyloid deposits in Alzheimer's disease, Acta Neuropathol., 78, 337, 1989.

McGeer, P. L., Kawamata, T., Walker, D. G., Akiyama, H., Tooyama, I., and McGeer, E. G., Microglia in degenerative neurological disease, Glia, 7, 84, 1993. Prineas, J. W., Kwan, E. E., Cho, E. S., and Sharer, L. R., Continual breakdown and regeneration of myelin in progressive multiple sclerosis, Ann. N.Y. Acad. Sci., 436, 11, 1984.

Zajicek, J. P., Wing, M., Scolding, N. J., and Compston, D. A. S., Interactions between oligodendrocytes and microglia: a major role for complement and tumour necrosis factor in oligodendrocyte adherence and killing, Brain, 115, 1611, 1992. Guilian, D., Vacq, K., and Corpuz, M., Brain glia release factors with opposing actions upon muronal survival, J. Neurosci., 13, 29, 1993.

Vass, K., Lassmann, H., Wekerle, M., and Wisniewski, H. M., The distribution of Ia antigens in the lesions of rat acute experimental allergic encephalomyelitis, Acta Neuropathol., 70, 149, 1986.

Hayes, G. M., Woodroofe, M. N., and Cuzner, M. L., Microglia are the major cell type expressing MHC class II in human white matter, J. Neurol. Sci., 80, 25, 1987. Huitinga, I., van Rooijen, N., de Groot, C. J. A., Vitalehagg, B. M. J., and Dijkstra, C. D., Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages, J. Exp. Med., 172, 1025, 1990.

Streit, W. J., Graeber, M. B., and Kreutzberg, G. W., Functional plasticity of microglia: a review, Glia, 1, 301, 1988.

Adams, C. W. M., Pathology of multiple sclerosis. Progression of the lesion, Br. Med. Bull., 33, 15, 1977.

Adams, C. W. M., The general pathology of multiple sclerosis: morphological and chemical aspects of the lesion, in Multiple Sclerosis: Pathology, Diagnosis and Management, Hallpike, J. F., Adams, C. W. M., and Tourtellotte, W. W., Eds., Chapman and Hall, London, 1983, 205.

Adams, C. W. M, Poston, R. N., Buck, S. J., Sikhu, Y. S., and Vipand, H., Inflammatory vasculitis in multiple sclerosis, J. Neurol. Sci., 69, 269, 1985. Compston, D. A. S., Neurological Disease, in Immunology in Medicine, 2nd ed., Holborow, E. J. and Reeves, W. G., Eds., Academic Press, New York, 1983, 467. Prineas, J. W., Kwan, E., Goldenberg, P. Z., et al., Multiple sclerosis: oligodendrocyte proliferation and differentiation on fresh lesions, Lab. Invest., 61, 489, 1989. Brinkman, C. J., ter Loak, H. J., Hommer, O. R., Poppema, S., and Delmotti, P., T-lymphocyte subpopulations in multiple sclerosis lesions, N. Engl. J. Med., 307, 1644, 1982.

Nyland, H., Matre, R., Mark, S., Bjerke, J.-R., and Naess, A., T-lymphocyte subpopulations in multiple sclerosis lesions, N. Engl. J. Med., 307, 1643, 1982. Traugott, U., Reinherz, E. L., and Raine, C. S., Multiple sclerosis: distribution of T cells, T cell subsets and Ia-positive macrophages in lesions of different ages, J. Neuroimmunol., 4, 201, 1983.

Booss, J., Esiri, M. M., Tourtellotte, W. W., and Mason, D. Y., Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis, J. Neurol. Sci., 62, 219, 1983.

McCallum, K., Esiri, M., Tourtellotte, W. W., and Booss, J., T cell subset in multiple sclerosis gradient at plaque borders and differences in non-plaque regions, Brain, 110, 1297, 1987.

Brown, A., McFarlin, D. E., and Raine, C. S., The chronologic neuropathology of relapsing experimental allergic encephalomyelitis in the mouse, Lab. Invest., 46, 171, 1982. Traugott, U., McFarlin, D. E., and Raine, C. S., Immunopathology of the lesion in chronic relapsing experimental autoimmune encephalomyelitis in the mouse, Cell. Immunol., 99, 395, 1986.

Raine, C. S., Biology of disease. The analysis of autoimmune demyelination: its impact upon multiple sclerosis, Lab. Invest., 50, 608, 1984.

Steinman, L., Rosenbaum, J., Sriram, S., and McDevitt, H. O., In vivo effects of antibodies to immune response gene products. Prevention of experimental allergic encephalomyelitis, Proc. Natl. Acad. Sci. U.S.A., 78, 7111, 1981. Brostoff, S. W. and Mason, D. W., Experimental allergic encephalomyelitis: successful treatment in vivo with a monoclonal antibody that recognises T helper cells, J. Immunol., 133, 1938, 1984.

Ben-Nun, A., Wekerle, H., and Cohen, I. R., Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein, Nature, 293, 60, 1981.

Miller, S. D., McRae, B. L., Vanderlugt, C. L., et al., Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases, Immunol. Rev., 144, 225, 1995.

Wucherpfennig, K. W., Weiner, H. L., and Hafler, D. A., T cell recognition of myelin basic protein, Immunol. Today, 12, 277, 1991.

Martin, R., McFarland, H. F., and McFarlin, D. E., Immunological aspects of demyelinating diseases, Annu. Rev. Immunol., 10, 153, 1992.

Wisniewski, H. M., Immunopathology of demyelination in autoimmune diseases and virus infections, Br. Med. Bull., 33, 54, 1977.

Fujinama, R. S., and Oldstone, M. B. A., Amino acid homology between the enceph-alitogenic site of myelin basic protein and virus: mechanism for autoimmunity, Science, 230, 1043, 1985.

Shaw, S. Y., Lawson, R. A., and Lees, M. B., Analagous amino acid sequence in myelin proteolipid and viral proteins, FEBS Lett., 207, 266, 1986. Tuohy, V. K., Fritz, R. B., and Ben-Nun, A., Self determinants in autoimmune demyelinating disease: changes in T-cell response specificity, Curr. Opin. Immunol., 6, 887, 1994.

Waisman, A., Ruiz, P. J., Hirschberg, D. L., et al., Suppressive vaccination with DNA

encoding a variable region gene of the T cell receptor prevents autoimmune enceph-

alomyelitis and activates Th2 immunity, Nat. Med., 2, 899, 1996.

Wilson, D. B., Steinman, L., and Gold, D. P., The V-region disease hypothesis: new evidence suggests it is probably wrong, Immunol. Today, 14, 376, 1993.

Utz, U. and McFarland, H. F., The role of T cells in multiple sclerosis: implications for therapies targeting the T cell receptor, J. Neuropathol. Exp. Neurol., 53, 351, 1994.

Vandenbark, A. A., Chou, Y K., Whitham, R., et al., Treatment of multiple sclerosis with

T-cell receptor peptides: results of a double-blind pilot trial, Nat. Med., 2, 1109, 1996.

Hickey, W. I., Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation, Brain Pathol., 1, 97, 1991.

Birnbaum, G., Stress proteins: their role in the normal central nervous system and in disease states, especially multiple sclerosis, Springer Semin. Immunopathol., 17, 107,

1995.

Bernard, C. C. A. and de Rosbo, N. K., Multiple sclerosis: an autoimmune disease of multifactorial aetiology, Curr. Opin. Immunol., 4, 760, 1992.

Selmaj, K., Brosnan, C. F., and Raine, C. S., Colocalisation of lymphocytes bearing gd T-cell receptor and hsp 65+ oligodendrocytes in multiple sclerosis, Proc. Natl. Acad. Sci. U.S.A., 88, 6452, 1991.

Selmaj, K. W., and Raine, C. S., Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro, Ann. Neurol., 23, 339, 1988.

Rook, G., Cell-mediated immune reactions, in Immunology, 3rd ed., Roitt, E., Brostoff, J., and Male, D., Eds., C. V. Mosby, London, 1993, chap. 8. Scolding, N. J., Morgan, B. P., Campbell, A. K., and Compston, D. A., Complement mediated serum cytotoxicity against oligodendrocytes: a comparison with other cells of the oligodendrocyte-type 2 astrocyte lineage, J. Neurol. Sci., 97, 155, 1990. Loughlin, A. J., Woodroofe, M. N., and Cuzner, M. L., Modulation of interferon-gamma-induced major histocompatibility complex class-II and Fc-receptor expression on isolated microglia by transforming growth-factor-beta-1, interleukin-4, nora-drenaline and glucocorticoids, Immunology, 79, 125, 1993.

Merrill, J. E., Kono, D. H., Clayton, J., Ando, D. G., Hinton, D. R., and Hofman, F. M., Inflammatory leukocytes and cytokines in the peptide-induced disease of experimental allergic encephalomyelitis in SJL and B10.PL mice, Proc. Natl. Acad. Sci. U.S.A., 89, 574, 1992.

Opdenakker, G. and Van Damme, J., Cytokine-regulated proteases in autoimmune diseases, Immunol. Today, 15, 103, 1994.

Hofman, F. M., Hinton, D. R., Johnson, K., and Merrill, J. E., Tumour necrosis factor identified in multiple sclerosis brain, J. Exp. Med., 170, 607, 1989. Renno, T., Zeine, R., Girard, J. M., Gillani, S., Dodelet, V., and Owens, T., Selective enrichment of Th1 CD45 RB low CD4+ T cells in autoimmune infiltrates in experimental allergic encephalomyelitis, Int. Immunol., 6, 347, 1994. Mosmann, T. R., Properties and functions of interleukin-10, Adv. Immunol., 56, 1, 1994.

Massague, J., The transforming growth factor-P family, Annu. Rev. Cell Biol., 6, 597, 1990.

Powrie, F. and Coffmann, R. L., Cytokine regulation of T cell function: potential for therapeutic intervention, Trends Pharmacol. Sci., 14, 164, 1993.

Cuzner, M. L. and Smith, T., Immune responses in the central nervous system in inflammatory demyelinating disease, in Immune Response in the Nervous System,

Rothwell, N. J., Ed., BIOS Scientific Publishers, London, 1995.

Kennedy, M. K., Torrance, D. S., Picha, K. S., and Mohler, K. M., Analysis of cytok-

ine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery, J. Immunol., 149, 2496, 1992.

Raine, C. S., Multiple sclerosis: a pivotal role for the T cell in lesion development, Neuropathol. Appl. Neurobiol., 17, 265, 1991.

Allen, I. and Kirk, J., Demyelinating diseases, in Greenfield's Neuropathology, 5th ed., Adams, H. J. and Duchen, L. W., Eds., Edward Arnold, London, 1992, 447. Brosnan, C. F., Cammer, W., Norton, W. T., and Bloom, B. R., Proteinase inhibitors suppress the development of experimental allergic encephalomyelitis, Nature, 285, 235, 1980.

Merrill, J. E., Ignarro, L. J., Sherman, M. P., Melinek, J., and Lane, T. E., Microglial cell toxicity of oligodendrocytes is mediated through nitric oxide, J. Immunol., 151, 2132, 1993.

Prineas, J. W. and Connell, F., The fine structure of chronically active multiple sclerosis plaques, Neurology, 28, 68, 1978.

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