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.


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