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Autoimmune neurologic disorders occur
when immunologic tolerance to myelin and other neurologic antigens of
the schwann cell, the axon and the motor or ganglioside neuron are
lost. The resulting demyelinating dieases share the pathologic
features of destruction of myelin, accompanied by an inflammatory
infiltration in the brain, spinal cord, or the optic nerve. Based on
the location of the lesions, the occurrence of relapses, and the
nature of events, it is possible to separate the clinical neurologic
syndromes of multiple sclerosis, acute disseminated encephalomyelitis,
acute transverse myelitis, and optic neuritis.
The most common demyelinating disease
is multiple sclerosis. Multiple sclerosis (MS) is a disease of the
myelin central nervous system (CNS) that is clinically characterized
by episodes of neurologic dysfunction separated by time and space.
Pathologically, multiple sclerosis may be diagnosed by measuring the
infiltration of monocytes helper T-cells demyelination, as well as the
measurement of antibody levels against myelin basic protein (MBP),
myelin oligodendrocyte glycoprotein (MOG) and α-β
crystallin. The striking appearance of inflammatory cells in the
brain, spinal cord, and cerebrospinal fluid in MS patients further
indicates that an attack against the immune system, directed at some
components of CNS myelin, is central to the pathogenesis of MS.
The hallmark of the MS lesion is the
plaque, an area of demyelination sharply demarcated from the usual
white matter shown in MRI scans. The histologic appearance of the
plaques varies in different stages of the disease. In active lesions,
the blood-brain barrier is damaged, thereby permitting extravasation
of serum proteins into the extra cellular space. Inflammatory cells
can be seen in perivascular cuffs and throughout the white matter.
Activated monocytes derived macrophages and activated lymphocytes
predominate. CD4 T-cells, especiallyT-helper-1 (but not CD8 cells)
accumulate around postcapillary venules at the edge of the plaque and
are also scattered in the white matter. In active lesions,
up-regulation of adhesion molecules and markers of lymphocyte and
monocyte activation, such as IL2-R and CD26,have also been observed.
Demyelination inactive lesions is not accompanied by destruction of
oligodendrocytes. In contrast, in the chronic phase of the disease,
the lesions are characterized by the loss of oligodendrocytes and
hence, the presence of MOG antibodies in the blood. T-cells bearing
the γ-δ T-cell receptor are found in MS lesions and may be
involved in the selective destruction of oligodendrocytes. The γ-δ
T-cells are reacting with heat shock proteins (HSP65), such as α-β
crystallin, which may be found in oligodendrocytes under stressful
conditions. This particular re-action of γ-δ T-cells with
oligodendrocytes results in selective cellular destruction, the
re-lease of α-β crystallin into circulation, the
presentation of macrophages and T-cells, and the production of
specific antibodies against MOGand α-β crystallin.
The activated helper T-cells that are
CD45RA(phenotype associated with memory or activated T-cells)
accumulate in the brain and spinal cord of MS sufferers. These
findings imply that activated T-cells, activated monocytes/macrophages
and their cytokines have a special role in the pathogenesis of the
disease. Activated T-helper cells release interleukin-2,interferon-γ
and lymphotoxins, while monocytes release tumor necrosis factor-α
(TNF-α). The monocytes are primed by T-cell-de-rived interferon-γ
to release TNF-α. TNF-α and lymphotoxins have been reported
to be injurious to myelin and oligodendrocytes. In-deed, it can be
said that lymphotoxins or TNF-β can cause apoptosis of cultured
oligodenrocytes. Thus, the liberation of toxic cytokines by monocytes
and T-helper-1 cells, coupled with macrophage activation with re-lease
of free radicals, may ultimately culminate in the destruction of
myelin in MS.
The role of Th1/Th2 cytokines,
microglia and astrocytes in regulating immune responses and the
development of neuropathologies.
T-helper-1 (Th1) and Th2 cells can be
redefined as polarized forms of immune responses that not only
represent a useful model for under-standing the pathogenesis of
several diseases, but also one that can provide the basis for the
development of immunotherapeautic strategies. Mechanisms that regulate
the balance ofTh1 and Th2 cells, such as cytokines, are of great
interest because they can determine the outcome of the disease. For
example,interleukin-12 (IL-12) promotes the development of Th1 cells,
whereas IL-4 leads to the expansion of Th2 cells. In CNS inflammation,
it has been shown that there might be a balance between microglia and
astrocytes in regulating local immune reactions, including Th1/TH2
responses.
Figure 9 - Regulation of Th1/Th2
Responses by the Balance or Imbalance Between Microglia and Astrocytes
in Demyelinating Processes
As shown in the figure, microglia
produces IL-12, which primarily promotes the development of Th1 cells.
Astrocytes cannot produce IL-12and induce mainly Th2-cell responses,
there by representing important homeostatic mechanisms during recovery
from Th1-mediated inflammation.
The capacity of microglia and
astrocytes to stimulate Th1 and Th2 cells depends on their surface
molecules, such as MHC class II, B7and CD40. MHC class II-positive
microglia directly induce encephalitogenic myelin basic protein
(MBP)-reactive CD4+ T-cells to pro-duce interferon-y (IFN-y) and TNF-α in vivo. After treatment with
IFN-y and/or bacterial antigens
(LPS), microglia express CD40, which contributes to Th1 activation.
Th1 cells can stimulate microglia to
produce prostaglandin E2 (PGE2), which provides a negative feedback
mechanism for downregulation of Th1-cell responses within the CNS.
During antigen presentation within the CNS,IFN-y secreted by
activated microglia and Th1cells can induce astrocytes to secrete PGE2
and contribute to the downregulation of microgliaand Th1-cell
responses.
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