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From Basic Immunology to Immune-Mediated Demyelination
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There was a problem with saving your item s for later. You can go to cart and save for later there. Average rating: 0 out of 5 stars, based on 0 reviews Write a review. Gianvito Martino. Tell us if something is incorrect. Add to Cart. Free delivery. Linkage with genetic loci was compared for 23 published autoimmune or immune-mediated diseases after genome-wide scans had been performed. The majority of the human positive linkages map nonrandomly into 18 distinct clusters, supporting the hypothesis that, in some cases, clinically distinct autoimmune diseases may be controlled by a common set of susceptibility genes Furthermore, whereas MS patients may have the same susceptibility genes as other patients suffering from different autoimmune diseases, tissue specific genetic factors probably determine which organ is affected in the disease.
Computational genomic sequence comparison be-tween various species can identify plausible regulatory elements, which besides coding sequences might play an important role in autoimmunity Future studies on the genetic influence on MS will have to resolve the question of disease heterogeneity An infectious etiology of MS has been indicated by epidemiological studies as well as by similarities to infectious demyelinating diseases.
Immunology of MS
However, infectious agents more likely shape the immune response against self-antigens and may induce disease under special circumstances, rather than implicating a single virus in the case of MS Epidemiological studies have correlated viral infections with exacerbation of MS and have shown that disease prevalence increases with latitude. Migration before puberty from low-prevalence areas to high-prevalence areas results in a higher risk to develop disease A role of infectious agents is further supported by the analysis of MS epidemics: MS was absent from the Faroe Islands located in the North Atlantic until World War II when first cases were described and linked to the arrival of the British troops Viral demyelinating diseases provide examples on how a viral infection may cause demyelination.
In JC virus-induced progressive multifocal leukoencephalopathy PML , demyelination is caused by a viral infection and direct damage of oligodendrocytes 5. A recent neuropathological analysis of MS lesions has shown a demyelination pattern that appears to be induced primarily by a functional disturbance of oligodendrocytes. The authors hypothesize that it might be the result of infection with an unknown virus or damage mediated by an unknown toxin 4.
In subacute sclerosing panencephalitis SSPE , virus-infected oligodendrocytes are subject to immune-mediated damage. In postinfectious demyelinating encephalomyelitis, erupting 10 to 40 days following an infection with measles, varicella or vaccinia virus, demyelination is most likely caused by a virus-induced immune response against myelin An association between HHV-6, a beta herpesvirus with a seroprevalence of 72 to percent in healthy adults worldwide, and MS has been suggested by the demonstration of viral antigen in oligodendrocytes of MS white matter lesion but not in control brain Furthermore, MS patients have been shown recently to have an increased lymphoproliferative response to HHV-6A lysate 24 and elevated antibody titer to HSV-6 antigens in serum and CSF compared with unaffected brains Over the years, several reports have demonstrated increased virus-specific proliferative response in MS patients compared with controls.
One must use caution interpreting these data, and additional molecular, serological, and cellular immune response studies are necessary to clarify the role of HHV-6 in MS.
Besides a direct role in CNS damage during demyelinating diseases, infectious agents may shape the immune response against self-antigens and may induce disease under special circumstances: MBP-specific T cells can be found in the CSF during postmeasles encephalomyelitis, rubella panencephalitis, and chronic CNS Lyme disease 27, Target cells might be damaged as innocent bystanders by the ongoing immune process.
Alternatively, infectious agents may trigger an autoimmune response by the infection of target tissues e.
The latter involves reactivity of T and B cells with either peptides or antigenic determinants shared by infectious agents and myelin antigens. If a T cell recognizes a self-antigen at intermediate levels of affinity in the thymic environment, it will not be deleted; i. Autoimmune T cells may be activated by cross-reactive foreign antigens, cross the blood-brain barrier BBB , infiltrate the CNS, and mediate pathological and clinical damage Complete sequence homology between self-peptide and foreign peptide is not required for molecular mimicry. Single amino acid substitutions in each position of the sequence may be tolerated, cause a reduction or abolition in the response, or generate a superagonist peptide that can be even more potent stimulator of T cell clone functions Molecular mimicry is therefore influenced by HLA genes, and individuals bearing the susceptibility-associated HLA alleles may be more prone to pathogen-induced autoimmunity Different patterns of demyelination in active MS lesions have been shown, suggesting that the targets myelin or oligodendrocytes and mechanisms of injury are probably distinct in different subgroups of MS patients and at different stages of disease development.
These different patterns might reflect different pathogenetic mechanisms of demyelination 4. In particular, after an encounter with foreign antigens, T cells undergo clonal expansion and change from naive to effector phenotype up-regulating costimulatory and adhesion proteins: lymphocyte function-associated LFA antigen-1 and very late activation VLA -4 molecule that facilitate adhesion to the endothelial cells EC layer.
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A recent EAE study has shown that, promptly after injection, the freshly stimulated T cells down-regulate their activation markers, up-regulate a set of chemokine receptors, and increase MHC class II molecules on their surface. Upon arrival in the CNS, the T effector cells are reactivated following an encounter of the autoantigen presented by local antigen-presenting cells Cytokines, chemokines, and their receptors play an important role in MS IL, produced by antigen-presenting cells, is necessary for developing Th1 response, and IL knockout mice are completely resistant to EAE Chemokines seem to be expressed in the brain secondarily to the initial phase of cell infiltration A parallel enrichment in chemokine receptor-bearing cells in the intrathecal compartment has been reported by the same authors.
Inflammatory responses, occurring in parallel and involving negative and positive feedback, are directed against the autoantigen, presumably a component of myelin or oligodendrocytes, and result in demyelination that leads to the development of clinical symptoms. While less prominent than demyelination, loss of axons in MS is well described and is important in determining clinical disability 44, Neuropathologic and imaging studies have recently provided evidence for axonal damage even in the early stages of disease.
PDF From Basic Immunology to Immune-Mediated Demyelination (Topics in Neuroscience)
Axonal loss, detectable in areas of normal-appearing white matter, probably is due to Wallerian degeneration of axons transected in the demyelinating lesions During neurologic disorders associated with neuronal damage, protein increases in the CSF. In a recent study, the detection of protein in the CSF, at the first neurologic event suggestive of MS, was associated with conversion to a clinically definite disease in a shorter time Although evidence exists to support an immunologic function for astrocytes and microglia in CNS inflammation , the specific role of each cell type in the pathogenesis of MS lesion remains a subject of debate The inflammation of MS subsequently subsides, at least in most cases, and is paralleled by clinical stabilization.
Animal data show that most of the inflammatory cells in the MS plaque undergo apoptosis, whereas other authors have suggested that immunoregulatory cells contribute appreciably to the resolution of inflammation. Resting T cells express low levels of Fas. Following activation via the antigen receptor of the T cells, the expression of Fas increases within hours and the cells undergo apoptosis in response to the FasL present on other activated T cells.
FasL expression has been demonstrated on astrocytes and neurons, and it has been suggested that they may form an immunologic brain barrier, limiting cell invasion during the relapse. Elevated production of soluble CD95 in RRMS patients, compared with healthy controls, might interfere with CDmediated apoptosis and thus limit ongoing immune response However, both mutually interacting cellular and humoral immune components may contribute to immune-mediated demyelination.
The first hint to an important contribution of humoral factor to inflammatory demyelination in EAE came from the observation that sera from animals affected with EAE displayed demyelinating activity in vitro The importance of the humoral component is further supported by the observation that myelin oligodendrocyte glycoprotein MOG -specific antibodies enhance clinical severity of EAE and dramatically augment demyelination Furthermore, in the common marmoset Callithrix jacchus EAE model, autoantibodies against MOG are responsible for the disintegration of myelin sheaths.
Many EAE models lack the early demyelination in the lesions, while this model has a prominent MS-like demyelinating component 6. A large percentage of MS patients is positive for antibodies against an imunodominant MBP peptide 62 , which is also recognized by MBP-specific T cells derived from HLA-DR2 positive patients, suggesting that sustained antibody responses may be driven by T cells.
The antibody response against MOG, a surface-exposed myelin component, is best characterized and has been implicated most convincingly in demyelination 6. Elevated antibody titers against a variety of antigens have been described, including myelin components, oligodendrocyte proteins, viruses, cell nuclei, endothelial cells, fatty acids, gangliosides, and axolemma From a large pathology sample of MS biopsies and autopsies, four different patterns of demyelination were found: one of these pattern II was distinguished from the others by a pronounced Ig reactivity associated with degenerating myelin at the active plaque edge and complement C9neo deposition, suggesting an important role of antibodies 4.
Recently, oligodendrocyte precursors have been identified as possible targets of the humoral immune response in some MS patients: an immune attack toward these cells with major remyelinating capacity could compromise repair mechanisms in MS Intrathecally synthesized oligoclonal IgG or "oligoclonal bands" are present in 95 percent of MS patients throughout the disease.