Anales de Neurología y Neurocirugía
Número 78, 14 de Dic. de 2009
Noticia adicional
NEUROLOGY: -Gray-matter injury in multiple sclerosis
Such findings have led to the perception that multiple sclerosis is a demyelinating disease affecting the white matter. In the past 25 years, many magnetic resonance imaging (MRI) studies have shown lesions scattered through the white matter.
These lesions develop at disease onset and accumulate over time. However, white-matter lesions, quantified by various MRI techniques, correlate weakly with neurologic disability.
This paradox may be at least partly explained by demyelinating lesions and neuronal disease in the cerebral cortex and deep gray matter.1
Unfortunately, lesions in the gray matter cannot be detected with the use of standard image-acquisition sequences on MRI in living patients or by visual inspection of brains on postmortem examination; this further solidifies the perception of multiple sclerosis as a white-matter disease.
However, longitudinal studies involving patients with multiple sclerosis have shown accelerated rates of gray-matter atrophy — one consequence of gray-matter lesions.
Early in the disease, gray-matter atrophy proceeds 3 times faster in affected patients than in unaffected persons, and with progressive neurologic disability, this rate of atrophy increases to 14 times faster in affected patients than in unaffected persons.2,3
Gray-matter atrophy correlates with physical disability and cognitive disability more strongly than white-matter atrophy.4
However, much remains to be clarified regarding gray-matter disease in multiple sclerosis, including its mechanism or mechanisms, the elucidation of which depends both on the development of sensitive imaging markers that allow the visualization and quantitation of gray-matter lesions and on the validation of biologic markers for gray-matter disease.
A recent article by Derfuss and colleagues5 is therefore welcome. The investigators used an unbiased approach to identify glycoprotein autoantigens in patients with multiple sclerosis.
This approach led to the discovery that certain patients with multiple sclerosis have autoantibodies and type 1 helper T (Th1) and type 17 helper T (Th17) cells in the cerebrospinal fluid or serum that recognize contactin 2, the rat orthologue of which is called transiently expressed axonal glycoprotein 1 (TAG-1).
In human adults, contactin 2 is expressed in specialized regions of myelinated fibers by oligodendrocytes, Schwann cells, and the axons of a subpopulation of neurons, including those in the hippocampus and spinal cord; this distribution is consistent with the hypothesis that an autoimmune response to contactin 2 mediates the destruction of myelin, axons, and neurons in multiple sclerosis.
To test this hypothesis, Derfuss et al. transferred TAG-1–specific T cells into rats.
A mild form of experimental allergic encephalomyelitis, an autoimmune disease affecting the central nervous system, subsequently developed in these animals.
Derfuss et al. observed inflammation of gray-matter blood vessels, a finding that was absent in classic models of experimental allergic encephalomyelitis induced with myelin proteins.
The investigators then tested a "two-hit" model of experimental allergic encephalomyelitis in rats by administering antibodies against a protein of myelin — myelin oligodendrocyte glycoprotein — after the administration of the TAG-1–specific T cells.
(Antibodies against the myelin oligodendrocyte glycoprotein have been detected in lesions of patients with multiple sclerosis.) They observed widespread demyelination in both white and gray matter.
These findings suggest a mechanism for cortical demyelination in multiple sclerosis. Three types of demyelinating lesions have been described in the cortex of brains of patients with multiple sclerosis on postmortem examination (Figure 1).1
Pattern I lesions involve both white and gray matter.
Pattern II lesions are small perivascular areas of cortical demyelination.
Pattern III lesions are bands of cortical demyelination below the pial surface that often cover several gyri and stop at cortical layer three or four.
There has been much speculation that the pattern III lesions are related to immune follicles in the subarachnoid space.
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Figure 1. Model of Lesion Formation in Multiple Sclerosis.
Demyelinating lesions in the cerebral cortex in patients with multiple sclerosis occur in three patterns, but how they arise is not known.1 Derfuss and colleagues5 recently described a model whereby two separate pathogenic "hits" — an activation hit and a demyelination hit — trigger the pathologic process. In pattern I and pattern II lesions (Panels A through D), the activation hit may be caused by circulating contactin-2–reactive T cells. These cells activate cortical central nervous system vasculature, permitting circulating antimyelin antibodies to gain access. The antimyelin antibodies mediate the demyelination hit, causing cortical demyelination. In pattern III lesions (Panels E through H), contactin-2–reactive T cells within lymphoid follicles in the subarachnoid space mediate the activation hit, permitting antimyelin antibodies originating within the subarachnoid space to gain access. These antimyelin antibodies mediate the demyelination hit. Panels C and D are enlarged images of the boxed area in Panel A, and Panels G and H are enlarged images of the boxed area in Panel E.
On the basis of their data, Derfuss et al. proposed a two-hit model (Figure 1) consistent with these observations.The model posits that immune-mediated inflammation targeted at contactin 2 on or near gray-matter endothelial cells opens the blood–brain barrier or alters endothelial cells in the gray matter, permitting effectors of demyelination (such as antibodies to myelin proteins) to gain access to gray matter.
This model is consistent with the finding that most gray-matter demyelinating lesions are disconnected from foci of white-matter demyelination and with the observation that conditions exist in which gray-matter inflammation occurs in the absence of demyelination.
Future studies should focus on the two-hit model of cortical disease, on the development of sensitive biologic and imaging markers of the process (contactin 2 may turn out to be one such marker), and ultimately, on therapeutic approaches that target gray-matter disease.
Dr. Rudick reports receiving grant support from Biogen Idec, consulting fees from Biogen Idec, Genzyme-Bayer, Millennium Pharmaceuticals, Novartis, and Wyeth Pharmaceuticals, and lecture fees from Biogen Idec and Teva Neuroscience; and Dr. Trapp, grant support from Merck Serono and Vertex Pharmaceuticals, consulting fees from Biogen Idec and Pfizer, and lecture fees from Biogen Idec and Teva Neuroscience.
No other potential conflict of interest relevant to this article was reported.
NEJM Volume 361:1505-1506 October 8, 2009 Number 15
Richard A. Rudick, M.D., and Bruce D. Trapp, Ph.D.
http://content.nejm.org/cgi/content/full/361/15/1505
http://www.e-medicum.com/noticiasDelDia/verNoticia.php?noticia=84213
