Forschung - Publikationsliste
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Res Bull. 2003 Aug 15;61(3):321-6.
J Immunol 2003 Jan 15;170(2):1062-9 New loci regulating rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. Becanovic K, Wallstrom E, Kornek B, Glaser A, Broman KW, Dahlman I, Olofsson P, Holmdahl R, Luthman H, Lassmann H, Olsson T. Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4, 10, 15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 x PVG.1AV1) male/female F(2) population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1(av1) MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae16 on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms. J Neuropathol Exp Neurol 2003 Jan;62(1):25-33 Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. Aboul-Enein F, Rauschka H, Kornek B, Stadelmann C, Stefferl A, Bruck W, Lucchinetti C, Schmidbauer M, Jellinger K, Lassmann H. Destruction of myelin and oligodendrocytes leading to the formation of large demyelinated plaques is the hallmark of multiple sclerosis (MS) pathology. In a subset of MS patients termed pattern III, actively demyelinating lesions show preferential loss of myelin-associated glycoprotein (MAG) and apoptotic-like oligodendrocyte destruction, whereas other myelin proteins remain well preserved. MAG is located in the most distal periaxonal oligodendrocyte processes and primary "dying back" oligodendrogliopathy may be the initial step of myelin degeneration in pattern III lesions. In the present study, various human white matter pathologies, including acute and chronic white matter stroke, virus encephalitis, metabolic encephalopathy, and MS were studied. In addition to a subset of MS cases, a similar pattern of demyelination was found in some cases of virus encephalitis as well as in all lesions of acute white matter stroke. Brain white matter lesions presenting with MAG loss and apoptotic-like oligodendrocyte destruction, irrespective of their primary disease cause, revealed a prominent nuclear expression of hypoxia inducible factor-1alpha in various cell types, including oligodendrocytes. Our data suggest that a hypoxia-like tissue injury may play a pathogenetic role in a subset of inflammatory demyelinating brain lesions.
Neurology 2001 Sep 11;57(5):853-7
Apolipoprotein E epsilon 4 is associated with rapid progression of multiple
Fazekas F, Strasser-Fuchs S, Kollegger H, Berger T, Kristoferitsch W, Schmidt H,
Enzinger C, Schiefermeier M, Schwarz C, Kornek B, Reindl M, Huber K, Grass R,
Wimmer G, Vass K, Pfeiffer KH, Hartung HP, Schmidt R.
OBJECTIVE: The apolipoprotein E (APOE) polymorphism is known to impact on
various neurologic disorders and has differential effects on the immune system
and on CNS repair. Previous findings concerning a possible modulation of the
clinical course of MS have been inconsistent, however. METHODS: In a
cross-sectional study, the authors investigated 374 patients with clinically
definite MS and a disease duration of at least 3 years and related their
clinical and demographic findings to the allelic polymorphism of the APOE gene.
The genotype distribution of patients with MS was compared with a cohort of 389
asymptomatic, randomly selected elderly volunteers. RESULTS: The authors found
no significant differences in the distribution of genotypes between patients
with MS and controls. However, patients with MS with the epsilon4 allele (n =
85) had a significantly higher progression index of disability (0.46 +/- 0.4
versus 0.33 +/- 0.26; p < 0.004) and a worse ranked MS severity score (5.1 +/-
1.9 versus 5.7 +/- 1.7; p = 0.05) than their non-epsilon4 counterparts, despite
significantly more frequent long-term immunotherapy in epsilon4 carriers (74%
versus 58%; p < 0.007). The annual relapse rate in epsilon4 carriers (0.87 +/-
0.56) was significantly higher than in patients with MS without an epsilon4
allele (0.71 +/- 0.47; p = 0.03). CONCLUSIONS: These results suggest no effect
of the APOE genotype on susceptibility to MS, but indicate an association of the
APOE epsilon4 allele with a more severe course of the disease.
Immunogenetics 2001 Jul;53(5):410-5
Congenic mapping confirms a locus on rat chromosome 10 conferring strong
protection against myelin oligodendrocyte glycoprotein-induced experimental
Jagodic M, Kornek B, Weissert R, Lassmann H, Olsson T, Dahlman I.
Myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune
encephalomyelitis (EAE) in rats closely mimics the human disease multiple
sclerosis (MS). As in MS, genetic predisposition to MOG-EAE is regulated by both
MHC and non-MHC genes. Based on disease regulatory influences on MOG-EAE on
chromosome 10 in an F2 cross between susceptible DA and resistant ACI rats, we
have now isolated this locus in a congenic rat strain to enable further
dissection of disease mechanisms. This region is of particular interest, since
it is homologous to human 17q for which human whole-genome scans have indicated
harbors genes regulating susceptibility to MS. Phenotypic comparison between DA
and the congenic DA.ACI-D10Rat2-D10Rat29 strain confirms that the chromosomal
segment harbors gene(s) conferring strong protection against MOG-EAE.
Furthermore, resistance to EAE in this congenic strain is associated with
absence or a low level of inflammation and demyelination in the central nervous
system. Levels of anti-MOG antibody isotypes did not differ between parental and
congenic rats, thus an action on Th1/Th2 differentiation is unlikely. In
conclusion, this is the first example of an EAE-regulating locus isolated in a
congenic rat strain with retained phenotype. The mechanism by which gene(s) in
the region act is still unclear and will require further studies with this
congenic rat strain as a tool.
Brain 2001 Jun;124(Pt 6):1114-24
Distribution of a calcium channel subunit in dystrophic axons in multiple
sclerosis and experimental autoimmune encephalomyelitis.
Kornek B, Storch MK, Bauer J, Djamshidian A, Weissert R, Wallstroem E, Stefferl
A, Zimprich F, Olsson T, Linington C, Schmidbauer M, Lassmann H.
Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are
immune-mediated diseases of the CNS. They are characterized by widespread
inflammation, demyelination and a variable degree of axonal loss. Recent
magnetic resonance spectroscopy studies have indicated that axonal damage and
loss are a reliable correlate of permanent clinical disability. Accordingly,
neuropathological studies have confirmed the presence and timing of axonal
injury in multiple sclerosis lesions. The mechanisms of axonal degeneration,
however, are unclear. Since calcium influx may mediate axonal damage, we have
studied the distribution of the pore-forming subunit of neuronal (N)-type
voltage-gated calcium channels in the lesions of multiple sclerosis and EAE. We
found that alpha(1B), the pore-forming subunit of N-type calcium channels, was
accumulated within axons and axonal spheroids of actively demyelinating lesions.
The axonal staining pattern of alpha(1B) was comparable with that of
beta-amyloid precursor protein, which is an early and sensitive marker for
disturbance of axonal transport. Importantly, within these injured axons,
alpha(1B) was not only accumulated, but also integrated in the axoplasmic
membrane, as shown by immune electron microscopy on the EAE material. This
ectopic distribution of calcium channels in the axonal membrane may result in
increased calcium influx, contributing to axonal degeneration, possibly via the
activation of neutral proteases. Our data suggest that calcium influx through
voltage-dependent calcium channels is one possible candidate mechanism for
axonal degeneration in inflammatory demyelinating disorders.
Neuropediatrics 2001 Feb;32(1):28-37
Long-term MRI observations of childhood-onset relapsing-remitting multiple
Balassy C, Bernert G, Wober-Bingol C, Csapo B, Kornek B, Szeles J, Fleischmann
D, Prayer D.
PURPOSE: Long-term MRI follow-up of childhood-onset relapsing-remitting multiple
sclerosis (RRMS) was carried out in 4 cases. MRI findings were correlated with
clinical course and characteristic differences from adult-onset RRMS were
elaborated. METHODS: Two girls and one boy with true childhood-onset, and one
girl with juvenile-onset RRMS underwent 5-16 MRI examinations within 6-8 years.
The total number of lesions, the numbers of new, active, disappearing and
reappearing lesions, infratentorial and U-fibre lesions, "giant" plaques and
"black holes" were counted. Callosal atrophy and general brain atrophy were
assessed. The findings were related to the physical status according to the
Expanded Disability Status Scale (EDSS). RESULTS AND CONCLUSIONS: Results showed
that the primary differences in childhood-onset RRMS compared to adult-onset
RRMS lie in the lack of, or slower development of irreversible changes ("black
hole" formation, brain atrophy). Despite callosal atrophy and intensive U-fibre
region involvement, school performance was unchanged. Regarding the frequency of
"giant" lesions, an even more pronounced white matter involvement was found in
our children compared to adults. All children exhibited a rather "benign"
disease course. A more intensive remyelination, less severe neuronal loss, and
higher functional brain plasticity at younger ages may account for these
Am J Pathol 2000 Jul;157(1):267-76
Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative
quantitative study of axonal injury in active, inactive, and remyelinated
Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington
C, Schmidbauer M, Lassmann H.
Recent magnetic resonance (MR) studies of multiple sclerosis lesions indicate
that axonal injury is a major correlate of permanent clinical deficit. In the
present study we systematically quantified acute axonal injury, defined by
immunoreactivity for beta-amyloid-precursor-protein in dystrophic neurites, in
the central nervous system of 22 multiple sclerosis patients and 18 rats with
myelin-oligodendrocyte glycoprotein (MOG)-induced chronic autoimmune
encephalomyelitis (EAE). The highest incidence of acute axonal injury was found
during active demyelination, which was associated with axonal damage in
periplaque and in the normal appearing white matter of actively demyelinating
cases. In addition, low but significant axonal injury was also observed in
inactive demyelinated plaques. In contrast, no significant axonal damage was
found in remyelinated shadow plaques. The patterns of axonal pathology in
chronic active EAE were qualitatively and quantitatively similar to those found
in multiple sclerosis. Our studies confirm previous observations of axonal
destruction in multiple sclerosis lesions during active demyelination, but also
indicate that ongoing axonal damage in inactive lesions may significantly
contribute to the clinical progression of the disease. The results further
emphasize that MOG-induced EAE may serve as a suitable model for testing
axon-protective therapies in inflammatory demyelinating conditions.
Hum Mol Genet 1999 Nov;8(12):2183-90
Linkage analysis of myelin oligodendrocyte glycoprotein-induced experimental
autoimmune encephalomyelitis in the rat identifies a locus controlling
demyelination on chromosome 18.
Dahlman I, Wallstrom E, Weissert R, Storch M, Kornek B, Jacobsson L, Linington
C, Luthman H, Lassmann H, Olsson T.
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of
the central nervous system (CNS) with a complex etiology comprising a
genetically determined predisposition and a suspected auto- immune pathogenesis.
Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS, which
can be used to define susceptibility loci for autoimmune neuroinflammation. We
have recently established a chronic relapsing EAE model characterized by
inflammation and focal demyelination in the CNS by immunizing a variety of rat
strains with the CNS-specific myelin oligodendrocyte glycoprotein (MOG). This
model is more MS-like than any other rodent EAE model described up to now. Here
we present the first systematic genome search for chromosomal regions linked to
phenotypes of MOG-induced EAE in a (DA x ACI) F(2)intercross. A genome-wide
significant susceptibility locus linked to demyelination was identified on
chromosome 18. This region has not been described in inflammatory diseases
affecting other organs and the responsible gene or genes may thus be nervous
system specific. Other chromosomal regions showing suggestive linkage to
phenotypes of MOG-induced EAE were identified on chromosomes 10, 12 and 13. The
chromosome 10 and 12 regions have previously been linked to arthritis in DA
rats, suggesting that they harbour immunoregulatory genes controlling general
susceptibility to autoimmune diseases. We conclude that identification of
susceptibility genes for MOG-induced EAE on rat chromosomes 10, 12, 13 and 18
may disclose important disease pathways for chronic inflammatory demyelinating
diseases of the CNS such as MS.
Brain Pathol 1999 Oct;9(4):651-6
Axonal pathology in multiple sclerosis. A historical note.
Kornek B, Lassmann H.