Franz Benninger
&
Andreas Karwautz aktualisierten  diese Seite letztmalig am 08.11.2010

Forschung - Publikationsliste

Publikationsliste nach Themen gereiht (zur Übersicht):  

G35

Encephalitis disseminata

Brain Res Bull. 2003 Aug 15;61(3):321-6. 
Neuropathology of multiple sclerosis-new concepts.
Kornek B, Lassmann H.
Multiple sclerosis is a chronic inflammatory disease of the central nervous
system with profound heterogeneity in clinical course, neuroradiological
presentation and response to therapy. The pathological analysis of 235 actively
demyelinating lesions coming from three centers revealed different structural
and immunological features suggesting that different pathogenetic mechanisms are
involved in lesion formation. On the basis of the presence or absence of
immunoglobulin and complement deposition, myelin protein loss and the patterns
of oligodendrocyte degeneration beside a T cell- and macrophage-dominated immune
response, four distinct patterns of demyelination have been identified. In this
short review, possible paraclinical markers for tissue destruction on the basis
of the main features of myelin destruction are discussed. Furthermore, the
importance of early axonal damage in multiple sclerosis is highlighted.

Neuropediatrics. 2003 Jun;34(3):120-6. 
Glatiramer acetate treatment in patients with childhood and juvenile onset
multiple sclerosis.
Kornek B, Bernert G, Balassy C, Geldner J, Prayer D, Feucht M.
Recent data indicate that in multiple sclerosis disease onset before
the age of 16 is more common than previously assumed. However, current
therapeutic options are limited to the treatment of acute attacks in these
patients. Glatiramer acetate has been successfully applied in adults with
relapsing-remitting multiple sclerosis, but there are no data available about
the use of glatiramer acetate in childhood and juvenile onset multiple
sclerosis.
Seven patients with relapsing-remitting multiple sclerosis
and disease onset between 9 and 16 years of age were treated with daily
subcutaneous injection of 20 mg glatiramer acetate (Copaxone). Patients were
followed for 24 months. Treatment was initiated in all patients before the age
of 18. 
The use of glatiramer acetate in our cohort of early onset
multiple sclerosis patients was safe and well tolerated. Two out of seven
patients remained relapse-free during the two year period. Clinical disability
as measured by the EDSS remained stable in three out of seven patients. Due to the small number of patients the efficacy of the treatment has to be interpreted with caution. However, there might be a more pronounced treatment benefit in patients with low disability at treatment initiation and early treatment onset.

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

sclerosis.

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

autoimmune encephalomyelitis.

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

sclerosis.

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

differences.

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

lesions.

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.

zur Übersicht