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Multiple sclerosis Classification revisited reveals homogeneity and recapitulation.

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EDITORIALS
Multiple Sclerosis: Classification Revisited
Reveals Homogeneity and Recapitulation
Classifying the multiple sclerosis (MS) lesion, the
subject of this editorial highlighting Breij and colleagues’1 article in this issue of Annals, has proved
something of a contentious topic over recent years.
Not entirely surprising for a disease such as MS with
its wide-ranging clinical and pathological phenotype,
a single predominant disease mechanism has not yet
emerged. Although few would query the compelling
evidence for an immune-mediated pathogenesis,2 precisely how the various players of the immune system
contribute to the pathognomonic established MS
plaque remains an enigma. It is widely held that the
initial lesion in MS follows a systemic infection that
causes proinflammatory cytokines to be released into
the general circulation, leading to upregulation of
adhesion-related molecules on central nervous system
(CNS) endothelium and homing of leukocytes to
CNS vasculature, which traverse vessels to enter the
normally sequestered CNS. Should lymphocytes programmed to recognize myelin antigens be present in
the infiltrate, then the stage is set for the formation of
an acute, inflammatory demyelinating lesion. This
hypothetical scenario, supported by immunopathological reports on MS plus convincing data from animal models, is believed to underlie the MS plaque,
which has traditionally and didactically been presented as developing in a spectrum of acute and
chronic stages, matched clinically by exacerbations
and remissions. However, recognizing the current
consensus that lesion pathogenesis in MS may be heterogeneous, any proposal suggesting that lesions develop in a uniform, linear fashion is likely to invite
merited criticism.
In the late 1990s, followers of the above spectrum
concept were challenged by a series of insightful communications from the laboratories of Lucchinetti
and colleagues, who took on the formidable task of
rearranging MS lesions according to perceived underlying pathological mechanisms, as opposed to stages.
The beginning reclassification strategy centered not
on immunopathogenesis per se but on the response of
the myelinating cell, the oligodendrocyte. In their
first article, published in 1996, these investigators
were able to discriminate among five lesional
types based on oligodendrocyte loss.3 In 1998, there
followed one review further analyzing these five lesion
subtypes and the associated oligodendrocyte pathology,4 and a second review that mentioned “at least five
different subtypes,”5 implying the possibility of more.
Then in 1999, a careful morphometric analysis of oligodendrocytes in lesions from 113 cases of MS appeared in which two lesion groups (further divided
into five subtypes) were identified: one showing presence and the other absence of oligodendrocyte recruitment.6 Retrospectively, and given the enormity
of the task, the authors deserve considerable credit for
even attempting to bring order to a lesion as complex
as the MS plaque. Nevertheless, the above classification systems appear not to have served their purpose
because in 2000, the same authors, approaching the
problem from a different standpoint, presented the
heterogeneic MS lesion as a collection of lesion types
defined not by oligodendrocyte-related changes as before, but by distinct pathogenetic mechanisms.7 In
this much-quoted, important article, 4 lesion types
(patterns) were identified from paraffin blocks from
81 cases of MS (32 autopsy, 49 biopsy), displaying
short disease duration and active demyelination. Remarkably, lesion patterns were stated to be heterogeneous between patient subgroups but homogeneous
in different lesions from the same patient. The four
patterns were segregated according to their being mediated by T cells and macrophages alone (pattern I),
immunoglobulin (Ig) and complement (pattern II),
apoptosis of oligodendrocytes and absence of Ig, complement and remyelination (pattern III), and oligodendrocyte dystrophy and no remyelination (pattern
IV). This article marshaled a number of previously
published mechanisms deemed relevant to the acute
MS lesion. Reiterated in numerous reviews spawned
since 2000 (eg, Lassmann and colleagues8 –11), the
four-pattern system still awaits confirmation; although without highly comparable clinical material,
this promises to be difficult. Probably the most one
might expect in the foreseeable future will be that selected facets of the four-pattern dogma will be reappraised separately.
In this latter regard, this issue of Annals hosts an
article by Breij and colleagues,1 a group with a long
and respectable track record in MS, who have examined pathogenetic events in inflammatory, actively demyelinating lesions from a series of 27 cases of established MS and as control subjects, inflammatory,
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
1
nondemyelinating, or inactive lesion areas from another 12 cases. Magnetic resonance imaging–guided
sampling of lesions was employed, and the classification strategy and technologies applied previously7
were followed carefully. Additional markers for
complement, Fc receptors, human leukocyte antigen
D related, fibrinogen, and hypoxia inducible
factor-1␣ were tested, and frozen sections were incorporated for more precise localization of immune
system molecules. In contrast with the earlier study
on fulminant cases of short duration, 7 Breij and
colleagues 1 investigated to what extent the fourpattern criteria translated to active lesions from patients with established MS (mean duration, 22.2
years).
To this reader, Breij and colleagues’1 study appears
meticulously executed. Lesion heterogeneity was carefully scrutinized, and several parameters key to the
four-pattern system, namely, localization and role of
IgG and complement, preferential loss of myelinassociated glycoprotein, occurrence of oligodendrocyte apoptosis, and hypoxia-like damage, were diligently weighed. Made abundantly clear from the
current results was that active chronic lesions exhibited consistent association with deposition of Ig
and complement on macrophages, a feature equating
with pattern II in the previous study.7 Moreover,
oligodendrocyte apoptosis, a key determinant for patterns III and IV,7 was absent or rare. Likewise,
hypoxia-like damage to oligodendrocytes, a criterion
added later to the four-pattern system,12 was rare.
More significant were observations that active established MS lesions displayed an homogeneous profile, that lesion heterogeneity could not be confirmed, and that there was no interindividual
heterogeneity with respect to Ig and complement immunoreactivity.
Thus, according to this report,1 as far as actively
demyelinating established lesions are concerned, several building blocks of the dogma for lesion categorization that Lucchinetti and colleagues laid down for
early active lesions appear not to hold up. How can
we reconcile the differences? Most workers in the
field have been raised on the mantra that expanding
chronic MS lesions probably recapitulate acute events
and would be quite comfortable with many of these
observations having relevance to the acute lesion. Certainly many similarities exist between the two, such as
the expression of the same immune system molecules
and the occurrence of identical patterns of myelin pathology among acute and chronic active MS lesions,
for example, IgG on macrophages,13,14 attachment of
(?opsonized) myelin debris to clathrin-coated pits
2
Annals of Neurology
Vol 63
No 1
January 2008
on macrophage surfaces,13,15 and association of
myelin-specific IgG with degenerating myelin.14
Thus, it is probably safe to assume that chronic active
lesions recapitulate events encountered in acute lesions. Although only direct comparison between acute
and chronic active lesions will settle comments such
as whether these patterns represent those of a common later pathway (unlikely in view of the abovementioned similarities), incontrovertible and intriguing from this detailed analysis was that homogeneity
and involvement of Ig and complement were consistent features in active older lesions.
In the interest of completeness, it is worth noting
that Barnett and Prineas’s16 2004 study of acute
MS reported lesions containing oligodendrocyte apoptosis, complement activation, and remyelination,
findings that suggest overlap in the four-pattern system, leaving these authors to question the validity of
pattern III. More recently, Stadelmann and colleagues,12 reporting on a rare variant of acute MS,
Baló’s concentric sclerosis, seemingly restricted pattern III to the concentric lesions. Because only 8 of
the original 22 cases displaying pattern III were Baló’s,7 one is left to wonder about the nature of the
displaced cases. Finally, there has long been discussion on the significance of the oligodendrocyte response in the active MS lesion. The observed lack of
oligodendrocyte apoptosis that Breij and colleagues1
detailed is in accord with previous accounts on active established lesions in MS (eg, Raine and colleagues17 and Bonetti and Raine18) and with descriptions of oligodendrocyte survival, proliferation, and
protection,17–20 observations militating against an apoptotic mechanism for the oligodendrocyte depletion
in MS.
Where then does this leave us with regard to the
classification of the active MS lesion? Does this
account (and that of Barnett and Prineas16) mean
that those MS lesions separated by oligodendrocyte behavior3– 6 (systems apparently usurped), as
well as patterns III and IV of the 2000 report,7 might
be in doubt? In the absence of works confirming the
four-pattern system, the negatives currently appear to
outweigh the positives. From Breij and colleagues’1
report, lesions did not segregate by oligodendrocyte
behavior and had a uniform pattern II phenotype. If
recapitulation of immunopathogenetic events in
acute and chronic active lesions is valid, then categorization of lesions according to oligodendrocyte pathology may have to be excluded from the schema,
bringing us back to a system akin to the spectrum
concept that was in vogue before 1996. In the famous
last words of Ned Kelly (the Australian “hero” bandit), “Such is life.”
Cedric S. Raine, PhD, DSc
Departments of Pathology (Neuropathology), Neurology,
and Neuroscience
Albert Einstein College of Medicine
Bronx, NY
19. Cannella B, Gaupp S, Omari KM, et al. Multiple sclerosis:
death receptor expression and oligodendrocyte apoptosis
in established lesions. J Neuroimmunol 2007;188:
128 –137.
20. Raine CS, Wu E, Ivanyi J, et al. Multiple sclerosis: a protective
or pathogenic role for heat shock protein 60 in the central nervous system? Lab Invest 1996;75:109 –122.
References
1. Breij EC, Brink BP, Veerhuis R, et al. Homogeneity of active
demyelinating lesions in established multiple sclerosis. Ann
Neurol.
2. Frohman EM, Racke MK, Raine CS. Multiple sclerosis: the
plaque and its pathogenesis. N Engl J Med 2006;354:
942–955.
3. Lucchinetti CF, Brück W, Rodriguez M, et al. Distinct patterns
of multiple sclerosis pathology indicates heterogeneity of pathogenesis. Brain 1996;6:259 –274.
4. Lucchinetti CF, Brueck W, Rodriguez M, et al. Multiple
sclerosis: lessons from neuropathology. Semin Neurol 1998;18:
337–349.
5. Lassmann H. Neuropathology in multiple sclerosis: new concepts. Mult Scler 1998;4:93–98.
6. Lucchinetti C, Brück W, Parisi J, et al. A quantitative analysis
of oligodendrocytes in multiple sclerosis lesions: a study of 113
cases. Brain 1999;122:2279 –2295.
7. Lucchinetti C, Brück W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707–717.
8. Lassmann H, Brück H, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001;7:115–121.
9. Lassmann H, Ransohoff RM. The CD4-Th1 model for multiple sclerosis: a crucial re-appraisal. Trends Immunol 2004;25:
132–137.
10. Lassmann H. Recent neuropathological findings in MS—implications for diagnosis and therapy. J Neurol 2004;251:IV/
2–IV/5.
11. Lassmann H, Brück W, Lucchinetti C. The immunopathology
of multiple sclerosis: an overview. Brain Pathol 2007;17:
210 –218.
12. Stadelmann C, Ludwin S, Tabira T, et al. Tissue preconditioning may explain concentric lesions in Balo’s type of multiple
sclerosis. Brain 2005;128:979 –987.
13. Prineas JW, Graham JS. Multiple sclerosis: capping of surface
immunoglobulin G on macrophages in myelin breakdown. Ann
Neurol 1981;20:149 –158.
14. Genain CP, Cannella B, Hauser S, et al. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 1999;5:170 –175.
15. Lee SC, Moore GRW, Golenwsky G, et al. A role for astroglia
in active demyelination suggested by class II MHC expression
and ultrastructural study. J Neuropathol Exp Neurol 1990;49:
122–136.
16. Barnett MH, Prineas JW. Relapsing and remitting multiple
sclerosis: pathology of the newly forming lesion. Ann Neurol
2004;55:458 – 468.
17. Raine CS, Scheinberg L, Waltz JM. Multiple sclerosis: oligodendrocyte survival and proliferation in an active, established
lesion. Lab Invest 1981;45:534 –546.
18. Bonetti B, Raine CS. Multiple sclerosis: oligodendrocytes display cell death-related molecules in situ but do not undergo
apoptosis. Ann Neurol 1997;42:74 – 84.
Targeting Splicing in Spinal
Muscular Atrophy
Spinal muscular atrophy (SMA) is a devastating autosomal recessive motor neuron disease caused by insufficient expression levels of the survival of motor neuron (SMN) protein. With a carrier frequency of 1 in
50 and an incidence of 1 in 10,000 births, SMA is
the most common inherited disease that is lethal to
infants. Importantly, SMA has a strikingly broad
range of phenotypic severity ranging from profound
weakness at birth associated with death before 2 years
to mild proximal weakness beginning in adulthood
without a shortened life span.
In humans, the SMN protein is encoded by two
genes located on chromosome 5, the telomeric SMN1
gene and the centromeric SMN2 gene.1 Because of
deletion or missense mutations, all SMA patients lack
a functional copy of the SMN1 gene but retain at
least one copy of the SMN2 gene.2 Transcripts encoded by the SMN1 gene contain a normal complement of eight exons, but most of the transcripts encoded by the SMN2 gene are alternatively spliced to
exclude exon 7.3,4 SMN delta 7 transcripts code for a
truncated SMN protein that fails to oligomerize or
associate with its binding partners and is therefore
rapidly degraded. A small proportion of transcripts
arising from the SMN2 gene are full length and code
for full-length SMN protein, but this reduced level of
SMN protein expression is insufficient to prevent
SMA in most patients. The number of copies of the
SMN2 gene varies in the population but is usually
between one and four copies. In SMA patients, increased SMN2 copy number is inversely associated
with disease severity. Some individuals with four or
five copies of the SMN2 gene may be phenotypically
normal with a total loss of SMN1.5 Because the
SMN2 gene substantially modifies SMA disease
severity and is retained in all patients, it is a promising target for therapeutic development.6 Currently investigated treatment strategies that take advantage of
the SMN2 gene to increase SMN protein levels are to
Burnett and Sumner: Targeting Splicing in SMA
3
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homogeneity, revisited, classification, sclerosis, multiple, reveal, recapitulation
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