Transcript HLA-DRB1*1501 - The Neurology Report

Advances in Basic and Translational
Science Research in Multiple Sclerosis
Salim Chahin, MD, MSCE
University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
A REPORT FROM THE 66TH ANNUAL MEETING OF THE AMERICAN ACADEMY OF NEUROLOGY (AAN 2014)
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1
Neuropathology of Multiple Sclerosis
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2
The Dynamic Nature of MS Pathology

Active lesions are characterized by relative axonal
preservation and macrophage infiltration.
» Early active demyelination—minor myelin proteins (MAG,
MOG)
» Late active lesions—major myelin proteins (proteolipid
protein and MBP).

Smoldering lesions have an inactive center and a rim
of activated macrophages and microglia.

Inactive lesions have substantial axonal loss and are
completely demyelinated.

Shadow lesions represent remyelinated areas.
Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185; Popescu BF et al. Continuum (Minneap Minn).
2013;19(4 Multiple Sclerosis):901
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The Dynamic Nature of MS Pathology
Stages of demyelination
Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185
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The Dynamic Nature of MS Pathology

Relationship to disease course
» Active lesions—RRMS and SPMS with relapses
» Inactive and smoldering lesions—SPMS and PPMS
» Shadow lesions—similar rate in RR and progressive MS

Remyelination
» Thinly myelinated axons with short intermodal distances
» Depends on availability of OPCs and inflammatory balance
» Remyelination failure may be due to:
•
•
•
•
Recurrent demyelination
Axonal injury inhibiting remyelination
Glial scarring
Age-dependent loss of trophic support from microglia
Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185; Popescu BF et al. Continuum (Minneap Minn).
2013;19(4 Multiple Sclerosis):901; Barkhof F et al. Arch Neurol. 2003;60:1073; Franklin RJ et al. Nat Rev
Neurosci. 2008;9:839
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Heterogeneity of Early Active MS Plaques
MS lesions can be classified into four immunopatterns
Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185
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Pathologic Substrate of Disease Progression

Axonal pathology
» Occurs early in the disease
» Correlates with degree of inflammation
» Remains clinically silent until a threshold of axonal loss is
reached where the compensatory capacity is surpassed

Mitochondrial injury, oxidative stress, and iron
accumulation
» Mitochondrial injury triggered by reactive oxygen and nitrogen
»
»
species leads to oligodendrocyte and neuronal damage.
Iron, in liberated form, may generate reactive oxygen species
and contribute to neurodegeneration.
A decrease in iron in normal-appearing white matter has been
observed in chronic MS.
Bjartmar C et al. J Neurol Sci. 2003;206:165; Fischer MT et al. Brain. 2012;135(pt 3):886; Aboul-Enein F et al.
Acta Neuropathol. 2005;109:49; Hametner S et al. Ann Neurol. 2013;74:848
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Pathologic Substrate of Disease Progression

Cortical pathology
» Can occur early in the disease process
» Results from demyelination with the gray matter or through
retrograde degeneration from white matter pathology
» Meningeal inflammation may also contribute to gray matter
pathology in MS
» Types of cortical lesions:
• Subpial lesions—from the pial surface to the deep cortical layers—
common in chronic MS
• Intracortical lesions—small perivascular lesions confined to the
cortex
• Leukocortical lesions—involve both gray and white matter at the
gray-white matter junction
Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185; Calabrese M et al. Nat Rev Neurol. 2010;6:438;
Howell OW et al. Brain. 2011;134(pt 9):2755
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Pathologic Substrate of Disease Progression

Neurodegeneration and inflammation
» Studies have suggested that degeneration occurs separately
from inflammation in MS.
» However, it is more likely that degeneration occurs on an
inflammatory background.
» Cortical lesions, which are highly inflammatory, are
present even early in the disease, suggesting a stronger role
for inflammation at this early stage of the disease.
» The process by which inflammation leads to degeneration
is not completely understood.
Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185; Dutta R, Trapp BD. Prog Neurobiol. 2011;93:1
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Epidemiology of Multiple Sclerosis
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10
Epidemiology of Multiple Sclerosis

MS in relatively common in the US, Europe, Canada,
New Zealand, and parts of Australia.

Lifetime risk is 1 in 400 in white non-Hispanic
individuals.

The incidence of MS follows a latitude gradient—risk
is low in the tropics and increases with increasing
latitude.

Migration from a high- to low-risk area changes the
risk of the disease in a graded, age-related fashion.

Studies suggest a rising incidence in certain
populations, especially women.
Ascherio A et al. Nat Rev Neurol. 2012;8:602
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Known Environmental Risk Factors

Epstein-Barr virus (EBV)
» The geography and epidemiology of infectious mononucleosis
are similar to those of MS.
» Older age at EBV infection increases the risk for MS.
» Pediatric studies have shown an association between EBV
infection and the risk of developing MS.

Other viruses
» Contrary to EBV infections, cytomegalovirus (CMV) infections
are associated with a lower risk of developing MS.
» A complex relationship exists between infection with herpes
simplex virus (HSV)-1 and genetic risk factors for MS (a strong
interaction was observed with the gene HLA-DRB1).
Ascherio A et al. Nat Rev Neurol. 2012;8:602; Henle W et al. Sci Am. 1979;241:48; Waubant E et al. Neurology.
2011;76:1989
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Known Environmental Risk Factors
Risk of developing MS in children and adults
Waubant E et al. Neurology. 2011;76:1989; Sundqvist E et al. Mult Scler. 2014;20:165
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Known Environmental Risk Factors

Vitamin D
» The geography of MS also correlates with degree of sun
exposure (the primary source of vitamin D).
» Vitamin D is hypothesized to play an immunomodulatory
role in several diseases, including MS.
» Several studies have shown a lower risk of MS in people with
regular vitamin D intake or high serum levels of vitamin D.
» Vitamin D deficiency may also contribute to a more severe
disease course and progression in MS.
» Several clinical trials are under way to further investigate
the role of vitamin D in MS.
Ascherio A et al. Nat Rev Neurol. 2012;8:602; Ebers GC. Lancet Neurol. 2008;7:268; Handel AE et al. Nat Rev
Neurol. 2010;6:156
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Known Environmental Risk Factors

Cigarette smoking
» The risk of MS is higher in smokers compared with that in
people who have never smoked.
» Cigarette smoking also contributes to more rapid disease
progression in patients with established MS.

Dietary sodium intake
» Sodium and increased dietary salt intake may be implicated
in the pathogenesis of MS and may play a role in modulating
the immune system and the development of autoimmune
diseases such as MS.
Hernan MA et al. Am J Epidemiol. 2001;154:69; Wingerchuk DM et al. Ther Adv Neurol Disord. 2012;5:13
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15
Genetics of Multiple Sclerosis
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Genetic Susceptibility

The genetic contribution to MS succeptibility is
suggested by several observations
» The risk of MS in monozygotic twins is 25%, whereas in
dizygotic twins the risk is 5%.
» Having a sibling with MS increases the risk 20–40 fold
compared with the risk of MS in the general population.

Multiple interacting polymorphic genes have been
identified as contributing to the risk of MS.

The strongest genetic risk is conferred by the HLADRB1*1501 allele.

Genome-wide association studies have identified
over 110 non-HLA genes involved in the risk of MS.
Ascherio A et al. Nat Rev Neurol. 2012;8:602; Ebers GC. Nature. 1995;377:150; Beecham AH et al. Nat Genet.
2013;45:1353
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Environmental/Genetic Interactions

MS is likely caused by a complex interaction between
multiple genes and environmental factors.

Examples of such interactions include:
» The interaction between HSV-1 and HLA-DRB1.
» The role of latitude in increased concordance among
monzygotic twins.
» The vitamin D response element located in the HLA-DRB1
promoter region.

Future, more expansive studies are needed to further
explore these interactions and understand better the
pathophysiology of MS.
Ascherio A et al. Nat Rev Neurol. 2012;8:602; Islam T et al. Ann Neurol. 2006;60:56; Waubant E et al.
Neurology. 2011;76(23):1989
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Environmental/Genetic Interactions

Role of epigenetic factors
» The effect of environmental risk factors on genetic
susceptibility can be explained by epigenetic modifications.
» Epigenetic changes influence gene expression without
altering the DNA sequence.
» Examples of such epigenetic factors include such processes
as:
• DNA methylation
• Histone modification
• MicroRNA (miRNA) associated gene silencing
• Heterochromatin
Ascherio A et al. Nat Rev Neurol. 2012;8:602; Koch MW et al. Nat Rev Neurol. 2013;9:35
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19
Neuroimmunology of Multiple Sclerosis
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20
T-Cell Involvement

Studies have shown that auto-reactive, myelinspecific T lymphocytes can result in demyelination.

T cells in MS patients have a greater proinflammatory
phenotype.

Both CD4+ and CD8+ T cells are implicated in the
pathogenesis of MS.

The suppressive capacity of CD8+ cells is reduced in
MS patients during a relapse.

In a clinical trial on altered peptide ligands, an
increase in T cells responding to a component of
myelin basic protein was observed.
Pettinelli CB, McFarlin DE . J Immunol. 1981;127:1420; Lovett-Racke AE et al. J Clin Invest. 1998;101:725;
Crawford MP et al. Blood. 2004;103:4222; Bielekova B et al. Nat Med. 2000;6:1167
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T-Cell Involvement

T-cell phenotype in MS
» T cells from MS patients produce inteferon-g, consistent
with a T helper (Th) 1 cell response.
» T cells from healthy individuals producde cytokines
consistent with a Th2 response.
» A subset of T cells (Th17) produce interleukin-17 (IL-17) and
are triggered by IL-23.

The differentiation of encephalitogenic Th1 and Th17
cells may differentiate between MS patients.

These differences may also explain why some
patients fail to respond to treatment with certain
disease-modifying agents such as interferons.
Pettinelli CB, McFarlin DE. J Immunol. 1981;127:1420; Trinchieri G et al. Immunity. 2003;19:641
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B-Cell and Humoral Involvement

Cerebospinal fluid levels of B cells, plasma cells, and
antibodies are increased in patients with MS.

Evidence on the role of B cells in MS pathogenesis
also comes from therapeutic trials that have shown
successful results from targeting B cells.

KIR4-1 antigen is an inward-rectifying potassium
channel located on astrocytes and oligodendrocytes
» Antibodies to KIR4-1 were present in 47% of patients with
MS, compared with less than 1% of patients with other
neurologic disorders.
» Results were replicated in children with acute
demyelinating disorders.
Cepok S et al. Brain. 2005;128(pt 7):1667; Srivastava R et al. N Engl J Med. 2012;367:115; Kraus V et al.
Neurology. 2014;82:470; Cross AH et al. J Neuroimmunol. 2006;180:63
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Epigenetics and the Role of MicroRNAs

MicroRNAs have emerged as a leading epigenetic
mechanism via regulation of gene expression and
T-cell activation.

MicroRNAs can be influenced by both genetic and
environmental factors.

Increased expression of three microRNAs (miR-128,
miR-27a/b, and miR-340) has been identified in
naïve T cells of patients with MS.

These microRNAs target a transcription factor that
drives Th2 differentiation and IL-4 expression.
Keller A et al. PLoS One. 2009;4:e7440; Guerau-de-Arellano A et al. Brain. 2011;134(pt 12):3578
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Mechanisms of Action of
Current and Future MS Therapies
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Current and Future MS Therapies

Type 1 interferons (interferon b-1a and b-1b)
» The first disease-modifying therapies developed for the
treatment of MS.
» Although several mechanisms have been proposed, the
exact mechanism of action remains unknown.
» We have gained insight into how interferons work through
knowledge of their effect in neuromyelitis optica (NMO).
» Interferons may worsen disease status when the Th17
immune response is prominent.
» Patients with NMO have elevated levels of IL-17 compared
with MS patients; treating NMO with interferons can have
devastating consequences.
Borden EC et al. Nat Rev Drug Discov. 2007;6:975; Axtell RC et al. Trends Immunol. 2011;32:272
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Current and Future MS Therapies

Glatiramer acetate
» Several proposed mechanisms of actions
» An anti-inflammatory monocyte, termed M2, is elicited in
»

response to glatiramer acetate.
Results in increased secretions of anti-inflammatory
cytokines, such as IL-10, and a shift from Th1 to INF-g
response to a modulating pathway through Th2.
Natalizumab
» Humanized monoclonal antibody.
» Targets a4 integrins.
» Interferes with lymphocyte transmigration across the
»
blood-brain barrier.
Impedes both T and B lymphocyte entry into the CNS.
Weber MS et al. Nat Med. 2007;13:935; Rudick R et al. JAMA Neurol. 2013;70:172
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Current and Future MS Therapies

Fingolimod
»
»
»

Sphingosine phosphate receptor agonist
The S1P1 subtype is present on immune cells and neural cells.
Fingolimod caused the S1P1 receptor to be internalized, trapping
lymphocytes in the lymph nodes and impeding their egress.
Teriflunomide
»
»
»
Active metabolite of leflunomide
»
Decreases lymphocyte proliferation and activation toward key
myelin antigens in MS
Complex mechanism of action
Interferes with pyrimidine synthesis through reversible
inhibition of dihydroorotate dehydrogenase.
Brinkmann V et al. Nat Rev Drug Discov. 2010;9:883; O'Connor P et al. N Engl J Med. 2011;365:1293
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Current and Future MS Therapies

Dimethyl fumarate
» Likely affords cytoprotection from oxidative stress
» May be beneficial in protecting against neuroinflammation,
neurodegeneration, and oxidative stress.
» Mainly works via activation of nuclear 1 factor (erythroidderived 2)-like2 (Nrf2) antioxidant pathways
» Other potential mechanisms of action
• Shifting dendritic-cell differentiation
• Suppressing proinflammatory cytokines
• Directly inhibiting proinflammatory pathways
Gold R et al. N Engl J Med. 2012;367:1098; Fox RJ et al. N Engl J Med. 2012;367:1087
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Current and Future MS Therapies

Alemtuzumab
» Monoclonal antibody that targets CD52 receptors
» Depletes T and B lymphocytes and monocytes mainly via
»


antibody-dependent cytotoxicity and complement-mediated
cell lysis
Alemtuzumab drives immune programming—when the cells
repopulate, they don’t have the same autoimmune response.
In 30% of cases, new autoimmune diseases (notably,
immune thrombocytopenia) may emerge.
Ocrelizumab
» Recombinant humanized antibody that targets CD20
»
receptors on B cells
Results in antibody-dependent, cell-mediated cytotoxic effect
Hersh CM, Cohen JA. Immunotherapy. 2014;6:249; Wiendl H, Kieseier B. Nat Rev Neurol. 2013;9:125; Kappos L
et al. Lancet. 2011;378:1779
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