David Hafler, M.D.
William S. and Lois Stiles Edgerly Professor of Neurology and Professor of Immunobiology
Chair, Department of Neurology, Yale School of Medicine
Benjamin A. Lerner, A.B.
Medical Student and Research Fellow, Yale School of Medicine
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Multiple sclerosis (MS), the most
common neurologic disease of young adults, is an autoimmune disease of the
central nervous system (CNS), i.e. the brain and spinal cord. Myelin, the lipid-rich
substance that envelops many axons, speeds transmission of electrical signals
between neurons. In MS, the body’s own immune system attacks myelin and
oligodendrocytes, the cells that produce myelin in the CNS, and the resulting
damage slows or completely stops nerve conduction.
People with MS can have a variety
of neurologic symptoms, including stiffness, visual impairment, bladder
dysfunction, vertigo, clumsiness, altered sensation, and weakness. Specific
symptoms correspond to the location of MS lesions, which can form anywhere in
the CNS. For example, a lesion in the optic nerve can cause vision loss and
pain worsened by eye movement; a lesion in the cerebellum can cause clumsiness
and poor balance.
Most patients experience an
initial “clinically isolated syndrome,” symptoms seem to flare up and then ease
off, returning to near-normal neurologic function before flaring up again later.
This pattern of disease is known as relapsing remitting MS (RRMS). A subset of
patients with RRMS disease develops secondary progressive MS (SPMS), in which
the acute attacks grow worse, leading slowly to loss of function, usually walking,
and accumulation of other disability. Patients with the rarest type, primary
progressive MS (PPMS), have symptoms that worsen from the start; they don’t
experience discrete attacks.
In the body, bouts of localized
inflammation cause the flares of RRMS, while neurodegeneration contributes to
the progressive forms of the disease. Diagnosis of MS is based on a patient’s medical
history, physical exam, and MRI scans, seeing the presence of lesions, where
they are, and how they change or increase over time. In early relapsing
remitting disease there are frequent MS lesions with associated breakdown of
the blood-brain barrier, as measured by gadolinium enhancement. In secondary
progressive disease, there are little to no new MS lesions but instead,
progressive loss of brain parenchymal volume 1.
Over the past two decades, our
understanding of MS has greatly expanded. We now have a good working model for
RRMS, having identified many of the genetic and environmental factors that contribute
to risk of developing the disease. In parallel with this deeper insight into
pathogenesis has come the development of highly effective drugs that have dramatically
altered the course of disease for many patients. However, we still don’t know whether
the early treatment of patients with relapsing remitting disease prevents
secondary progressive MS.
We now know that MS pathogenesis
is driven by cells of the adaptive immune system, the branch of the immune
system whose lymphocytes (B cells and T cells) each respond only to a single specific
cells, a subset of T cells that normally protect the body from extracellular
bacteria and fungi, are crucial to initiating the disease. Studies of
experimental autoimmune encephalomyelitis (EAE), a good animal model for
investigating the immune basis of MS, suggest that autoreactive Th17 cells (Th17
cells that specifically recognize a body component as an antigen) cross the
blood-cerebrospinal fluid (CSF) barrier by interacting with a specific protein expressed
on the choroid plexus, a structure that produces CSF in the ventricles of the
brain 2. These autoreactive T cells then enter the
periventricular parenchyma or the pia and subpial cortex of the brain. Once
there, they release the cytokines IL-17 and IL-22, which increase blood-brain
barrier permeability and initiate immune cell penetration by additional autoreactive
Th17 cells and other types of lymphocytes: Th1 cells, CD8 T cells, B cells and plasma
Regulatory T cells (Tregs), a
subpopulation of T cells that help maintain tolerance to self-antigens, are
also critical in MS. Our group has shown that Tregs from MS patients are less
able to suppress autoreactive T cells 4. Additionally, we observed that patients with RRMS
have an increased frequency of Th1-like, IFNγ-secreting,
pro-inflammatory Tregs compared with healthy subjects. We showed both in vitro and ex vivo that these Tregs acquire their pro-inflammatory phenotype
when they are stimulated in the presence of IL-12 5. Support for this mechanism in vivo comes from the observation in
people with RRMS that IFN-β treatment decreases IL-12 levels and normalizes the
frequency of IFNγ-secreting Tregs.
B cells and plasma cells, the
immune cells that produce antibodies, have also long been recognized as
important cell types in MS pathology. This is due in part to the oligoclonal bands,
reflecting antibodies of different specificities, which are often seen in the
spinal fluid of people with MS. In people with SPMS, clinicians have seen ectopic
lymphoid follicle-like structures containing proliferating B cells in the
membranes surrounding brain and spinal cord. A gradient of worsening neuronal loss
near these meningeal follicles has been observed, suggesting that antibody-mediated
cell death may be partially responsible for disease in the gray matter of the
Researchers are striving to
identify the self-antigens to which autoreactive lymphocytes respond in MS. Much
work has focused on T cell reactivity to myelin antigens, specifically myelin
basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). The general
consensus is that there are several pathologic antigens involved in MS. Although
initial autoreactivity may be specific to one particular antigen, the process
spreading likely expands the pool of specific triggers of activated immune
cells to include multiple epitopes of the target antigen and even additional
Genetic factors contribute to the development of MS;
studies show high rates of disease concordance in twins and other first-degree
relatives. Our knowledge of MS genetics has expanded dramatically in the past
decade as a result of fundamental advances in human genetics. Genome-wide
association studies (GWAS), large case-control studies designed to detect
genetic variants that confer modest risk for common diseases, have now identified
194 MS-associated loci that, in aggregate, account for approximately half of
the genetic risk for MS. Among these loci there is significant enrichment of
genes linked to lymphocyte regulation.
In addition, approximately two-thirds of these
susceptibility loci are shared with other autoimmune diseases, hinting that
there may be common autoimmunity pathways 8. These genetic variants are beneficial and
apparently lead to increases in immune responsiveness. But, perhaps, too much
of a good thing may be bad and lead to an autoimmune response.
While genetic risk is critical for MS onset, there
are clearly environmental factors that influence the disease. One interesting
epidemiological observation is that MS frequency varies with geography, but child
immigrants tend to take on the risk level of the area to which they move. This
has led many to suggest that early exposure to an environmental factor may be important.
Epstein-Barr virus (EBV), the virus that causes infectious mononucleosis and countless
milder infections, is an often-cited suspect.
Recently, our group has suggested that salt may play
an important role in MS pathology. We showed that Th17 cells generated under
high-salt conditions display a highly pathogenic pro-inflammatory phenotype,
and that mice fed a high-salt diet develop a more-severe form of EAE 9. Similarly, other researchers have found higher sodium intake to be associated
with increased clinical and radiological disease activity in people with MS10. A recent paper identified melatonin,
a hormone involved in maintenance of circadian rhythms, as a possible
contributor to the seasonality of MS relapses; the authors showed that
melatonin levels negatively correlate with MS activity in patients, and that
melatonin limits development of EAE and blocks differentiation of pathogenic
Th17 cells 11. Thus, it is not bad genes or a bad environment but
a poor interaction between genes and environment that cause MS.
Many of the advances in MS over the past two decades
have revolved around the development of effective disease-modifying drugs,
medications that target the underlying pathology of MS and that can alter
long-term outcomes. Approved by the FDA in 1993, interferon beta-1b (IFN-β1b) was the first disease-modifying drug for MS. It
changes the expression of many pro- and anti-inflammatory genes and reduces the
number of immune cells that cross the blood-brain barrier. Glatiramer acetate,
another early MS drug, is a random polymer of four amino acids that drives T
cells towards a non-inflammatory state. Both IFN-β
and glatiramer acetate are administered by subcutaneous injection, reduce
the annual relapse rate by about 30 percent, and have excellent long-term
safety profiles 12.
Natalizumab, a monoclonal antibody that blocks T
cells from crossing the blood-brain barrier, is one of the most effective MS
drugs on the market. Administered by monthly intravenous infusion, natalizumab
was shown to reduce the rate of clinical relapse at one year by 68 percent and
decrease the accumulation/enlargement of MRI lesions over two years by 83
percent 13. A very small but real number of
natalizumab-treated patients developed progressive multifocal
leukoencephalopathy (PML), a rare, often fatal, brain infection caused by
reactivation of JC virus. For
this reason, before starting natalizumab, patients should be tested for
antibodies against JC virus, presence of which indicates previous infection and
Fingolimod is a highly effective oral drug, with
55-60 percent lower relapse rates compared with placebo. It works by trapping
naive and central memory T lymphocytes in lymph nodes. Newer MS medications
include the oral immunomodulatory drugs teriflunomide and dimethyl fumarate 12. Recent studies with ocrelizumab,
a monoclonal antibody directed against B cells, demonstrate a significant reduction
in the relapse rate without serious side effects.
In summary, MS is a multifocal demyelinating disease of the CNS caused
by an autoimmune response to self-antigens in genetically susceptible people. While
our understanding of relapsing remitting disease and treatment options have
expanded enormously in recent years, understanding the mechanism of secondary
and primary progressive MS, including the neurodegenerative aspects of these
diseases, remains a central question.
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