In this slides deck, Prof. Ayman Nassef clarifies the role of Myelin Olidodendrocyte Glycoprotein (MOG) in demyelinating conditions, and explains how MOG-IgGs cause damage of myelin and axons and the impact of such damage on the disease.

2. Ayman Nassef
Prof. of Neurology
Ain Shams University

3.  Myelin oligodendrocyte glycoprotein (MOG) is a
protein expressed only on the outermost lamellae of
the myelin sheath and on the surface of
oligodendrocytes in the central nervous system (CNS).
 MOG represents less than 0.05% of total myelin
proteins but despite its low concentration, it is
believed to be involved in important functions, such as
being a surface marker of the mature oligodendrocyte
and participating in the interactions between myelin
and its players .

5.  The better structural characterization of
MOG as well as its location rapidly made it an
antigen used successfully in the induction of
experimental models of demyelination such as
 Experimental autoimmune
encephalomyelitis (EAE)
 The gene for MOG, found on chromosome
6 p21.3-p22, was first sequenced in 1995.

6.  Thereafter, the presence of anti-MOG antibodies
was investigated in those diseases that
represented the clinical prototype of
demyelinating conditions:
 Acute disseminated encephalomyelitis (ADEM)
in children and
 Multiple sclerosis (MS) in adults .
 Although anti-MOG antibodies have been found
in such prototypical situations, probably for
laboratory methodological reasons, the clinical
utility of antibody detection as a reliable
biomarker was abandoned.

7.  Anti-MOG status is different depending whether it is
measured by ELISA or by cell based assay (CBA)
 The proper way to identify it is by microarray (CBA),
reacting patient serum with living cells, and detecting
the binding IgG via a fluorescent-labeled secondary
antibody.
 The development of a more specific and sensitive
laboratory methodology
(cell based assay)
(CBA)
allowed to revisit the anti-MOG antibody in
demyelinating diseases and to establish it as
a new biomarker.

8.  Ogawa et al.(2017) described 4 young men with
unilateral encephalitis and epileptic seizures of benign
evolution and response to steroids in which the anti-
MOG antibody was the only one detected.
 Costa et al.(2017) describe 6 patients ( four men) with
optic neuritis ( five monophasic, four bilateral) and
serum anti-MOG antibody in very high titers .
 So , in the differential diagnosis of idiopathic optic
neuritis, the possibility of anti-MOG spectrum must be
considered.

9.  MOG-IgGs cause temporary damage of myelin
and axons and alter axonal proteins’ expression.
 Importantly, MOG-IgGs do not produce axonal
loss, neuronal or astrocyte death .
 MOG-IgG binding might result in MOG
conformational changes and internalization,
which in turn leads to changes in myelin
structure.

10. The presence of anti-MOG autoantibodies has been associated
with the following conditions:
 1-Some cases of aquaporin-4-seronegative neuromyelitis
optica: (40%)
(NMO derived from an antiMOG )
2-Some cases of ADEM specially the recurrent ones and the
fulminant courses. (Pediatric)
 3-Some cases of multiple sclerosis.
Some cases of pattern-II multiple sclerosis.
(Spadaro et al., 2016)
 4-Isolated optic neuritis or transverse myelitis
(Longitudinal extensive transverse myelitis).
 5-Recurrent optic neuritis.
 The repetition of an idiopathic optic neuritis is considered a
distinct clinical condition, and it has been found to be
associated with anti-MOG autoantibodies

11. Patterns of MS
Pattern I
lesions show T cell and
macrophage infiltration
Pattern III
is characterized by distal oligodendrogliopathy with
dysregulated myelin protein expression and oligodendrocyte
apoptosis, but still occurs on an inflammatory background.
Pattern II
is defined by additional antibody and complement
deposition, suggesting a contribution of humoral
mechanisms to disease pathology.
A fourth pattern,
defined by oligodendrocyte degeneration in the
periplaque white matter, has been described in
few autopsy cases of primary-progressive
MS, but is rare

12.  In pediatric demyelination:
 Percentage of children with anti-MOG antibodies
in a demyelinating sample is higher than for
adults. (Tenembaum et al. 2015)
Longitudinal myelitis was evident on MRI in 76%
NMOSD
4
Non R
4
Relapsing
ON
ADEM Relapsing
tumefactive
MS
CIS
829 3 1
41 children
17
Relapse

14.  1-More frequently male.
 2-Tend to have a single or a lower number of disease
attacks.
 3- Bilateral, simultaneous optic neuritis attacks are more
common .
 4-Brainstem symptoms (nausea, vomiting and hiccups) and
painful tonic spasms were significantly less frequent.
 5- Moreover, they usually demonstrate better recovery from
the attack.
 6-A better outcome in comparison with AQP4-IgG
seropositive patients regardless of the course of the disease .

15.  7-Brain lesions visualized on MRI are Less
common in MOG-IgG seropositive patients
(37.5%) .
 8-Spinal cord lesions on MRI are also
significantly less frequent in MOG-IgG
seropositives (37.5%).
 9- lesions in patients with MOG-IgG are
usually distributed in the lower parts of the
spinal cord, in the thoracolumbar region.

16.  There are histopathologic and neuroimmunologic differences
between patients with MOG and AQP4 antibodies and they
should be
clearly separated in view of the
potential therapeutic and clinical implications.
Whereas AQP4 antibody–associated NMO spectrum
disorder (NMOSD) is
an astrocytopathy,
MOG antibody–associated inflammatory
demyelinating diseases represent
an oligodendropathy.
MOG antibody–positive disease with a NMO-like presentation
can be classified as a variant of opticospinal MS .

19. Glial fibrillary acidic protein (GFAP) may
be released upon injury to astrocytes.
Damage to oligodendrocytes or myelin
may be associated with release MBP
T follicular helper (Tfh)
T effector cells (Teff)

21.  From a clinical perspective, there are
compelling reasons to include this
MOG Ig+ subgroup of patients under the
umbrella of NMOSD.
 Physicians and their patients rely on
appropriate diagnosis when initiating
therapeutic intervention.

22.  When patients are
attempting to secure
insurance coverage
for costly NMO
treatments
 Interferon β and
natalizumab, 2 medications
approved for treatment of
multiple sclerosis (MS), may
exacerbate AQP4-
seropositive NMO.
 One can imagine that
treatment decisions may
become more complex if the
pathology of this
 MOG Ig+ opticospinal
inflammatory condition is
different from AQP4-
seropositive NMOSD.

23.  Since the discovery of NMO IgG in 2004,
the presence of these antibodies in patients
has provided diagnostic confirmation and
served to distinguish NMO from MS or other
forms of CNS demyelinating disease.
 In contrast to MS, in NMO there is relative
sparing of myelin, considered the primary
immune target in MS.
 The presence of antibodies is a hallmark feature
of type 2 MS pathologic lesions.

24.  Furthermore, anti-MOG antibodies have been
identified in MS lesions, in particular those
associated with vesicular demyelination.
 The MOG Ig+ NMOSD-like clinical phenotype
might therefore
Represent an opticospinal
type 2 MS variant

25.  Whereas lymphocytes are characteristic of newly
forming MS lesions, the cellular composition of NMO
lesions is marked by the presence of neutrophils and
eosinophils,
2 leukocyte subtypes not normally detected in MS
 When both T cells and B cells target MOG, they
spontaneously develop an opticospinal form of
experimental autoimmune encephalomyelitis (EAE) that
is characterized by lymphocytic infiltrates

26. NMOMS
neutrophils and eosinophilslymphocytes
MOG POSITIVE CASES
Lymphocytes
NMOMS
detected in only a minorityoligoclonal IgG bands (OBs) are
identified in the CSF of most
patients
MOG POSITIVE CASES
(OBs )Rarely detected

27. NMOMS
HLA-DR17 (DRB1*0301)(HLA)-DR2 (DRB1*1501)
MOG POSITIVE CASES
?

28.  It is recognized that NMO IgG is mostly produced
outside the CNS, as studies have demonstrated that its
concentration in serum is many times higher than in
CSF.
 Thus, both the identification of MOG-specific
antibodies in the serum and the relative absence of
CSF OBs suggest that, like in NMO, the MOG-specific
humoral immune process occurs predominantly
outside the CNS in these patients.

29.  However, the term MOG Ig+ AQP4-seronegative
NMOSD represents a fundamental disconnect with our
current understanding of NMO as an astrocytopathy.
 Thus, one should be cautious in applying the term
NMOSD to MOG IgG+ patients.
 While one may consider categorization according to
antigen specificity, e.g., AQP4 autoimmunity
(“aquaporinopathy”) and MOG autoimmunity
(“MOG-opathy”), this may not accurately reflect
the AQP4-seronegative astrocytopathy,
currently classified as NMOSD.

30.  Because the majority of NMOSD is AQP4-seropositive
and
a minority of AQP4-seronegative NMOSD is MOG Ig+,
pathologic examination of sufficient numbers of
AQP4-seronegative, MOG Ig-seronegative NMOSD
cases is particularly important. (double negative)
e.g. autoantibodies against Aquaporin-1
(AQP1-Abs)

31.  Ultimately, neuropathologic examination of several
AQP4-seronegative and MOG Ig+ cases may dictate
whether opticospinal inflammatory disease associated
with MOG-specific antibodies is classified as a
member of NMOSD,
as opticospinal MS, OR as a
a unique condition.
 Until that time,
the MOG Ig+ opticospinal phenotype
should be separated from NMOSD.

32.  Some NMO patients present double positive
for autoantibodies to AQP4 and MOG.
 These patients have :
MS-like brain lesions,
multifocal spine lesions and
retinal and optic nerves atrophy.

34.  Study design for recruitment of patients for MOG-ab and
AQP4-ab assessment.

35. Patients with only MOG-abDouble-positive patients
a higher ratio of monophasic
disease course
mild residual disability.
70% had MS-like brain lesions
Spinal cord MRI illustrated
multifocal cord lesions with mild
edema
more severe edematous, multifocal
regions on spinal (MRI)
brain MRIs showed more lesions
around lateral ventricles.
• pronounced decreases of retinal
nerve fiber layer thickness
• atrophy of optic nerves
exhibited an “intermediate”
phenotype between NMOSD and MS
exhibited combined features of
prototypic NMO and relapsing-
remitting form of MS,

38.  If MOG-IgG is involved in NMO pathogenesis,
treatment with steroids or plasma exchange
should be effective in MOG-IgG seropositive
NMO patients.
 Several new potential therapies for AQP4-IgG
seropositive NMO patients, like sivelestat
(inhibiting neutrophils) or eculizumab
(inhibiting complement), are probably less
effective in NMO patients with MOG-IgG