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MYASTHENIA GRAVIS

GENOMIC MEDICINE AND PERSONALIZED HEALTH


Konstantinos Poulas
Associate Professor,
Laboratory of Mol. Biology and Immunology
Department of Pharmacy, University of Patras
GREECE
Email: kpoulas@upatras.gr
KPJ Conference 2014

FINANCIAL COMPETING INTERESTS

None

All the research results are obtained after National (Greek) and European Union Gr

The travel is covered by KPJ Healthcare

SPECIAL THANKS
KPJ Healthcare
Dr Mohd Harris Lu, Medical Director of Sentosa Medical Centre
Dr K V Anitha, KPJ Healthcare
Sarah Joseph, KPJ Healthcare
Special Mention: Datin Jasmin Tan

A FEW WORDS FOR GREECE

A FEW WORDS FOR GREECE

A FEW WORDS FOR GREECE

A FEW WORDS FOR GREECE

A FEW WORDS FOR GREECE

A FEW WORDS FOR GREECE

GREECE IS ALSO KNOWN FOR A NUMBER OF FAMOUS PHILOSOPHS:

Aristoteles
Socrates

Platon

Myasthenia Gravis (MG)


Autoimmune disease of the NMJ
Basic clinical characteristics: eyelid drooping and
diplopia, weakness and fatigability of various
skeletal muscles
Prevalence: ~150-200/ million
F/M ratio: prevalence: ~2:1; incidence ~1/1
~ 80 85 % of MG patients have auto-Abs to the
AChR
Several of the rest have anti-MuSK antibodies

Epidemiology in Greece (but not only)

Incidence: 20 per million


Prevalence: 200 per million

Bimodal appearance (3rd and 7th decade)


Female : Male = 2 : 1

Age distribution of new incident cases

No. of patients

200
150
100
50
0

0-9

10-19

20-29

30-39

40-49

Age of onset

50-59

60-69

>70

Age distribution of prevalence


300
70,63/million

Prevalence rate

250
200
150
100
50
0

0-9

10-19

20-29

30-39

40-49

Age group

50-59

60-69

>70

Epidemiology in Malaysia (1980 )

No of Patients: 62 (University Hospital, KL)


Incidence: 2.6 cases per 10000 admissions

Prevalence: Female : Male = 1 : 1

Clinical Features
Cardinal feature: Weakness and fatigability of muscles. The weakness increases during

repeated use (fatigue) and may improve following rest or sleep.


Exacerbations and remissions may occur, particularly during the first few years after the onset.
Remissions are rarely complete or permanent. Unrelated infections or systemic disorders often
lead to increased myasthenic weakness and may precipitate crisis.
The cranial muscles, particularly the lids and extraocular muscles, are often involved early in

the course of MG, and diplopia and ptosis are common initial complaints. Weakness in
chewing is most noticeable after prolonged effort, as in chewing meat.
Speech may have a nasal timbre. Difficulty in swallowing may occur
In many patients, the weakness becomes generalized, affecting the limb muscles as well. If
weakness of respiration becomes so severe as to require respiratory assistance, the patient is
said to be in crisis.

1973: Understanding Myasthenia


Immunization with acetylcholine receptor (AChR )
induces experimental myasthenia gravis (Patrick &
Lindstrom)

The neuromuscular junctions of myasthenics are


having reduced AChRs (Drachman and
collaborators)

1985: Myasthenia in Greece Hellenic Pasteur Institute


Understanding AChR as the autoantigen

MAIN IMMUNOGENIC REGION = MIR

Diagnosis with (RadioImmunoAssays) RIAs


Epidemiology of MG in GREECE

Expressing all the AChR subunits with


prokaryotic and eukaryotic expression systems

New Autoantigens New diagnostic assays

Snail AChBP

Muscle-type Torpedo AChR

Extracellular
domain (ECD)
70

Smit, Sixma & col, 2001

Cytoplasmic
domain

Unwin & col.

Torpedo AChR at 4 resolution

Extra-cellula
domain
(ECD)

Cyto-plasmic
domain

Unwin, 2005

NEUROMUSCULAR JUNCTION

Normal

Vesicles
with ACh
Nerve
Terminal

Muscle

Myasthenia gravis

MECHANISMS OF ACTION OF ANTI-ACHR ANTIBODIES

Complement

Ach binding
site

Direct blockage of AChR


function

Complement-mediated
membrane lysis
Accelerated internalization and
degradation of AChRs

INDUCTION AND MAINTENANCE OF


ANTI-ACHR ANTIBODIES IN IDIOPATHIC MG

Defect in the immune system

Defect in the neuromuscular system

Thymus

hyperplasia
thymoma
thymectomy
myoid cells - AChR

Microorganisms (antigenic mimicry, superantigens, bystander


activation, other?)

Genetic factors (HLA, parents, twins)

CURRENT THERAPIES OF MG
APC

Thymectomy
Immunosupressives

B7

MHC
TCR

CD28
Regulatory T cell

Resting T
cell

(Prednizone, Azathioprine,
Cyclophosphamide,
Cyclosporine A,
mycophenolate mofetil)

Activated T cell

IVIg
B cell

Plasmapheresis

Ab to
AChR

Inhibitors of
Ach-esterase

AChR
Muscle

AUTOANTIGENS IN MYASTHENIA

Autoantigen

Generalized MG

Ocular MG

80-85%

50%

AChR

(1973-76)

MuSK

(2001)

~5%

~0%

LRP4

(2011)

~~2%

~~10%

grin, ColQ

(2012)

Agrin LRP4 MuSK rapsyn AChRs aggregation


Agrin

LRP-4

LRP-4

AChR

MuSK

1st antigen: AChR


Diagnosis for anti-AChR antibodies
. Radio Immuno Assay (RIA) Lindstrom 1976:
?

radioactive
AChR

+ serum
of patient

+ anti-serum

~85% of patients with generalized MG


~50% of patients with ocular MG

radioactive precipitant

2001 - 2nd antigen: muscle specific kinase (MuSK) Vincent et


al.
Anti-MuSK antibodies:
~40% of anti-AChR-negative with generalised MG (=~4-6% of MGs)
Non-detectable in ocular MG
They are of IgG4 subclass (rare)
Are they the pathogenic factor for MuSK-MG;

Are the anti-MuSK antibodies the pathogenic factor for


MuSK-MG;
;
Experimental MuSK-MG:
- Recombinant MuSK immunization
- Injection with MuSK-MG sera
- Injection with IgG4 from MuSK-MGs

3rd antigen: LRP4


20% of anti-AChR-negative
Not yet known if they are pathogenic

Anti-LRP4 and anti-MuSK antibodies:


o They sometimes coexist
o F:M = ~3/1
o Anti-LRP4 antibodies:
Are detected even in opthalmic MG
They do not belong to IgG4 subclass

MYASTHENIA GRAVIS
GENOMIC MEDICINE AND PERSONALIZED
HEALTH
Konstantinos Poulas
Associate Professor,
Laboratory of Mol. Biology and Immunology
Department of Pharmacy, University of Patras
GREECE
Email: kpoulas@upatras.gr
KPJ Conference 2014

2000: Myasthenia in Greece University of Patras


Understanding AChR as the autoantigen

Diagnosis with (RadioImmunoAssays) RIAs


Epidemiology of MG in GREECE

Expressing all the AChR subunits with


prokaryotic and eukaryotic expression systems

Genomics SNPs identification

Is the anti-AChR antibodies depletion enough for removing the


myasthenic symptoms?

MG symptoms within 24-48 hours


MG sera

Whole
serum

Depleting serum (without


the anti-AChR antibodies)

Anti-AChR
antibodies

MG1 (anti-)

+++

+++

MG2 (anti-)

++

+++

MG3 (anti-)

MG4 (anti-)

= only the anti-AChR antibodies can cause G


= the depletion of anti-AChR antibodies can be enough for therapeutic purposes

THANK YOU KL
:PLOS ONE Decision: Accept [PONE-D-14-20638R1] - [EMID:915a8a9090c8d3d7]
:2014-08-21 15:04
:"PLOS ONE" <em@editorialmanager.com>
:"George Lagoumintzis" <glagoum@upatras.gr>
:"PLOS ONE" <plosone@plos.org>
PONE-D-14-20638R1

Direct proof of the in vivo pathogenic role of the AChR autoantibodies from myasthenia gravis patients
PLOS ONE

Dear Dr Lagoumintzis,
I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations!
Your manuscript will now be passed on to our Production staff, who will check your files for correct formatting and completeness.
Your manuscript will remain under a strict press embargo until the publication date and time. For more information please contact
onepress@plos.org.

Please contact one_production@plos.org if you have any other questions or concerns. Thank you for submitting your work to PLOS ONE.
With kind regards,
William Phillips
Academic Editor
PLOS ONE

Each patient is different by any other.

Myasthenia is a multifactorial and not


monolithic diasease

More than 50 sera were used and the antibodies

were characterized, by using the recombinant


AChR extracellular domains

AIMS ABOUT MG (IN GREECE, MALAYSIA, WORLD)


Understanding the nature of the disease

Better diagnosis
Is there any genetic base?

Pharmacogenomics

Continuous support to the patients

DONT MISS
SUNDAY11:00-11:55

Main Hall
SYMPOSIUM 7

THE ART AND SCIENCE OF MEDICINE: Delivering State of Art Care


(Organised by the Committee of Medical Directors: Chaired by Dato Dr Ngun Kok Weng and
Dato' Dr.N.Sivamohan)
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Heal Wounds Clinical, Histological and Cellular Data, by Prof. K. Poulas, University of Patras, Greece
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Thank you!!!!!

Email: kpoulas@upatras.gr

Patras

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