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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: [email protected]
KPJ Conference 2014
FINANCIAL COMPETING INTERESTS
None
All the research results are obtained after National (Greek) and European Union Grants.
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 anddiplopia, 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
0
50
100
150
200
No
. of
pa
tie
nts
10-19 20-29 30-39 40-49 50-59 60-69 >70
Age of onset
0-9
Age distribution of new incident cases
0
50
100
150
200
250
300
0-9 10-19 20-29 30-39 40-49 50-59 60-69 >70
Prev
alen
ce ra
te
Age group
Age distribution of prevalence
70,63/million
Epidemiology in Malaysia (1980 )
No of Patients: 62 (University Hospital, KL)
Incidence: 2.6 cases per 10000 admissions
Prevalence: -
Female : Male = 1 : 1
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.
Clinical Features
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)
Understanding AChR as the autoantigen
MAIN IMMUNOGENIC REGION = MIR
1985: Myasthenia in Greece – Hellenic Pasteur Institute
Expressing all the AChR subunits with prokaryotic
and eukaryotic expression systems
New Autoantigens – New diagnostic assaysDiagnosis with (RadioImmunoAssays) RIAs –
Epidemiology of MG in GREECE
α
β γ/ε
δ α
70 Å
αβ
γ/ε
δ α
Unwin & col.
Extracellular
domain (ECD)
Muscle-type Torpedo AChR Snail AChBP
Smit, Sixma & col, 2001Cytoplasmic
domain
Torpedo AChR at 4 Å resolution
Unwin, 2005
Extra-cellular
domain
(ECD)
Cyto-plasmic
domain
NEUROMUSCULAR JUNCTION
Vesicles
with AChNerve
Terminal
Muscle
Normal Myasthenia gravis
MECHANISMS OF ACTION OF ANTI-ACHR ANTIBODIES
Direct blockage of AChR
function
Accelerated internalization and
degradation of AChRs
Complement-mediated membrane
lysis
Complement
Ach binding site
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)
APC
MHC
TCR CD28
B7
Resting T cell Regulatory T cell
Activated T cell
B cell
Ab to
AChR
AChR
Muscle
IVIg
Immunosupressives(Prednizone, Azathioprine,
Cyclophosphamide,
Cyclosporine A,
mycophenolate mofetil)
Inhibitors of
Ach-esterase
Plasmapheresis
Thymectomy
CURRENT THERAPIES OF MG
Autoantigen Generalized MG Ocular MG
AChR (1973-76) 80-85% 50%
MuSK (2001) ~5% ~0%
LRP4 (2011) ~~2% ~~10%
Αgrin, ColQ (2012) ? ?
AUTOANTIGENS IN MYASTHENIA
AChR
PP
MuSK
LRP-4 LRP-4
Agrin LRP4 MuSK rapsyn AChRs aggregation
Agrin
radioactive + serum + anti-serum radioactive precipitant
AChR of patient
?
U?
~85% of patients with generalized MG
~50% of patients with ocular MG
Α. Radio Immuno Assay (RIA) – Lindstrom 1976:
Diagnosis for anti-AChR antibodies
1st antigen: AChR
• ~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;
Anti-MuSK antibodies:
2001 - 2nd antigen: muscle specific kinase (MuSK) –Vincent et al.
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
• 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
3rd antigen: LRP4
Konstantinos Poulas
Associate Professor,
Laboratory of Mol. Biology and Immunology
Department of Pharmacy, University of Patras
GREECE
Email: [email protected]
KPJ Conference 2014
MYASTHENIA GRAVIS
GENOMIC MEDICINE AND PERSONALIZED HEALTH
Understanding AChR as the autoantigen
2000: Myasthenia in Greece – University of Patras
Expressing all the AChR subunits with prokaryotic
and eukaryotic expression systems
Genomics – SNPs identificationDiagnosis with (RadioImmunoAssays) RIAs –
Epidemiology of MG in GREECE
Whole blood or plasma of patients
Immobilized -expressed ECDs E. coli
Immobilizedyeast-expressed ECDs
CNBrSepharose
CNBr
Sepha rose
γ
γ
α1
α1
β1
β1
ε
ε
Column Beads
AChR or MuSK domains
(immunoadsorbents)
Autoantibodies
«Useful» antibodies
AChR and MuSK domains as immunoadsorbents
MG symptoms within 24-48 hours
MG sera Whole
serum
Depleting serum (without
the anti-AChR antibodies)
Anti-AChR
antibodies
MG1 (anti-α) +++ - +++
MG2 (anti-α) ++ - +++
MG3 (anti-β) + - ?
MG4 (anti-β) + - ?
= only the anti-AChR antibodies can cause ΜG
= the depletion of anti-AChR antibodies can be enough for therapeutic purposes
Is the anti-AChR antibodies’ depletion enough for removing the
myasthenic symptoms?
THANK YOU KL
PONE-D-14-20638R1
Direct proof of the in vivo pathogenic role of the AChR autoantibodies from myasthenia gravis patientsPLOS 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
Please contact [email protected] 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
Θέμα:PLOS ONE Decision: Accept [PONE-D-14-20638R1] - [EMID:915a8a9090c8d3d7]Ημερομηνία:2014-08-21 15:04Αποστολέας:"PLOS ONE" <[email protected]>Παραλήπτης:"George Lagoumintzis" <[email protected]>
Απάντηση στο:"PLOS ONE" <[email protected]>
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
DON’T 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)
Recent Advances in Laser Refractive Surgery by Dr ChoongYen Yaw, Centre For Sight, Tawakal Health Centre
Updates in Colorectal Cancers by Dr Sangeetha Poovaneswaran, KPJ Damansara
Wireless Micro Current Stimulation (WMCS) - An Innovative Technology for the Management of Hard-to-Heal
Wounds – Clinical, Histological and Cellular Data, by Prof. K. Poulas, University of Patras, Greece
Advances in Thyroid Surgery by Prof. Mr. Rohaizak bin Muhammad, UKM
