Myasthenia gravis By: Nikki Young

Overview I: Epidemiology II: Risk Factors III: Symptoms of MG IV: Types of MG V: Pathophysiology and Mechanisms of MG VI: Treatment of MG VII: References and Study Questions

Gender and ethnicity are linked to rate of MG prevalence 20 per 100,000 US Incidence 1.7 to 10.4 per 1 million Gender < 40 women > 50 men Ethnic origin Low in Europe, North America High in China Earlier onset

HLA association is a known risk factor of MG Common HLA Association HLA-DR3, B8, DR9 early onset HLA-DR2, B7 late onset DR14, DQ5 (Anti-MuSK) Mostly unknown causes Possible risks: genetic link, other AI disease, thymoma https://dreamerbiologist.wordpress.com/2013/04/19/hla-complex-in-predictive-medicine/

Main symptoms of MG include muscle weakness and fatigue Eyes/Face Ptsosis, diplopia Facial muscle weakness (eyelid closure, drooling) Bulbar Dysphagia, Dysarthria, Dysphonia Jaw fatigue Head/neck Head droop Limbs Arms > legs (waddling) Respiratory Dyspnea Respiratory failure (myasthenic crisis) http://pivotalphysio.com/exercise-myasthenia-gravis/

MG is not just an autoimmune disease Autoimmune MG Ocular (oMG) ~10% Generalized (gMG) w/in 2 years Neonatal MG Maternal Abs Congenital Myasthenia Genetic mutations

Two known types of autoimmune MG Anti-AChR (acetylcholine receptor) Focus: ~80-90%, known mechanisms Anti-MuSK (muscle specific kinase) Differences, 30-40% remaining cases Unsure of pathophysiology Others seronegative

What are the three mechanisms of Anti-AChR MG? 1) Complement Activation IgG 1 and 3 MAC Flattened membrane 2) Antigenic Modulation Crosslinking Abs Endocytosis, degradation 3) AChR Block Bind Ach binding site Block neuromuscular transmission

Mechanisms of Anti-MuSK MG are still being researched MuSK important for AChR clustering and membrane stability Complement activation unlikely IgG4 Abs

Differences between Anti-AChR and Anti-MuSK MG AChR-MG MuSK-MG Age of onset Bimodal: <40 & >50 4th decade Gender Female <40, Male >50 85% female Pattern of weakness Predominant ocular involvement Bulbar and limb weakness Neck, shoulder, bulbar and respiratory weakness Distinctive features Initially ocular, later becomes generalized Cranial and bulbar atrophy, triple furrowing of the tongue HLA association DR3, B8, DR9 early onset DR2, B7 late onset DR14, DQ5

What role to Th cells play in MG? Anti-AChR MG Anti-Musk MG Th1 cells Th2 cells Increased MHC-II expression B-cells to produce IgG4 Complement activation

Cholinesterase Inhibitors Treatments for MG Cholinesterase Inhibitors Longer ACh activity Immune Therapies Short-term Plasma Exchange IV Ig Long-term Corticosteroids Immunosuppressant drugs Thymectomy http://peaknootropics.com/using-acetylcholinesterase-inhibitors-nootropics/

References Meriggioli, M. N., & Sanders, D. B. (2009). Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. The Lancet Neurology, 8(5), 475-490. Conti-Fine, B. M., Milani, M., & Kaminski, H. J. (2006). Myasthenia gravis: past, present, and future. The Journal of clinical investigation, 116(11), 2843-2854. Hurst, R. L., & Gooch, C. L. (2016). Muscle-Specific Receptor Tyrosine Kinase (MuSK) Myasthenia Gravis. Current Neurology and Neuroscience Reports, 16(7), 1-4. doi:10.1007/S11910-016-0668-Z Verschuuren, J., Huijbers, M., Plomp, J., Niks, E., Molenaar, P., Martinez-Martinez, P., . . . Losen, M. (2013). Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmunity Reviews, 12(9), 918-923. doi:10.1016/J.AUTREV.2013.03.001 Symptoms Image: http://pivotalphysio.com/exercise-myasthenia-gravis/ Koneczny, I., Cossins, J. and Vincent, A. (2014), The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J. Anat., 224: 29–35. doi:10.1111/joa.12034 https://dreamerbiologist.wordpress.com/2013/04/19/hla-complex-in-predictive-medicine/ http://peaknootropics.com/using-acetylcholinesterase-inhibitors-nootropics/

Study Questions 1) Which is not an immunological mechanism of Anti-AChR MG? Complement binding and activation Inhibition of acetylcholine release AChR block Antigenic modulation 2) Which is not a role of Th cells in MG? Complement activation IgG4 production by plasma cells Decreased ACh production Increased MHC-II expression in muscle cells

3) What is not a current treatment for MG? Cholinesterase inhibitors Complement inhibition Thymectomy Corticosteroids 4) The most common symptoms of MG include: Muscle weakness Fatigue Myasthenic crisis Both A and B

Short Answer: What is the difference in the target of Anti-AChR and Anti-MuSK Abs, and what is a possible difference in the clinical presentation of these two types of MG?