Researchers from School of Medicine revealed a new mechanism of autoimmune disease Myasthenia Gravis

  Recently, Du Ailian‘s groupfrom the Department of Neurology ofthe affiliated Tongren Hospital, combined withXU Congfeng’s group from the Shanghai Institute of Immunology autophagypublished an article entitledSuppression of CHRN endocytosis by carbonic anhydrase CAR3 in the pathogenesis of myasthenia gravis inAutophagy, the authored journal in the field of autophagy, whichreveals the molecular mechanism that carbonic anhydrase III (CAR3) ameliorates myasthenia gravis by maintaining the stability of nAChR, an acetylcholine receptor in skeletal muscle cells.

  Myasthenia gravis (MG) is a classical antibody-mediated autoimmune disease and is also the most common type of disease in the neuromuscular junction delivery disorders. It often affects extraocular muscles, limb muscles, swallowing muscles and even respiratory muscles, leading to morbid fatigue, swallowing difficulties, breathing difficulties and evensevere life-threatening respiratory failure, causing heavy burdens on patients‘ lives and families. In the development of myasthenia gravis, autoantibodies are directed against the cholinergic receptor nicotinic (CHRN) on the postsynaptic membrane of skeletal muscle motility end-plates, resulting in the destruction of the normal structure of the postsynaptic membrane, the dysfunction of neuro-muscle conduction and then muscle weakness symptoms. However, the mechanisms of autoantibody production and how they work are not clear. Doctor Du Ai Lian once participated in Professor Lu Chuanzhen’sa series of studiesof pathogenesis of myasthenia graviswhen she was pursuing Ph.D inHuashan Hospitalaffiliated to Fudan University, and found that P25 protein was specifically reduced in skeletal muscle in MGpatients, which wasconfirmed to be carbonic anhydrase (CAR3) (Autoimmunity, 2009)by flight mass spectrometry, etc. In recent years Xu Congfeng‘s group has further explored the mechanism of CAR3 in the pathogenesis of myasthenia gravis, in whichthroughusing acetylcholine-receptor-induced experimental autoimmune myasthenia gravis model (homolog of CA3mouse),they found that CAR3 agonists couldmaintain the stability of nAChR and alleviate the symptoms of myasthenia gravis in myasthenia gravis mice. Further mechanism studies demonstrated that activation of CAR3 would maintain the stability of nAChR by inhibiting the internalization and degradation of nAChR on the surface of skeletal muscle cells by regulating chaperone-assisted selective autophagy (CASA).

  CAR3, accounting for up to 3%in skeletal muscle,in addition to the involvement ofacetylcholine receptor internalization and degradation, also participates in the production of muscle-specific autoantibodies, suggesting that CAR3 may be involved in the development of myasthenia gravis by a variety of mechanisms, which is possible to reveal a new pathogenesis, and the relevant part of the work is also submitted. Since CAR3 is predominantly expressed in skeletal muscle, CAR3 agonists will be highly effective with little side effects. CAR3 agonist screening work is also underway, which is expected to become a new treatment for myasthenia gravis, and some of them have been patented.

  This study was completed by Shanghai Institute of Immunology, Institute of Health Sciences, Tongren Hospital affiliated to Shanghai Jiao Tong University School of Medicine and Huashan Hospital affiliated to Fudan University. This research has been funded by the National Natural Science Foundation of China (81200967, 31570905, 81190133), Shanghai Municipal Science and Technology Commission and Shanghai Talent Development Fund.