Myasthenia gravis pathophysiology: Difference between revisions
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Myasthenia gravis is a [[neuromuscular disease]] caused by an [[autoimmune]] reactions. The main problem in this disease is the abnormal transmission of [[nerve impulses]] to [[muscle fibers]] in [[Neuromuscular junction|NMJ]].<ref name="pmid11231638">{{cite journal |vauthors=Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A |title=Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies |journal=Nat. Med. |volume=7 |issue=3 |pages=365–8 |date=March 2001 |pmid=11231638 |doi=10.1038/85520 |url=}}</ref> In the nerve terminals of [[Alpha motor neuron|alpha motor neurons]], there are lots of vesicles containing [[Acetylcholine|ACh]]. When the [[action potential]] reaches the synaptic end, [[Voltage gated calcium channel|voltage gated Ca channels]] will open and trigger the release of these vesicles. [[Acetylcholine|ACh]] will diffuse into [[synaptic cleft]] and binds to [[Acetylcholine receptor|AChR]]. The action of [[Acetylcholine|ACh]] will end with the work of [[Acetylcholinesterase|AChE]]. [[Acetylcholine receptor|ACh receptors]] consist of 5 subunits and are [[transmembrane proteins]]. There are other proteins which help [[Acetylcholine receptor|AChR]] clustering and signal transduction including [[MuSK protein|MuSK]]. It is the receptor of a protein named [[agrin]]. When these two bind to each other, the result is maintaining the clustering of [[Acetylcholine receptor|AChRs]].<ref name="pmid7684117">{{cite journal |vauthors=Horton RM, Manfredi AA, Conti-Tronconi BM |title=The 'embryonic' gamma subunit of the nicotinic acetylcholine receptor is expressed in adult extraocular muscle |journal=Neurology |volume=43 |issue=5 |pages=983–6 |date=May 1993 |pmid=7684117 |doi= |url=}}</ref><ref name="pmid11231638">{{cite journal |vauthors=Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A |title=Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies |journal=Nat. Med. |volume=7 |issue=3 |pages=365–8 |date=March 2001 |pmid=11231638 |doi=10.1038/85520 |url=}}</ref><ref name="pmid9464682">{{cite journal |vauthors=Ruegg MA, Bixby JL |title=Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction |journal=Trends Neurosci. |volume=21 |issue=1 |pages=22–7 |date=January 1998 |pmid=9464682 |doi= |url=}}</ref> | Myasthenia gravis is a [[neuromuscular disease]] caused by an [[autoimmune]] reactions. The main problem in this disease is the abnormal transmission of [[nerve impulses]] to [[muscle fibers]] in [[Neuromuscular junction|NMJ]].<ref name="pmid11231638">{{cite journal |vauthors=Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A |title=Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies |journal=Nat. Med. |volume=7 |issue=3 |pages=365–8 |date=March 2001 |pmid=11231638 |doi=10.1038/85520 |url=}}</ref> In the nerve terminals of [[Alpha motor neuron|alpha motor neurons]], there are lots of vesicles containing [[Acetylcholine|ACh]]. When the [[action potential]] reaches the synaptic end, [[Voltage gated calcium channel|voltage gated Ca channels]] will open and trigger the release of these vesicles. [[Acetylcholine|ACh]] will diffuse into [[synaptic cleft]] and binds to [[Acetylcholine receptor|AChR]]. The action of [[Acetylcholine|ACh]] will end with the work of [[Acetylcholinesterase|AChE]]. [[Acetylcholine receptor|ACh receptors]] consist of 5 subunits and are [[transmembrane proteins]]. There are other proteins which help [[Acetylcholine receptor|AChR]] clustering and signal transduction including [[MuSK protein|MuSK]]. It is the receptor of a protein named [[agrin]]. When these two bind to each other, the result is maintaining the clustering of [[Acetylcholine receptor|AChRs]].<ref name="pmid7684117">{{cite journal |vauthors=Horton RM, Manfredi AA, Conti-Tronconi BM |title=The 'embryonic' gamma subunit of the nicotinic acetylcholine receptor is expressed in adult extraocular muscle |journal=Neurology |volume=43 |issue=5 |pages=983–6 |date=May 1993 |pmid=7684117 |doi= |url=}}</ref><ref name="pmid11231638">{{cite journal |vauthors=Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A |title=Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies |journal=Nat. Med. |volume=7 |issue=3 |pages=365–8 |date=March 2001 |pmid=11231638 |doi=10.1038/85520 |url=}}</ref><ref name="pmid9464682">{{cite journal |vauthors=Ruegg MA, Bixby JL |title=Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction |journal=Trends Neurosci. |volume=21 |issue=1 |pages=22–7 |date=January 1998 |pmid=9464682 |doi= |url=}}</ref> | ||
Not all of the [[Myasthenia gravis|MG]] patients share the same [[Autoantibody|auto antibodies]]. One of these [[Autoantibody|autoantibodies]] is antibody against [[Acetylcholine receptor|AChR]]. They will destruct [[Acetylcholine receptor|AChR]] by 3 mechanisms. First they will activate the [[complement]] system, second they will increase the degradation of [[Acetylcholine receptor|AChR]] by [[Antibody|Ab]] binding and third by blocking [[Acetylcholine receptor|AChR]]’s function.<ref name="pmid7373347">{{cite journal |vauthors=Sahashi K, Engel AG, Lambert EH, Howard FM |title=Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis |journal=J. Neuropathol. Exp. Neurol. |volume=39 |issue=2 |pages=160–72 |date=March 1980 |pmid=7373347 |doi= |url=}}</ref> The other type of [[autoantibody]] in [[Myasthenia gravis|MG]] patients are [[antibody]] against [[MuSK protein|MsUK protein]] (muscle-specific receptor tyrosine kinase).<ref name="pmid11231638">{{cite journal |vauthors=Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A |title=Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies |journal=Nat. Med. |volume=7 |issue=3 |pages=365–8 |date=March 2001 |pmid=11231638 |doi=10.1038/85520 |url=}}</ref><ref name="pmid14592891">{{cite journal |vauthors=Vincent A, McConville J, Farrugia ME, Bowen J, Plested P, Tang T, Evoli A, Matthews I, Sims G, Dalton P, Jacobson L, Polizzi A, Blaes F, Lang B, Beeson D, Willcox N, Newsom-Davis J, Hoch W |title=Antibodies in myasthenia gravis and related disorders |journal=Ann. N. Y. Acad. Sci. |volume=998 |issue= |pages=324–35 |date=September 2003 |pmid=14592891 |doi= |url=}}</ref> [[Acetylcholine receptor|AChR]] antibodies are IgG1 and IgG3 and can bind to [[complement]] and activates them, but in contrast [[antibodies]] against [[MuSK protein|MuSK]] are IgG4 and cannot activate [[complement]] system.(14-15-10) the function of the [[MuSK]] starts with the binding of [[agrin]] and LRP4. Activated [[MuSK protein|MuSK]] cause recruitment and clustering of [[Acetylcholine receptor|AChRs]]. | Not all of the [[Myasthenia gravis|MG]] patients share the same [[Autoantibody|auto antibodies]]. One of these [[Autoantibody|autoantibodies]] is antibody against [[Acetylcholine receptor|AChR]]. They will destruct [[Acetylcholine receptor|AChR]] by 3 mechanisms. First they will activate the [[complement]] system, second they will increase the degradation of [[Acetylcholine receptor|AChR]] by [[Antibody|Ab]] binding and third by blocking [[Acetylcholine receptor|AChR]]’s function.<ref name="pmid7373347">{{cite journal |vauthors=Sahashi K, Engel AG, Lambert EH, Howard FM |title=Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis |journal=J. Neuropathol. Exp. Neurol. |volume=39 |issue=2 |pages=160–72 |date=March 1980 |pmid=7373347 |doi= |url=}}</ref> The other type of [[autoantibody]] in [[Myasthenia gravis|MG]] patients are [[antibody]] against [[MuSK protein|MsUK protein]] (muscle-specific receptor tyrosine kinase).<ref name="pmid11231638">{{cite journal |vauthors=Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A |title=Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies |journal=Nat. Med. |volume=7 |issue=3 |pages=365–8 |date=March 2001 |pmid=11231638 |doi=10.1038/85520 |url=}}</ref><ref name="pmid14592891">{{cite journal |vauthors=Vincent A, McConville J, Farrugia ME, Bowen J, Plested P, Tang T, Evoli A, Matthews I, Sims G, Dalton P, Jacobson L, Polizzi A, Blaes F, Lang B, Beeson D, Willcox N, Newsom-Davis J, Hoch W |title=Antibodies in myasthenia gravis and related disorders |journal=Ann. N. Y. Acad. Sci. |volume=998 |issue= |pages=324–35 |date=September 2003 |pmid=14592891 |doi= |url=}}</ref> [[Acetylcholine receptor|AChR]] antibodies are IgG1 and IgG3 and can bind to [[complement]] and activates them, but in contrast [[antibodies]] against [[MuSK protein|MuSK]] are IgG4 and cannot activate [[complement]] system.(14-15-10) the function of the [[MuSK]] starts with the binding of [[agrin]] and LRP4. Activated [[MuSK protein|MuSK]] cause recruitment and clustering of [[Acetylcholine receptor|AChRs]].<ref name="pmid20974278">{{cite journal |vauthors=Ghazanfari N, Fernandez KJ, Murata Y, Morsch M, Ngo ST, Reddel SW, Noakes PG, Phillips WD |title=Muscle specific kinase: organiser of synaptic membrane domains |journal=Int. J. Biochem. Cell Biol. |volume=43 |issue=3 |pages=295–8 |date=March 2011 |pmid=20974278 |doi=10.1016/j.biocel.2010.10.008 |url=}}</ref><ref name="pmid20603078">{{cite journal |vauthors=Bergamin E, Hallock PT, Burden SJ, Hubbard SR |title=The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization |journal=Mol. Cell |volume=39 |issue=1 |pages=100–9 |date=July 2010 |pmid=20603078 |pmc=2917201 |doi=10.1016/j.molcel.2010.06.007 |url=}}</ref><ref name="pmid16794080">{{cite journal |vauthors=Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y |title=The muscle protein Dok-7 is essential for neuromuscular synaptogenesis |journal=Science |volume=312 |issue=5781 |pages=1802–5 |date=June 2006 |pmid=16794080 |doi=10.1126/science.1127142 |url=}}</ref> There are a group of [[Myasthenia gravis|MG]] patients which are [[seronegative]] for both [[Acetylcholine receptor|AChR]] and [[MuSK protein|MuSK]] [[antibodies]].(31-32) About 50 percent of them turn out to be positive for clustered [[Acetylcholine receptor|AChR]] [[antibodies]] after cell-based [[immunofluorescence]]. (15-33-34) The other half may be positive for other [[antibodies]] including [[antibody]] against LRP4 (which are IgG1)(35), [[cortactin]] (which help [[Acetylcholine receptor|AChR]] clustering)(38), [[ryanodine receptor]], [[titin]], [[myosin]], alpha actin, rapsyn and gravin.(40-41-42) Other than [[B cells]], [[T cells]] have a role in the pathology on [[Myasthenia gravis|MG]] too. They will not act as the effector cells but stimulate [[B cells]] to produce more [[antibodies]].(43) | ||
[[Thymus]] abnormalities including thymic hyperplasia and [[thymoma]] are very common in myasthenia gravis and [[thymectomy]] is one of the treatment of this disease.(1-2) In [[thymus]], we have myoid cells which present intact [[Acetylcholine receptor|AChR]] on their surface. On the other hand thymic epithelial cells produce [[Acetylcholine receptor|AChR]] subunits which activate [[helper T cells]]. These [[T cell|T cells]] attack [[Acetylcholine receptor|AChR]] on the myoid cells and the cascade of [[antibody]] production and [[complement]] activation will begin.(45-46-47) | [[Thymus]] abnormalities including thymic hyperplasia and [[thymoma]] are very common in myasthenia gravis and [[thymectomy]] is one of the treatment of this disease.(1-2) In [[thymus]], we have myoid cells which present intact [[Acetylcholine receptor|AChR]] on their surface. On the other hand thymic epithelial cells produce [[Acetylcholine receptor|AChR]] subunits which activate [[helper T cells]]. These [[T cell|T cells]] attack [[Acetylcholine receptor|AChR]] on the myoid cells and the cascade of [[antibody]] production and [[complement]] activation will begin.(45-46-47) | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Myasthenia gravis is a neuromuscular disease caused by an autoimmune reactions. The main problem in this disease is the abnormal transmission of nerve impulses to muscle fibers in NMJ.[1] In the nerve terminals of alpha motor neurons, there are lots of vesicles containing ACh. When the action potential reaches the synaptic end, voltage gated Ca channels will open and trigger the release of these vesicles. ACh will diffuse into synaptic cleft and binds to AChR. The action of ACh will end with the work of AChE. ACh receptors consist of 5 subunits and are transmembrane proteins. There are other proteins which help AChR clustering and signal transduction including MuSK. It is the receptor of a protein named agrin. When these two bind to each other, the result is maintaining the clustering of AChRs.[2][1][3]
Not all of the MG patients share the same auto antibodies. One of these autoantibodies is antibody against AChR. They will destruct AChR by 3 mechanisms. First they will activate the complement system, second they will increase the degradation of AChR by Ab binding and third by blocking AChR’s function.[4] The other type of autoantibody in MG patients are antibody against MsUK protein (muscle-specific receptor tyrosine kinase).[1][5] AChR antibodies are IgG1 and IgG3 and can bind to complement and activates them, but in contrast antibodies against MuSK are IgG4 and cannot activate complement system.(14-15-10) the function of the MuSK starts with the binding of agrin and LRP4. Activated MuSK cause recruitment and clustering of AChRs.[6][7][8] There are a group of MG patients which are seronegative for both AChR and MuSK antibodies.(31-32) About 50 percent of them turn out to be positive for clustered AChR antibodies after cell-based immunofluorescence. (15-33-34) The other half may be positive for other antibodies including antibody against LRP4 (which are IgG1)(35), cortactin (which help AChR clustering)(38), ryanodine receptor, titin, myosin, alpha actin, rapsyn and gravin.(40-41-42) Other than B cells, T cells have a role in the pathology on MG too. They will not act as the effector cells but stimulate B cells to produce more antibodies.(43)
Thymus abnormalities including thymic hyperplasia and thymoma are very common in myasthenia gravis and thymectomy is one of the treatment of this disease.(1-2) In thymus, we have myoid cells which present intact AChR on their surface. On the other hand thymic epithelial cells produce AChR subunits which activate helper T cells. These T cells attack AChR on the myoid cells and the cascade of antibody production and complement activation will begin.(45-46-47)
References
- ↑ 1.0 1.1 1.2 Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A (March 2001). "Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies". Nat. Med. 7 (3): 365–8. doi:10.1038/85520. PMID 11231638.
- ↑ Horton RM, Manfredi AA, Conti-Tronconi BM (May 1993). "The 'embryonic' gamma subunit of the nicotinic acetylcholine receptor is expressed in adult extraocular muscle". Neurology. 43 (5): 983–6. PMID 7684117.
- ↑ Ruegg MA, Bixby JL (January 1998). "Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction". Trends Neurosci. 21 (1): 22–7. PMID 9464682.
- ↑ Sahashi K, Engel AG, Lambert EH, Howard FM (March 1980). "Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis". J. Neuropathol. Exp. Neurol. 39 (2): 160–72. PMID 7373347.
- ↑ Vincent A, McConville J, Farrugia ME, Bowen J, Plested P, Tang T, Evoli A, Matthews I, Sims G, Dalton P, Jacobson L, Polizzi A, Blaes F, Lang B, Beeson D, Willcox N, Newsom-Davis J, Hoch W (September 2003). "Antibodies in myasthenia gravis and related disorders". Ann. N. Y. Acad. Sci. 998: 324–35. PMID 14592891.
- ↑ Ghazanfari N, Fernandez KJ, Murata Y, Morsch M, Ngo ST, Reddel SW, Noakes PG, Phillips WD (March 2011). "Muscle specific kinase: organiser of synaptic membrane domains". Int. J. Biochem. Cell Biol. 43 (3): 295–8. doi:10.1016/j.biocel.2010.10.008. PMID 20974278.
- ↑ Bergamin E, Hallock PT, Burden SJ, Hubbard SR (July 2010). "The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization". Mol. Cell. 39 (1): 100–9. doi:10.1016/j.molcel.2010.06.007. PMC 2917201. PMID 20603078.
- ↑ Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y (June 2006). "The muscle protein Dok-7 is essential for neuromuscular synaptogenesis". Science. 312 (5781): 1802–5. doi:10.1126/science.1127142. PMID 16794080.