Myasthenia gravis pathophysiology: Difference between revisions

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{{Myasthenia gravis}}
{{Myasthenia gravis}}


{{CMG}}
{{CMG}} {{Fs}}
==Overview==
==Overview==
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]]. Genes involved in the pathogenesis of Myasthenia gravis include: [[MHC|The Major Histocompatibility Complex]], the [[CHRNA1]] [[Locus]], the [[PTPN22]] [[Gene]], the [[FCGR2A|FCGR2]] [[Locus]] and the [[CTLA-4|CTLA4]] [[Locus]].


==Pathophysiology==
==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 [[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>
=== Physiology ===
* 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" /><ref name="pmid11231638" /><ref name="pmid9464682" />
 
=== Pathogenesis ===
* 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.<ref name="pmid15048899">{{cite journal |vauthors=McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, Vincent A |title=Detection and characterization of MuSK antibodies in seronegative myasthenia gravis |journal=Ann. Neurol. |volume=55 |issue=4 |pages=580–4 |date=April 2004 |pmid=15048899 |doi=10.1002/ana.20061 |url=}}</ref><ref name="pmid3621677">{{cite journal |vauthors=Rødgaard A, Nielsen FC, Djurup R, Somnier F, Gammeltoft S |title=Acetylcholine receptor antibody in myasthenia gravis: predominance of IgG subclasses 1 and 3 |journal=Clin. Exp. Immunol. |volume=67 |issue=1 |pages=82–8 |date=January 1987 |pmid=3621677 |pmc=1542559 |doi= |url=}}</ref><ref name="pmid18515870">{{cite journal |vauthors=Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, Beeson D, Willcox N, Vincent A |title=IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis |journal=Brain |volume=131 |issue=Pt 7 |pages=1940–52 |date=July 2008 |pmid=18515870 |pmc=2442426 |doi=10.1093/brain/awn092 |url=}}</ref>
* 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]].<ref name="pmid17310034">{{cite journal |vauthors=Deymeer F, Gungor-Tuncer O, Yilmaz V, Parman Y, Serdaroglu P, Ozdemir C, Vincent A, Saruhan-Direskeneli G |title=Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis |journal=Neurology |volume=68 |issue=8 |pages=609–11 |date=February 2007 |pmid=17310034 |doi=10.1212/01.wnl.0000254620.45529.97 |url=}}</ref>
** About 50 percent of them turn out to be positive for clustered [[Acetylcholine receptor|AChR]] [[antibodies]] after cell-based [[immunofluorescence]]. <ref name="pmid18515870">{{cite journal |vauthors=Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, Beeson D, Willcox N, Vincent A |title=IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis |journal=Brain |volume=131 |issue=Pt 7 |pages=1940–52 |date=July 2008 |pmid=18515870 |pmc=2442426 |doi=10.1093/brain/awn092 |url=}}</ref><ref name="pmid22689047">{{cite journal |vauthors=Jacob S, Viegas S, Leite MI, Webster R, Cossins J, Kennett R, Hilton-Jones D, Morgan BP, Vincent A |title=Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis |journal=Arch. Neurol. |volume=69 |issue=8 |pages=994–1001 |date=August 2012 |pmid=22689047 |doi=10.1001/archneurol.2012.437 |url=}}</ref><ref name="pmid25894002">{{cite journal |vauthors=Rodríguez Cruz PM, Al-Hajjar M, Huda S, Jacobson L, Woodhall M, Jayawant S, Buckley C, Hilton-Jones D, Beeson D, Vincent A, Leite MI, Palace J |title=Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine Receptors in the Diagnosis of Seronegative Myasthenia Gravis |journal=JAMA Neurol |volume=72 |issue=6 |pages=642–9 |date=June 2015 |pmid=25894002 |doi=10.1001/jamaneurol.2015.0203 |url=}}</ref>
** The other half may be positive for other [[antibodies]] including [[antibody]] against LRP4 (which are IgG1)<ref name="pmid21387385">{{cite journal |vauthors=Higuchi O, Hamuro J, Motomura M, Yamanashi Y |title=Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis |journal=Ann. Neurol. |volume=69 |issue=2 |pages=418–22 |date=February 2011 |pmid=21387385 |doi=10.1002/ana.22312 |url=}}</ref>, [[cortactin]] (which help [[Acetylcholine receptor|AChR]] clustering)<ref name="pmid20041195">{{cite journal |vauthors=Madhavan R, Gong ZL, Ma JJ, Chan AW, Peng HB |title=The function of cortactin in the clustering of acetylcholine receptors at the vertebrate neuromuscular junction |journal=PLoS ONE |volume=4 |issue=12 |pages=e8478 |date=December 2009 |pmid=20041195 |pmc=2793544 |doi=10.1371/journal.pone.0008478 |url=}}</ref>, [[ryanodine receptor]], [[titin]], [[myosin]], alpha actin, rapsyn and gravin.<ref name="pmid2323065">{{cite journal |vauthors=Ohta M, Ohta K, Itoh N, Kurobe M, Hayashi K, Nishitani H |title=Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-myosin, actomyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis |journal=Clin. Chim. Acta |volume=187 |issue=3 |pages=255–64 |date=March 1990 |pmid=2323065 |doi= |url=}}</ref><ref name="pmid9000000">{{cite journal |vauthors=Nauert JB, Klauck TM, Langeberg LK, Scott JD |title=Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein |journal=Curr. Biol. |volume=7 |issue=1 |pages=52–62 |date=January 1997 |pmid=9000000 |doi= |url=}}</ref><ref name="pmid9668284">{{cite journal |vauthors=Agius MA, Zhu S, Kirvan CA, Schafer AL, Lin MY, Fairclough RH, Oger JJ, Aziz T, Aarli JA |title=Rapsyn antibodies in myasthenia gravis |journal=Ann. N. Y. Acad. Sci. |volume=841 |issue= |pages=516–21 |date=May 1998 |pmid=9668284 |doi= |url=}}</ref>
* 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]].<ref name="pmid8429105">{{cite journal |vauthors=Yi Q, Pirskanen R, Lefvert AK |title=Human muscle acetylcholine receptor reactive T and B lymphocytes in the peripheral blood of patients with myasthenia gravis |journal=J. Neuroimmunol. |volume=42 |issue=2 |pages=215–22 |date=February 1993 |pmid=8429105 |doi= |url=}}</ref>
** The role of T cells: There are two kinds of [[CD4+ T cells]], [[Th1]] and [[Th2]]. Th1 cells produce [[IL-2]], IFN-γ and [[TNF-alpha|TNF- α]] which are proinflammatory [[cytokines]] and stimulate [[Cell-mediated immune response|cell-mediated immune responses]]. [[Th2]] cells produce [[IL-4]], [[IL-6]] and [[IL-10]] which are anti-inflammatory [[cytokines]] and stimulate [[humoral immune response]]. In the blood of [[Myasthenia gravis|MG]] patients we have anti-[[Acetylcholine receptor|AChR]] Th1 cells against which can induce [[B cell|B cells]] to produce high-affinity anti-[[Acetylcholine receptor|AChR]] antibodies. Based on this fact treatment against [[Th1]] cells can improve [[Myasthenia gravis|MG]] [[Symptom|symptoms]].<ref name="pmid11777558">{{cite journal |vauthors=Christadoss P, Goluszko E |title=Treatment of experimental autoimmune myasthenia gravis with recombinant human tumor necrosis factor receptor Fc protein |journal=J. Neuroimmunol. |volume=122 |issue=1-2 |pages=186–90 |date=January 2002 |pmid=11777558 |doi= |url=}}</ref><ref name="pmid15843529">{{cite journal |vauthors=Feferman T, Maiti PK, Berrih-Aknin S, Bismuth J, Bidault J, Fuchs S, Souroujon MC |title=Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis |journal=J. Immunol. |volume=174 |issue=9 |pages=5324–31 |date=May 2005 |pmid=15843529 |doi= |url=}}</ref><ref name="pmid10973283">{{cite journal |vauthors=Shi FD, Wang HB, Li H, Hong S, Taniguchi M, Link H, Van Kaer L, Ljunggren HG |title=Natural killer cells determine the outcome of B cell-mediated autoimmunity |journal=Nat. Immunol. |volume=1 |issue=3 |pages=245–51 |date=September 2000 |pmid=10973283 |doi=10.1038/79792 |url=}}</ref>
 
== Genetics ==
Genes involved in the pathogenesis of Myasthenia gravis include:
* [[MHC|The Major Histocompatibility Complex]]: In genetic etiology of most of the [[autoimmune diseases]] including [[Myasthenia gravis|MG]], [[MHC]] genes play the most important role.<ref name="pmid4544224">{{cite journal |vauthors=Feltkamp TE, van den Berg-Loonen PM, Nijenhuis LE, Engelfriet CP, van Rossum AL, van Loghem JJ, Oosterhuis HJ |title=Myasthenia gravis, autoantibodies, and HL-A antigens |journal=Br Med J |volume=1 |issue=5899 |pages=131–3 |date=January 1974 |pmid=4544224 |pmc=1633001 |doi= |url=}}</ref>
* The [[CHRNA1]] [[Locus]]: The [[Translation (genetics)|translation]] product of this [[gene]] is the alpha subunit of [[Acetylcholine receptor|AChR]], which is the target of many [[autoantibodies]] in myasthenia gravis patients.<ref name="pmid9700504">{{cite journal |vauthors=Tzartos SJ, Barkas T, Cung MT, Mamalaki A, Marraud M, Orlewski P, Papanastasiou D, Sakarellos C, Sakarellos-Daitsiotis M, Tsantili P, Tsikaris V |title=Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor |journal=Immunol. Rev. |volume=163 |issue= |pages=89–120 |date=June 1998 |pmid=9700504 |doi= |url=}}</ref>
* The [[PTPN22]] [[Gene]]: This [[gene]] is responsible for producing an intracellular protein phosphatase [[PTPN22]]. The impaired binding of this protein to protein tyrosine kinase Csk occurs as a result of a missense polymorphism which replace [[arginine]] with [[tryptophan]]. Activity of [[PTPN22]] will increase and inhibits [[T cell]] activation and [[interleukin 2]] production which leads to predisposition to [[autoimmunity]].<ref name="pmid15004560">{{cite journal |vauthors=Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T |title=A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes |journal=Nat. Genet. |volume=36 |issue=4 |pages=337–8 |date=April 2004 |pmid=15004560 |doi=10.1038/ng1323 |url=}}</ref><ref name="pmid17277778">{{cite journal |vauthors=Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen SL, Rosa R, Cumiskey AM, Serreze DV, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA, Peterson LB, Wicker LS, Santamaria P |title=Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity |journal=Nat. Genet. |volume=39 |issue=3 |pages=329–37 |date=March 2007 |pmid=17277778 |pmc=2886969 |doi=10.1038/ng1958 |url=}}</ref>
* The [[FCGR2A|FCGR2]] [[Locus]]: Some studies investigated the relationship between [[Polymorphisms|polymorphism]] of FC receptors [[gene]] and [[Myasthenia gravis|MG]] and suggested that R arginine variant in type 2 (FCGR2) can be related to this disease.<ref name="pmid9521619">{{cite journal |vauthors=Raknes G, Skeie GO, Gilhus NE, Aadland S, Vedeler C |title=FcgammaRIIA and FcgammaRIIIB polymorphisms in myasthenia gravis |journal=J. Neuroimmunol. |volume=81 |issue=1-2 |pages=173–6 |date=January 1998 |pmid=9521619 |doi= |url=}}</ref><ref name="pmid14597109">{{cite journal |vauthors=van der Pol WL, Jansen MD, Kuks JB, de Baets M, Leppers-van de Straat FG, Wokke JH, van de Winkel JG, van den Berg LH |title=Association of the Fc gamma receptor IIA-R/R131 genotype with myasthenia gravis in Dutch patients |journal=J. Neuroimmunol. |volume=144 |issue=1-2 |pages=143–7 |date=November 2003 |pmid=14597109 |doi= |url=}}</ref>
* The [[CTLA-4|CTLA4]] [[Locus]]: This [[gene]] is known to be responsible for many [[autoimmune diseases]].<ref name="pmid11196709">{{cite journal |vauthors=Kristiansen OP, Larsen ZM, Pociot F |title=CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity? |journal=Genes Immun. |volume=1 |issue=3 |pages=170–84 |date=February 2000 |pmid=11196709 |doi=10.1038/sj.gene.6363655 |url=}}</ref>
 
== Associated Conditions ==
Conditions associated with Myasthenia gravis include:
* Thymus abnormalities:
** Thymus abnormalities including thymic hyperplasia and [[thymoma]] are very common in myasthenia gravis and [[thymectomy]] is one of the treatment of this disease.<ref name="pmid8190158">{{cite journal |vauthors=Drachman DB |title=Myasthenia gravis |journal=N. Engl. J. Med. |volume=330 |issue=25 |pages=1797–810 |date=June 1994 |pmid=8190158 |doi=10.1056/NEJM199406233302507 |url=}}</ref><ref name="pmid12360217">{{cite journal |vauthors=Vincent A |title=Unravelling the pathogenesis of myasthenia gravis |journal=Nat. Rev. Immunol. |volume=2 |issue=10 |pages=797–804 |date=October 2002 |pmid=12360217 |doi=10.1038/nri916 |url=}}</ref>
 
==Gross Pathology==
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
 
 
== Microscopic Pathology ==
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].


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)
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 00:46, 13 September 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Fahimeh Shojaei, M.D.

Overview

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. Genes involved in the pathogenesis of Myasthenia gravis include: The Major Histocompatibility Complex, the CHRNA1 Locus, the PTPN22 Gene, the FCGR2 Locus and the CTLA4 Locus.

Pathophysiology

Physiology

Pathogenesis

Genetics

Genes involved in the pathogenesis of Myasthenia gravis include:

Associated Conditions

Conditions associated with Myasthenia gravis include:

  • Thymus abnormalities:
    • Thymus abnormalities including thymic hyperplasia and thymoma are very common in myasthenia gravis and thymectomy is one of the treatment of this disease.[31][32]

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].


Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].


References

  1. ↑ 1.0 1.1 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.
  2. ↑ 2.0 2.1 2.2 2.3 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.
  3. ↑ 3.0 3.1 Ruegg MA, Bixby JL (January 1998). "Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction". Trends Neurosci. 21 (1): 22–7. PMID 9464682.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, Vincent A (April 2004). "Detection and characterization of MuSK antibodies in seronegative myasthenia gravis". Ann. Neurol. 55 (4): 580–4. doi:10.1002/ana.20061. PMID 15048899.
  7. ↑ Rødgaard A, Nielsen FC, Djurup R, Somnier F, Gammeltoft S (January 1987). "Acetylcholine receptor antibody in myasthenia gravis: predominance of IgG subclasses 1 and 3". Clin. Exp. Immunol. 67 (1): 82–8. PMC 1542559. PMID 3621677.
  8. ↑ 8.0 8.1 Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, Beeson D, Willcox N, Vincent A (July 2008). "IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis". Brain. 131 (Pt 7): 1940–52. doi:10.1093/brain/awn092. PMC 2442426. PMID 18515870.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Deymeer F, Gungor-Tuncer O, Yilmaz V, Parman Y, Serdaroglu P, Ozdemir C, Vincent A, Saruhan-Direskeneli G (February 2007). "Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis". Neurology. 68 (8): 609–11. doi:10.1212/01.wnl.0000254620.45529.97. PMID 17310034.
  13. ↑ Jacob S, Viegas S, Leite MI, Webster R, Cossins J, Kennett R, Hilton-Jones D, Morgan BP, Vincent A (August 2012). "Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis". Arch. Neurol. 69 (8): 994–1001. doi:10.1001/archneurol.2012.437. PMID 22689047.
  14. ↑ Rodríguez Cruz PM, Al-Hajjar M, Huda S, Jacobson L, Woodhall M, Jayawant S, Buckley C, Hilton-Jones D, Beeson D, Vincent A, Leite MI, Palace J (June 2015). "Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine Receptors in the Diagnosis of Seronegative Myasthenia Gravis". JAMA Neurol. 72 (6): 642–9. doi:10.1001/jamaneurol.2015.0203. PMID 25894002.
  15. ↑ Higuchi O, Hamuro J, Motomura M, Yamanashi Y (February 2011). "Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis". Ann. Neurol. 69 (2): 418–22. doi:10.1002/ana.22312. PMID 21387385.
  16. ↑ Madhavan R, Gong ZL, Ma JJ, Chan AW, Peng HB (December 2009). "The function of cortactin in the clustering of acetylcholine receptors at the vertebrate neuromuscular junction". PLoS ONE. 4 (12): e8478. doi:10.1371/journal.pone.0008478. PMC 2793544. PMID 20041195.
  17. ↑ Ohta M, Ohta K, Itoh N, Kurobe M, Hayashi K, Nishitani H (March 1990). "Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-myosin, actomyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis". Clin. Chim. Acta. 187 (3): 255–64. PMID 2323065.
  18. ↑ Nauert JB, Klauck TM, Langeberg LK, Scott JD (January 1997). "Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein". Curr. Biol. 7 (1): 52–62. PMID 9000000.
  19. ↑ Agius MA, Zhu S, Kirvan CA, Schafer AL, Lin MY, Fairclough RH, Oger JJ, Aziz T, Aarli JA (May 1998). "Rapsyn antibodies in myasthenia gravis". Ann. N. Y. Acad. Sci. 841: 516–21. PMID 9668284.
  20. ↑ Yi Q, Pirskanen R, Lefvert AK (February 1993). "Human muscle acetylcholine receptor reactive T and B lymphocytes in the peripheral blood of patients with myasthenia gravis". J. Neuroimmunol. 42 (2): 215–22. PMID 8429105.
  21. ↑ Christadoss P, Goluszko E (January 2002). "Treatment of experimental autoimmune myasthenia gravis with recombinant human tumor necrosis factor receptor Fc protein". J. Neuroimmunol. 122 (1–2): 186–90. PMID 11777558.
  22. ↑ Feferman T, Maiti PK, Berrih-Aknin S, Bismuth J, Bidault J, Fuchs S, Souroujon MC (May 2005). "Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis". J. Immunol. 174 (9): 5324–31. PMID 15843529.
  23. ↑ Shi FD, Wang HB, Li H, Hong S, Taniguchi M, Link H, Van Kaer L, Ljunggren HG (September 2000). "Natural killer cells determine the outcome of B cell-mediated autoimmunity". Nat. Immunol. 1 (3): 245–51. doi:10.1038/79792. PMID 10973283.
  24. ↑ Feltkamp TE, van den Berg-Loonen PM, Nijenhuis LE, Engelfriet CP, van Rossum AL, van Loghem JJ, Oosterhuis HJ (January 1974). "Myasthenia gravis, autoantibodies, and HL-A antigens". Br Med J. 1 (5899): 131–3. PMC 1633001. PMID 4544224.
  25. ↑ Tzartos SJ, Barkas T, Cung MT, Mamalaki A, Marraud M, Orlewski P, Papanastasiou D, Sakarellos C, Sakarellos-Daitsiotis M, Tsantili P, Tsikaris V (June 1998). "Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor". Immunol. Rev. 163: 89–120. PMID 9700504.
  26. ↑ Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T (April 2004). "A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes". Nat. Genet. 36 (4): 337–8. doi:10.1038/ng1323. PMID 15004560.
  27. ↑ Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen SL, Rosa R, Cumiskey AM, Serreze DV, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA, Peterson LB, Wicker LS, Santamaria P (March 2007). "Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity". Nat. Genet. 39 (3): 329–37. doi:10.1038/ng1958. PMC 2886969. PMID 17277778.
  28. ↑ Raknes G, Skeie GO, Gilhus NE, Aadland S, Vedeler C (January 1998). "FcgammaRIIA and FcgammaRIIIB polymorphisms in myasthenia gravis". J. Neuroimmunol. 81 (1–2): 173–6. PMID 9521619.
  29. ↑ van der Pol WL, Jansen MD, Kuks JB, de Baets M, Leppers-van de Straat FG, Wokke JH, van de Winkel JG, van den Berg LH (November 2003). "Association of the Fc gamma receptor IIA-R/R131 genotype with myasthenia gravis in Dutch patients". J. Neuroimmunol. 144 (1–2): 143–7. PMID 14597109.
  30. ↑ Kristiansen OP, Larsen ZM, Pociot F (February 2000). "CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity?". Genes Immun. 1 (3): 170–84. doi:10.1038/sj.gene.6363655. PMID 11196709.
  31. ↑ Drachman DB (June 1994). "Myasthenia gravis". N. Engl. J. Med. 330 (25): 1797–810. doi:10.1056/NEJM199406233302507. PMID 8190158.
  32. ↑ Vincent A (October 2002). "Unravelling the pathogenesis of myasthenia gravis". Nat. Rev. Immunol. 2 (10): 797–804. doi:10.1038/nri916. PMID 12360217.

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