Myasthenia gravis pathophysiology
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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
- 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.[1][2][3]
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 NMJ.[2] 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.[1][2][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).[2][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.[6][7][8]
- The function of the MuSK starts with the binding of agrin and LRP4. Activated MuSK cause recruitment and clustering of AChRs.[9][10][11]
- There are a group of MG patients which are seronegative for both AChR and MuSK antibodies.[12]
- About 50 percent of them turn out to be positive for clustered AChR antibodies after cell-based immunofluorescence. [8][13][14]
- The other half may be positive for other antibodies including antibody against LRP4 (which are IgG1)[15], cortactin (which help AChR clustering)[16], ryanodine receptor, titin, myosin, alpha actin, rapsyn and gravin.[17][18][19]
- 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.[20]
- 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- α which are proinflammatory cytokines and stimulate 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 MG patients we have anti-AChR Th1 cells against which can induce B cells to produce high-affinity anti-AChR antibodies. Based on this fact treatment against Th1 cells can improve MG symptoms.[21][22][23]
Genetics
Genes involved in the pathogenesis of Myasthenia gravis include:
- The Major Histocompatibility Complex: In genetic etiology of most of the autoimmune diseases including MG, MHC genes play the most important role.[24]
- The CHRNA1 Locus: The translation product of this gene is the alpha subunit of AChR, which is the target of many autoantibodies in myasthenia gravis patients.[25]
- 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.[26][27]
- The FCGR2 Locus: Some studies investigated the relationship between polymorphism of FC receptors gene and MG and suggested that R arginine variant in type 2 (FCGR2) can be related to this disease.[28][29]
- The CTLA4 Locus: This gene is known to be responsible for many autoimmune diseases.[30]
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
- ↑ 1.0 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.
- ↑ 2.0 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.
- ↑ 3.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 8.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Drachman DB (June 1994). "Myasthenia gravis". N. Engl. J. Med. 330 (25): 1797–810. doi:10.1056/NEJM199406233302507. PMID 8190158.
- ↑ Vincent A (October 2002). "Unravelling the pathogenesis of myasthenia gravis". Nat. Rev. Immunol. 2 (10): 797–804. doi:10.1038/nri916. PMID 12360217.