Diagramas de la unión neuromuscular normal ( A ) y miasténica ( B ). AChE, acetilcolinesterasa. Véase el texto para obtener la descripción de la transmisión neuromuscular normal. La unión con MG muestra una terminación nerviosa normal; una cantidad menor del AChR ( punteado ); pliegues postsinápticos aplanados y simplificados y ensanchamiento del espacio sináptico. ( Modificada con autorización a partir de DB Drachman: N Engl J Med, 330:1797, 1994. )
Agrin binds to the agrin receptor , which includes MuSK and additional components. Stimulation of the receptor promotes rapsyn-dependent aggregation of the AChR. The nerve also secretes ARIA. ARIA receptors (ErbB) also cluster beneath the nerve terminal. ErbB activation stimulates transcription of AChR subunits in synaptic nuclei. ACh release from the nerve propagates a voltage change in the muscle membrane that depresses the expression of the AChR in extrasynaptic nuclei.
At the neuromuscular junction (NMJ), although it has not been proven formally, acetylcholine receptors (AChRs), rapsyn (R) and Src might partition into a lipid raft-like environment. AChR-rich synaptic membranes of the electric ray Torpedo californica contain high cholesterol (a constituent of lipid rafts; Box 4 ) and rapsyn partitions to lipid-raft-like membranes 107 . Moreover, both proteins are co-transported to the cell surface in T. californica 106 . Src is a lipid-raft-residing protein as shown in T cells. Lipid rafts function as platforms to concentrate signalling molecules and so their aggregation might facilitate signal transduction. Agrin can aggregate lipid rafts 7 and also maintain the signalling at postsynapses in the innervated muscle. At the NMJ, agrin might immobilize lipid rafts by its binding to laminin and /-dystroglycan–rapsyn complex or by binding to an unknown lipid-raft-residing protein (?). This protein might then recruit ErbB and/or muscle-specific kinase (MuSK) to lipid rafts, and also connect lipid rafts to the cortical F-actin cytoskeleton. Interestingly, cortactin — an actin polymerizing protein found at synapses in the brain and at the NMJ — also associates with the lipid-raft-like environment and so might anchor this to the cortical F-actin cytoskeleton. It should be noted that this is a schematic model.
At the muscle-specific kinase (MuSK)–Dishevelled (Dvl) scaffold, the p21-activated kinase (PAK) is phosphorylated through agrin–MuSK-activated Rac or Cdc42 and drives aggregation of acetylcholine receptors (AChRs). Integrins engaged by agrin directly or indirectly (through binding to laminin) might participate in cytoskeletal re-organization through focal adhesion kinase (FAK) and Src. Activated MuSK, ErbB receptors and integrins might in turn activate transcription factors such as c-jun and GABP to initiate synaptic transcription. The newly synthesized proteins, such as AChR, rapsyn (R) and utrophin might further stabilize the postsynapse by connecting it to the cytoskeleton. Formation and maintenance of a mature postsynapse involves 'crosstalk' between distinct pathways. Cortactin might function as a checkpoint for several pathways involved in the cytoskeleton rearrangement. Dystroglycan stabilizes the mature synapse by connecting the basal lamina to the cortical F-actin cytoskeleton. Integrins might also contribute to the stability of the neuromuscular junction (NMJ) by regulating the turnover of focal contacts through Src and PAK. PAK is recruited to integrin through a paxillin–PKL–PIX scaffold 125 . Dotted arrows with question marks indicate hypothetical interactions. The requirement of GABP and c-jun for MuSK, ErbB and rapsyn transcription has not been investigated (?). GABP, guanidine and adenosine-binding protein; PIK, PAK-interacting exchange factor; PKL, paxillin kinase linker.
The subunits of the acetylcholine receptor -- , , , and or -- are arranged like barrel staves around the central ion pore. Each subunit winds through the junctional membrane four times (sites M1, M2, M3, and M4). In the unfolded view of the subunit, the amino-terminal end of the subunit is extracellular, where it is accessible to acetylcholine, which binds at the site shown (amino acids 192 and 193). In myasthenia gravis, autoantibodies may bind to various epitopes of all subunits, but a high proportion of antibodies bind to the main immunogenic region of the subunit.
Effector mechanisms of anti-AChR Abs. (A) Ab binding to the AChR activates the complement cascade, resulting in the formation of membrane attack complex (MAC) and localized destruction of the postsynaptic NMJ membrane. This ultimately leads to a simplified, altered morphology of the postsynaptic membrane of the NMJ of MG patients, which lacks the normal deep folds and has a relatively flat surface. (B) Abs cross-link AChR molecules on the NMJ postsynaptic membrane, causing endocytosis of the cross-linked AChR molecules and their degradation (antigenic modulation). This ultimately leads to a reduced number of AChR molecules on the postsynaptic membrane. (C) Ab binding the ACh-binding sites of the AChR causes functional block of the AChR by interfering with binding of ACh released at the NMJ. This results in failure of neuromuscular transmission.
Antigen-presenting cells internalize the antigen (acetylcholine receptor), process it, and then present the processed peptides in association with major histocompatibility complex (MHC) class II molecules unique to the subject. The T-cell receptor of antigen-specific helper T cells (CD4+) binds to the specific MHC-peptide complex. The interaction of the antigen-presenting cell and the T cell requires additional costimulatory signals and is aided by adhesion molecules and cytokines, resulting in T-cell stimulation. The activated T cell helps acetylcholine-receptor-specific B cells. These B cells bind the antigen (acetylcholine receptor) to their surface antibodies, process it, and present the MHC-peptide complex, like other antigen-presenting cells. They thus interact with T cells by binding to the T-cell receptor. The T cell provides help to the B cells by means of surface molecules and cytokines (not shown), resulting in B-cell proliferation and the secretion of acetylcholinereceptor- specific antibody.
Figure 1. Immunomodulatory Actions of IVIG in Autoimmune Neuromuscular Diseases Intravenous immunoglobulin (IVIG) modulates multiple immunologic events (blue boxes) involved in the pathogenesis of autoimmune neuromuscular diseases. Diseases for which specific therapeutic actions of IVIG are supported by experimental evidence are listed in each box. In autoimmune neuromuscular diseases, an antigen, through molecular mimicry, defective clonal deletion, or other mechanisms, triggers an immune response that results in loss of immune tolerance to self-antigens. Infused IVIG interferes with costimulatory molecules involved in antigen presentation and modulates subsequent immunologic events. These events, mediated by activation of B cells with production of autoantibodies and by T cells, lead to tissue damage via complement activation, macrophage–Fc receptor interaction, and cytotoxic T cells. Other possible therapeutic actions of IVIG not shown in this illustration include increased catabolism of IgG, alteration of effector functions of T cells, and modulation of apoptosis. CIDP indicates chronic inflammatory demyelinating polyneuropathy; DM, dermatomyositis; GBS, Guillain-Barré syndrome; ICAM-1, intercellular adhesion molecule 1; IFN-, interferon ; IL, interleukin; LEMS, Lambert-Eaton myasthenic syndrome; MAC, membrane attack complex; MG, myasthenia gravis; MMP, matrix metalloproteinase; NO, nitric oxide; PM, polymyositis; SPS, stiff-person syndrome; TGF-, transforming growth factor ; TNF-, tumor necrosis factor ; VCAM-1, vascular cell adhesion molecule 1.