HLA-DQ6 Transgenic Mice Resistance to Experimental Autoimmune Myasthenia Gravis is Linked to Reduced Acetylcholine Receptor-specific IFN-γ, IL-2 and IL-10 Production

Poussin, Mathilde; Goluszko, Elzbieta; David, Chella S.; Franco, Juan U.; Christadoss, Premkumar

doi:10.1006/jaut.2001.0541

Cited by 15 publications

(7 citation statements)

References 31 publications

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“…Some studies have used mice that express individual DR or DQ alleles transgenically, to determine whether some DR or DQ molecules influence the development of EAMG. Those studies confirmed that expression of the DQ8 and DR3 molecules correlated with EAMG susceptibility and expression of the DQ6 molecule correlated with resistance (48,49).…”

Section: Role Of Cd4 + T Cells In Mg Pathogenic Anti-achrsupporting

confidence: 59%

Myasthenia gravis: past, present, and future

Conti‐Fine

Milani²,

Kaminski³

2006

J. Clin. Invest.

584

512

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Pathogenesis of MG: current state of the artStructure and function of the NMJ. The terminal arborization of α-motor neuron axons from the ventral horns of the spinal cord and brainstem provides the nerve terminals that form the NMJ (Figure 1). These myelinated axons reach the muscles through peripheral nerves; then each axon divides into branches that innervate many individual muscle fibers. As it approaches its target fiber, each branch loses the myelin sheath and further subdivides into many presynaptic boutons, which contain ACh-loaded synaptic vesicles and face the surface of the muscle fiber at the NMJ ( Figure 1). The synaptic bouton and the muscle surface are separated by the synaptic cleft, a 20 nm-thick space that contains acetylcholinesterase (AChE) and other proteins and proteoglycans involved in

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Section: Role Of Cd4 + T Cells In Mg Pathogenic Anti-achrsupporting

confidence: 59%

Myasthenia gravis: past, present, and future

Conti‐Fine

Milani²,

Kaminski³

2006

J. Clin. Invest.

584

512

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“…In our experiments, C3 Ϫ/Ϫ mice were unable to produce normal amounts of cytokines, including IL-6, IL-10, and IFN-␥, all of which are important for EAMG induction (28,29). This indicates that C3 may act not only as a central figure in the complement cascade, but also as an important immune mediator by up-regulating IFN-␥ and IL-6.…”

Section: Discussionmentioning

confidence: 64%

Genetic Evidence for Involvement of Classical Complement Pathway in Induction of Experimental Autoimmune Myasthenia Gravis

Tüzün

Scott

Goluszko

et al. 2003

The Journal of Immunology

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Abs to acetylcholine receptor (AChR) and complement are the major constituents of pathogenic events causing neuromuscular junction destruction in both myasthenia gravis (MG) and experimental autoimmune MG (EAMG). To analyze the differential roles of the classical vs alternative complement pathways in EAMG induction, we immunized C3−/−, C4−/−, C3+/−, and C4+/− mice and their control littermates (C3+/+ and C4+/+ mice) with AChR in CFA. C3−/− and C4−/− mice were resistant to disease, whereas mice heterozygous for C3 or C4 displayed intermediate susceptibility. Although C3−/− and C4−/− mice had anti-AChR Abs in their sera, anti-AChR IgG production by C3−/− mice was significantly suppressed. Both C3−/− and C4−/− mice had reduced levels of B cells and increased expression of apoptotis inducers (Fas ligand, CD69) and apoptotic cells in lymph nodes. Immunofluorescence studies showed that the neuromuscular junction of C3−/− and C4−/− mice lacked C3 or membrane attack complex deposits, despite having IgG deposits, thus providing in vivo evidence for the incapacity of anti-AChR IgGs to induce full-blown EAMG without the aid of complements. The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization. Accordingly, severe MG and other Ab- and complement-mediated diseases could be effectively treated by inhibiting C4, thus leaving the alternative complement pathway intact.

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“…Furthermore, miR-181c acts as a suppressor of human PBMC CD4? T cell activation by inhibiting the translation of IL-2 [9], a helper (Th)1-type cytokine which plays a pathological role in experimental autoimmune myasthenia gravis (EAMG) [10,11]. Another study demonstrated that TNF-a, one of the most typical proinflammatory cytokines, is also a direct target of miR-181c, and ectopic expression of miR-181c could alleviate microglia-mediated neuronal apoptosis by suppressing TNF-a production [12].…”

Section: Introductionmentioning

confidence: 96%

Decreased microRNA miR-181c expression in peripheral blood mononuclear cells correlates with elevated serum levels of IL-7 and IL-17 in patients with myasthenia gravis

et al. 2015

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miR-181c is a newly identified negative regulator of immune cell activation. In this study, we aimed to investigate the expression and functional role of miR-181c in myasthenia gravis (MG). miR-181c showed significant downregulation in peripheral blood mononuclear cells (PBMCs) from MG patients compared with healthy controls, with lower expression in generalized patients than in ocular ones. MG patients also had increased serum IL-7 and IL-17 levels. Additionally, serum IL-7 level presents a positive correlation with the serum IL-17 level. miR-181c levels were negatively correlated with serum levels of IL-7 and IL-17 in either generalized patients or ocular patients. A luciferase reporter assay revealed that miR-181c could directly bind to the 3'-UTR of interleukin-7. Forced expression of miR-181c led to decreased IL-7 and IL-17 release in cultured PBMCs, while depletion of miR-181c increased the secretion of these two proinflammatory cytokines. The results from our study suggested for the first time that miR-181c was able to negatively regulate the production of proinflammatory cytokines IL-7 and IL-17 in MG patients, and it is a novel potential therapeutic target for MG.

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HLA-DQ6 Transgenic Mice Resistance to Experimental Autoimmune Myasthenia Gravis is Linked to Reduced Acetylcholine Receptor-specific IFN-γ, IL-2 and IL-10 Production

Cited by 15 publications

References 31 publications

Myasthenia gravis: past, present, and future

Myasthenia gravis: past, present, and future

Genetic Evidence for Involvement of Classical Complement Pathway in Induction of Experimental Autoimmune Myasthenia Gravis

Decreased microRNA miR-181c expression in peripheral blood mononuclear cells correlates with elevated serum levels of IL-7 and IL-17 in patients with myasthenia gravis

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