Tissue plasminogen activator involvement in experimental autoimmune myasthenia gravis: Aggravation and therapeutic potential

Gur‐Wahnon, Devorah; Mizrachi, Tehila; Wald-Altman, Shane; Higazi, Abd Al‐Roof; Brenner, Talma

doi:10.1016/j.jaut.2013.12.017

Cited by 9 publications

(10 citation statements)

References 41 publications

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“…Study was carried out on 10‐week‐old (23–30 g) male C57BL/6J mice (WT, Envigo, Israel) and male tPA‐deficient C57BL/6 background mice (a generous gift of Prof. Talma Brenner, originally purchased from The Jackson Laboratory) (Gur‐Wahnon et al., 2014; Mizrachi et al., 2020). Animal handling and all experiments were approved and performed in accordance with the Animal Care and Use Committee of The Chaim Sheba Medical Center (#1026/10/ANIM), which adhere to the Israeli law on the use of laboratory animals and according to the ARRIVE Guidelines.…”

Section: Methodsmentioning

confidence: 99%

Increased brain plasmin levels following experimental ischemic stroke in male mice

Mindel

Weiss

Bushi

et al. 2020

J of Neuroscience Research

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Stoke is a severe condition with a narrow treatment window and high mortality rate (Feigin et al., 2016) caused by either blockage (ischemic) or rupture (hemorrhagic) of blood vessels. The damage is often permanent and irreversible and ischemic strokes are the most prevalent type, accounting for 82%-86% of all cases (Johnson et al., 2019). The final step in the coagulation cascade is the cleavage of fibrinogen into fibrin by thrombin (Bardehle et al., 2015). Additionally, thrombin regulates fibrinolysis and enhances the synthesis of a serine protease, tPA (Mandl-Weber et al., 1999). Once a blood clot is formed, tPA binds to fibrin and converts the zymogen plasminogen, already present in the clot, into the broad-spectrum serine protease

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Section: Methodsmentioning

confidence: 99%

Increased brain plasmin levels following experimental ischemic stroke in male mice

Mindel

Weiss

Bushi

et al. 2020

J of Neuroscience Research

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“…Purified Torpedo AChR (25 μ g and 5 mg/ml of M. tuberculosis H37Ra, (Difco, Detroit MI)), emulsified in complete Freund's adjuvant (CFA), was subcutaneously (s.c.) injected into the hind footpads and into the flank of 6-7-week-old C57BL female mice as previously described [ 29 ]. The clinical status was graded as the following: (0) no weakness or fatigue; (1) mildly decreased activity, weak grip with fatigue, weight loss > 3% body weight in one week; (2) moderate weakness accompanied by weak grip, 5–10% weight loss; (3) moderate-severe weakness, hunched back posture at rest, head down, and forelimb digit flexed, tremulous ambulation, 10% weight loss; and (4) severe general weakness, weak grip, weight loss > 10% [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

NMO-IgG and AQP4 Peptide Can Induce Aggravation of EAMG and Immune-Mediated Muscle Weakness

Mizrachi

Brill

Rabie

et al. 2018

Journal of Immunology Research

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Neuromyelitis optica (NMO) and myasthenia gravis (MG) are autoimmune diseases mediated by autoantibodies against either aquaporin 4 (AQP4) or acetylcholine receptor (AChR), respectively. Recently, we and others have reported an increased prevalence of NMO in patients with MG. To verify whether coexisting autoimmune disease may exacerbate experimental autoimmune MG, we tested whether active immunization with AQP4 peptides or passive transfer of NMO-Ig can affect the severity of EAMG. Injection of either AQP4 peptide or NMO-Ig to EAMG or to naive mice caused increased fatigability and aggravation of EAMG symptoms as expressed by augmented muscle weakness (but not paralysis), decremental response to repetitive nerve stimulation, increased neuromuscular jitter, and aberration of immune responses. Thus, our study shows increased disease severity in EAMG mice following immunization with the NMO autoantigen AQP4 or by NMO-Ig, mediated by augmented inflammatory response. This can explain exacerbation or increased susceptibility of patients with one autoimmune disease to develop additional autoimmune syndrome.

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“…Detection of human anti-AChR Abs. AChR-specific human Abs were detected in mouse serum via classical RIA, as described previously (63). Briefly, crude extracts of human muscles complexed with 125 I-α-bungarotoxin (α-BGT) were incubated with 10 μl of mouse serum.…”

Section: Methodsmentioning

confidence: 99%

Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model

Sudres¹,

Maurer²,

Robinet³

et al. 2017

JCI Insight

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Myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) Abs is an autoimmune disease characterized by severe defects in immune regulation and thymic inflammation. Because mesenchymal stem cells (MSCs) display immunomodulatory features, we investigated whether and how in vitro-preconditioned human MSCs (cMSCs) could treat MG disease. We developed a new humanized preclinical model by subcutaneously grafting thymic MG fragments into immunodeficient NSG mice (NSG-MG model). Ninety percent of the animals displayed human anti-AChR Abs in the serum, and 50% of the animals displayed MG-like symptoms that correlated with the loss of AChR at the muscle endplates. Interestingly, each mouse experiment recapitulated the MG features of each patient. We next demonstrated that cMSCs markedly improved MG, reducing the level of anti-AChR Abs in the serum and restoring AChR expression at the muscle endplate. Resting MSCs had a smaller effect. Finally, we showed that the underlying mechanisms involved (a) the inhibition of cell proliferation, (b) the inhibition of B cell-related and costimulatory molecules, and (c) the activation of the complement regulator DAF/CD55. In conclusion, this study shows that a preconditioning step promotes the therapeutic effects of MSCs via combined mechanisms, making cMSCs a promising strategy for treating MG and potentially other autoimmune diseases.

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Tissue plasminogen activator involvement in experimental autoimmune myasthenia gravis: Aggravation and therapeutic potential

Cited by 9 publications

References 41 publications

Increased brain plasmin levels following experimental ischemic stroke in male mice

Increased brain plasmin levels following experimental ischemic stroke in male mice

NMO-IgG and AQP4 Peptide Can Induce Aggravation of EAMG and Immune-Mediated Muscle Weakness

Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model

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