PMP2 regulates myelin thickening and ATP production during remyelination.

It is well established that axonal Neuregulin 1 type 3 (NRG1t3) regulates developmental myelin formation as well as EGR2-dependent gene activation and lipid synthesis. However, in peripheral neuropathy disease context, elevated axonal NRG1t3 improves remyelination and myelin sheath thickness without increasing Egr2 expression or activity, and without affecting the transcriptional activity of canonical myelination genes. Surprisingly, Pmp2, encoding for a myelin fatty acid binding protein, is the only gene whose expression increases in Schwann cells following overexpression of axonal NRG1t3. Here, we demonstrate PMP2 expression is directly regulated by NRG1t3 active form, following proteolytic cleavage. Then, using a transgenic mouse model overexpressing axonal NRG1t3 (NRG1t3OE) and knocked out for PMP2, we demonstrate that PMP2 is required for NRG1t3-mediated remyelination. We demonstrate that the sustained expression of Pmp2 in NRG1t3OE mice enhances the fatty acid uptake in sciatic nerve fibers and the mitochondrial ATP production in Schwann cells. In sum, our findings demonstrate that PMP2 is a direct downstream mediator of NRG1t3 and that the modulation of PMP2 downstream NRG1t3 activation has distinct effects on Schwann cell function during developmental myelination and remyelination.

IgG4 Valency Modulates the Pathogenicity of Anti-Neurofascin-155 IgG4 in Autoimmune Nodopathy.

BACKGROUND AND OBJECTIVES: IgG4 autoantibodies to neurofascin-155 (Nfasc155) are associated with a subgroup of patients with chronic inflammatory demyelinating polyneuropathy (CIDP), currently named autoimmune nodopathy. We previously demonstrated that those antibodies alter conduction along myelinated axons by inducing Nfasc155 depletion and paranode destruction. In blood, IgG4 have the potency to exchange their moiety with other unrelated IgG4 through a process called Fab-arm exchange (FAE). This process results in functionally monovalent antibodies and may affect the pathogenicity of autoantibodies. Here, we examined this issue and whether FAE is beneficial or detrimental for Nfasc155 autoimmune nodopathy. METHODS: The bivalency and monospecificity of anti-Nfasc155 were examined by sandwich ELISA in 10 reactive patients, 10 unreactive CIDP patients, and 10 healthy controls. FAE was induced in vitro using reduced glutathione and unreactive IgG4, and the ratio of the κ:λ light chain was monitored. To determine the pathogenic potential of bivalent anti-Nfasc155 IgG4, autoantibodies derived from patients were enzymatically cleaved into monovalent Fab and bivalent F(ab')2 or swapped with unreactive IgG4 and then were injected in neonatal animals. RESULTS: Monospecific bivalent IgG4 against Nfasc155 were detected in the serum of all reactive patients, indicating that a fraction of IgG4 have not undergone FAE in situ. These IgG4 were, nonetheless, capable of engaging into FAE with unreactive IgG4 in vitro, and this decreased the levels of monospecific antibodies and modulated the ratio of the κ:λ light chain. When injected in animals, monovalent anti-Nfasc155 Fab did not alter the formation of paranodes; by contrast, both native anti-Nfasc155 IgG4 and F(ab')2 fragments strongly impaired paranode formation. The promotion of FAE with unreactive IgG4 also strongly diminished the pathogenic potential of anti-Nfasc155 IgG4 in animals and decreased IgG4 clustering on Schwann cells. DISCUSSION: Our findings demonstrate that monospecific and bivalent anti-Nfasc155 IgG4 are detected in patients and that those autoantibodies are the pathogenic ones. The transformation of anti-Nfasc155 IgG4 into monovalent Fab or functionally monovalent IgG4 through FAE strongly decreases paranodal alterations. Bivalency thus appears crucial for Nfasc155 clustering and paranode destruction.

Effectiveness of mRNA-BNT162b2, mRNA-1273, and ChAdOx1 nCoV-19 vaccines against COVID-19 in healthcare workers: an observational study using surveillance data.

OBJECTIVES: Healthcare workers (HCWs) at increased risk of coronavirus disease 2019 (COVID-19) were among the primary targets for vaccine campaigns. We aimed to estimate the protective efficacy of the first three COVID-19 vaccines available in Western Europe. METHODS: We merged two prospective databases that systematically recorded, in our institution: (a) HCWs positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by RT-PCR on nasopharyngeal samples, and (b) HCWs who received at least one dose of COVID-19 vaccine. We excluded HCWs with SARS-CoV-2 infection during the 6 months prior to the study. HCWs were categorized as non-vaccinated if they received no vaccine and until the first injection +13 days, partially vaccinated from the first injection +14 days to the second injection +13 days, and fully vaccinated thereafter. RESULTS: Of the 8165 HCWs employed in our institution, 360 (4.4%) tested positive for SARS-CoV-2 by RT-PCR during the study period (4th January to 17th May 2021). Incidence was 9.1% (8.2-10.0) in non-vaccinated HCWs, 1.2% (0.7-1.9) after one dose of ChAdOx1 nCoV-19, 1.4% (0.6-2.3) and 0.5% (0.1-1.0) after one and two doses of mRNA BNT162b2, 0.7% (0.1-1.9) and 0% after one and two doses of mRNA-1273 (p < 0.0001). Vaccine effectiveness (Cox model) was estimated at, respectively, 86.2% (76.5-91.0), 38.2% (6.3-59.2), and 49.2% (19.1-68.1) 14 days after the first dose for ChAdOx1 nCoV-19, mRNA-1273, and mRNA-BNT162b2, and 100% (ND) and 94.6% (61.0-99.2) 14 days after the second dose for mRNA-1273 and mRNA-BNT162b2. CONCLUSIONS: In this real-world study, the observed effectiveness of COVID-19 vaccines in HCWs was in line with the efficacy reported in pivotal randomized trials.