INTRODUCTION Parkinson’s disease (PD) is the second most common neurodegenerative disorder that leads to slowness of movement, tremor, rigidity and in the later stages of PD, cognitive impairment. Pathologically PD is characterized by the accumulation of α-synuclein in Lewy bodies and neurites. There is degeneration of neurons throughout the nervous system with the degeneration of dopamine neurons in the substantia nigra pars compacta leading to the major symptoms of PD. RATIONALE In the brains of PD patients, pathologic α-synuclein seems to spread from cell-to-cell via self-amplification, propagation, and transmission in a stereotypical and topographical pattern among neighboring cells and/or anatomically connected brain regions. The spread or transmission of pathologic α-synuclein is emerging as potentially important driver of PD pathogenesis. The underlying mechanisms and molecular entities responsible for the transmission of pathologic α-synuclein from cell-to-to cell are not known, but the entry of pathologic α-synuclein into neurons is thought to occur, in part through an active clathrin-dependent endocytic process. RESULTS Using recombinant α-synuclein pre-formed fibrils (PFF) as a model system to study the transmission of misfolded α-synuclein from neuron to neuron, we screened a library encoding transmembrane proteins for α-synuclein-biotin PFF binding candidates via detection by streptavidin-AP (alkaline phosphatase) staining. Three positive clones were identified that bind α-synuclein PFF and include lymphocyte-activation gene 3 (LAG3), neurexin 1β and amyloid beta precursor-like protein 1 (APLP1). Of these three transmembrane proteins, LAG3 demonstrated the highest ratio of selectivity for α-synuclein PFF over the α-synuclein monomer. α-Synuclein PFF binds to LAG3 in a saturable manner (Kd = 77 nM), while the α-synuclein monomer does not bind to LAG3. Co-immunoprecipitation also suggests that pathological α-synuclein PFF specifically binds to LAG3. Tau PFF, β-amyloid oligomer and β-amyloid PFF do not bind LAG3 indicating that LAG3 is specific for α-synuclein PFF. The internalization of α-synuclein PFF involves LAG3 since deletion of LAG3 reduces the endocytosis of α-synuclein PFF. LAG3 colocalizes with the endosomal GTPases, Rab5 and Rab7 and co-endocytoses with pathologic α-synuclein. Neuron-to-neuron transmission of pathologic α-synuclein and the accompanying pathology and neurotoxicity is substantially attenuated by deletion of LAG3 or by LAG3 antibodies. The lack of LAG3 also substantially delayed α-synuclein PFF induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. CONCLUSION We discovered that pathologic α-synuclein transmission and toxicity is initiated by binding to LAG3 and that neuron-to-neuron transmission of pathological α-synuclein involves the endocytosis of exogenous α-synuclein PFF by the engagement of LAG3 on neurons. Depletion of LAG3 or antibodies to LAG3 substantially reduce the pathology set in motion by the transmission of pathologic α-...

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Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients with rheumatic and musculoskeletal diseases The immune response to SARS-CoV-2 messenger RNA (mRNA) vaccines in patients with rheumatic and musculoskeletal diseases (RMD) is undefined because these individuals were largely excluded from phase I-III studies. To better understand the immune response to vaccination in this patient population, we studied the antibody response in patients with RMD who completed the first dose of SARS-CoV-2 mRNA vaccination. Participants with RMD across the USA were recruited to participate in this prospective cohort via social media. Those with prior SARS-CoV-2 were excluded. We collected demographics, RMD diagnoses and immunomodulatory regimens and tested for SARS-CoV-2 antibodies at baseline and prior to the second vaccine dose. Antibody testing was conducted on the semiquantitative Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (EIA) which tests for antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. 1 We evaluated the association between demographic/clinical characteristics and positive antibody response using Fisher's exact test and Wilcoxon rank-sum test. We studied 123 participants who received their first SARS-CoV-2 vaccination dose between

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Background: While several studies have observed that solid organ transplant recipients experience diminished antibody responses to SARS-CoV-2 mRNA vaccination, data specific to heart and lung transplant (HT/LT) recipients remains sparse. Methods: US adult HT and LT recipients completed their vaccine series between January 7 and April 10, 2021. Reactogencity and SARS-CoV-2 anti-spike antibody were assessed after a priming dose (D1) and booster dose (D2). Modified Poisson regression with robust variance estimator was used to evaluate associations between participant characteristics and antibody development. Results: Of 134 heart recipients, there were 38% non-responders (D1-/D2-), 48% booster responders (D1-/D2+), and 14% priming dose responders (D1+/D2+). Of 103 lung recipients, 64% were non-responders, 27% were booster responders, and 9% were priming dose responders. Lung recipients were less likely to develop antibodies (p<0.001). Priming dose antibody response was associated with younger recipient age (p=0.04), transplant-to-vaccination time ≥ 6 years (p<0.01), and lack of anti-metabolite maintenance immunosuppression (p<0.001). Pain at injection site was the most commonly reported reaction (85% after D1, 76% after D2). Serious reactions were rare, the most common being fatigue (2% after D1 and 3% after D2). No serious adverse events were reported. Conclusions: HT and LT recipients experienced diminished antibody response following vaccination; reactogenicity was comparable to that of the general population. LT recipients may exhibit a more impaired antibody response than HT recipients. While current recommendations are to vaccinate eligible candidates and recipients, further studies characterizing the cell-mediated immune response and clinical efficacy of these vaccines in this population are needed.

Severe: prevents daily activity. d More than baseline. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Prior studies have demonstrated a decreased humoral response in solid organ transplant recipients (SOTRs) to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) messenger RNA (mRNA) vaccination (17% antibody response after dose 1 [D1], 54% after dose 2 [D2]) compared with the general population (100%).However, these studies were dominated by kidney transplant recipients and included only a small percentage of liver transplantation (LT) recipients (19.6%). (1)(2)(3)(4) Because LT recipients often receive milder induction and maintenance immunosuppression, they may have a more robust humoral response. To investigate this, we studied SARS-CoV-2 antibody development in a cohort of LT recipients who completed a 2-dose mRNA vaccine series of either mRNA-1273 (Moderna, Cambridge, MA) or BNT162b2 (Pfizer-BioNTech, New York, NY). Patients and MethodsInclusion criteria were post-LT patients with no reported prior positive SARS-CoV-2 polymerase chain reaction result. Participants were excluded if they were younger than 18 years old. Participants were recruited via convenience sampling through social media or transplant center advertisements and if they completed a 2-dose mRNA vaccine course between January 7, 2021, and March 26, 2021 and were followed through April 7, 2021. Data on demographics, body mass index (BMI), prior COVID-19 diagnosis, hospitalization, transplant information, medications, other immune conditions, and allergies were collected. The study had institutional review board approval, and informed consent was obtained. The blood sampling protocol used 2 SARS-CoV-2 spike protein immunoassays (EUROIMMUN [Lubek, Germany] to the subunit 1 [S1] domain and Roche Elecsys [Indianapolis, IN] to the receptor binding domain [RBD] of the SARS-CoV-2 spike protein) and has been described elsewhere. (1) We have shown in prior work that the distribution of vaccine responses did not differ when using the anti-S1 or anti-RBD assay. (4) The post-D1 assay was performed as close to D2 as possible, and the post-D2 assay was collected as close to 28 days as possible. Of note, the Roche assay is artificially truncated at >250 U/mL.

This research was made possible with generous support of the Ben-Dov family. This work was supported by grant number F32DK124941 (Boyarsky), K01DK101677 (Massie), and K23DK115908 (Garonzik-Wang