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Id Subject Object Predicate Lexical cue
T1 0-147 Sentence denotes A sugar‐coated strategy to treat a rare neurologic disease provides a blueprint for a decoy glycan therapeutic and a potential vaccine for CoViD‐19
T2 148-316 Sentence denotes An Editorial Highlight for “Selective inhibition of anti‐MAG IgM autoantibody binding to myelin by an antigen specific glycopolymer”on https://doi.org/10.1111/jnc.15021
T3 317-325 Sentence denotes STEINMAN
T4 327-335 Sentence denotes Abstract
T5 336-344 Sentence denotes Abstract
T6 346-609 Sentence denotes In a rare neurologic disease known as IgM monoclonal gammopathy the immune system targets a sulfated trisaccharide known as the Human Natural Killer‐1 (HNK‐1) epitope that comprises a constituent of the myelin sheath known as MAG (myelin‐associated glycoprotein).
T7 610-1061 Sentence denotes This Editorial highlights a study by Aliu and colleagues in the current issue of the Journal of Neurochemistry, in which the investigators constructed a biodegradable poly‐l‐lysine backbone with multiple copies of this sulfated HNK‐1 trisaccharide. This decoy, poly(phenyl disodium 3‐O‐sulfo‐β‐d‐glucopyranuronate)‐(1→3)‐β‐d‐galactopyranoside, known as PPSGG, removed anti‐MAG IgM autoantibodies from the blood, while not activating the immune system.
T8 1062-1206 Sentence denotes These findings provide a path for the selective removal of a pathogenic set of antibodies that target the myelin sheath resulting in neuropathy.
T9 1207-1525 Sentence denotes These findings are applicable to a parallel strategy for the generation of polysaccharides similar to those present in the receptor‐binding domain of CoViD‐19, which might inhibit viral adhesion to its receptor, the angiotensin‐converting enzyme‐2 (ACE2) protein, thereby impairing cellular uptake of the virus itself.
T10 1526-1690 Sentence denotes The deployment of complex polysaccharides that mimic actual COVID19 polysaccharides on the spike protein may also provide a feasible structural basis for a vaccine.
T11 1691-1806 Sentence denotes Carbohydrate mimics, if conjugated to a carrier or backbone, might provoke an immune response to the spike protein.
T12 1807-2037 Sentence denotes A vaccine that targets critical carbohydrates on COVID19, and then neutralizes the virus would recapitulate a successful strategy employed in other microbial vaccines, like the pneumococcal vaccines and the meningococcal vaccines.
T13 2038-2154 Sentence denotes These vaccines direct an immune response to complex carbohydrates and successfully prevent life‐threatening disease.
T14 2155-2275 Sentence denotes This paper provides lessons from a rare neurologic disease that may teach us strategies applicable to a global pandemic.
T15 2277-2716 Sentence denotes The present Editorial highlights a study by Aliu and colleagues, entitled “Selective inhibition of anti‐MAG IgM autoantibody binding to myelin by an antigen specific glycopolymer” published in the current issue of the Journal of Neurochemistry, in which the authors have developed a therapy directed to a highly specific target to treat a rare neurologic disease where a carbohydrate component of the myelin sheath is attacked by antibody.
T16 2717-2827 Sentence denotes The targeted therapy specifically blocks the antibody from binding to a particular sugar on the myelin sheath.
T17 2828-3084 Sentence denotes The authors' findings are applicable to a parallel strategy for the generation of polysaccharides similar to those present in the receptor‐binding domain of CoViD‐19, which might inhibit viral adhesion to its receptor and thus lead the way toward vaccines.
T18 3086-3101 Sentence denotes 1 INTRODUCTION
T19 3102-3252 Sentence denotes A demyelinating neuropathy targeting myelin‐associated glycoprotein (MAG) has an incidence of approximately one per 100,000 (Mygland & Monstad, 2001).
T20 3253-3489 Sentence denotes In this disease there is production of an IgM antibody resulting in a “monoclonal gammopathy” targeting a particular carbohydrate known as Cellular Differentiation antigen 57 (CD57) and also known as human natural killer cell‐1 (HNK‐1).
T21 3490-3652 Sentence denotes The HNK‐1 antigen is found on MAG, as well as on natural killer cells, neuroectodermal tissue, retina, brain, prostate and renal proximal tubules (Pernick, 2019).
T22 3653-3786 Sentence denotes CD57 belongs to a family of sialic acid‐binding Ig‐like lectins (siglecs) found on both peripheral and central nervous system myelin.
T23 3787-4036 Sentence denotes In this issue investigators (Aliu et al, 2020) showed that poly(phenyl disodium 3‐O‐sulfo‐β‐d‐glucopyranuronate)‐(1→3)‐β‐d‐galactopyranoside, known as PPSGG, removed anti‐MAG IgM autoantibodies from the blood in a mouse model of this IgM neuropathy.
T24 4037-4192 Sentence denotes In a previous study these investigators developed antigen‐specific molecules with nanomolar inhibitory potency for anti‐MAG IgM (Herrendorff et al., 2017).
T25 4193-4336 Sentence denotes Here the investigators also show that PPSGG blocked the binding of an anti‐MAG IgM from patients to sciatic nerve myelin of non‐human primates.
T26 4337-4422 Sentence denotes They also tested some of the pharmacokinetic and pharmacodynamic properties of PPSGG.
T27 4423-4595 Sentence denotes In patients suffering from this IgM monoclonal gammopathy, non‐specific strategies are used to diminish IgM antibody including targeting of all CD20 B cells with Rituximab.
T28 4596-4747 Sentence denotes On occasion flares of disease occur with increased IgM levels of antibody targeting MAG have followed therapy with Rituximab (Broglio and Luria, 2005).
T29 4748-4857 Sentence denotes The strategy employed with PPSGG is specific to the antigen that triggers the pathogenic IgM in this disease.
T30 4858-4937 Sentence denotes One can refer to such treatment as “antigen‐specific” immunotherapy (Figure 1).
T31 4938-5345 Sentence denotes FIGURE 1 The strategy employed by Aliu et al, provide a basis for a passive immune therapy with a decoy carbohydrate preventing the virus from docking on its receptor, and also provide a foundation for a carbohydrate‐based active immunization when coupled to a suitable carrier Investigations in the mouse model revealed that practical doses of PPSGG were able to sufficiently reduce IgM that binds to MAG.
T32 5346-5472 Sentence denotes Doses between 1 and 10 µg were sufficient to remove between 23 and 93% of IgM anti‐MAG antibody from blood in the mouse model.
T33 5473-5622 Sentence denotes Reductions in antibody were sustained for as long as 96 hr, demonstrating the pharmacologic feasibility of this highly specific therapeutic approach.
T34 5623-5763 Sentence denotes In addition the investigators showed that after exposure to PPSGG, there was no activation of B cells, including human IgM anti‐MAG B cells.
T35 5764-5829 Sentence denotes In addition, no activation of CD11b dendritic cells was observed.
T36 5830-5948 Sentence denotes These experiments provide some assurance on the safety of this approach, if it is translated to human clinical trials.
T37 5949-6041 Sentence denotes Engaging IgM targeting MAG with PPSGG appeared safe and effective in the pre‐clinical study.
T38 6042-6326 Sentence denotes Writing about these exquisite approaches to targeting carbohydrates for a potential antigen‐specific therapy for an inflammatory neuropathy characterized by sensory impairment, disturbance in gait, tremor, and ataxia (a form of incoordination following sensory loss) makes one wonder:
T39 6327-6504 Sentence denotes Could such an approach, targeting critical carbohydrates in a disease, have broader applicability to other diseases where complex carbohydrates play a key pathophysiologic role?
T40 6505-6719 Sentence denotes In these days of the COVID‐19 pandemic, the experiments described on monoclonal IgM neuropathy raise the issue that a similar strategy might be deployed to target the carbohydrates in the spike protein of COVID‐19.
T41 6720-6790 Sentence denotes Spike proteins in coronviruses are known to be camouflaged by glycans:
T42 6791-6939 Sentence denotes Mass spectrometry studies revealed in a feline coronavirus that high mannose and complex N‐Glycans accounted for a quarter of the mass of the spike.
T43 6940-7063 Sentence denotes Moreover, the N‐glycans are critical for providing the propeller like conformation of these structures (Yang et al., 2020).
T44 7064-7185 Sentence denotes In the so‐called receptor‐binding domain of the spike protein there are 22 glycan‐binding sites (Shahajan, Supekar et al.
T45 7186-7192 Sentence denotes 2020).
T46 7193-7316 Sentence denotes High mannose, hybrid and complex‐type glycans across the N‐glycosylation sites have been identified with mass spectrometry.
T47 7317-7525 Sentence denotes One could imagine building a therapeutic which might contain the carbohydrates, or a suitable mimic, of the spike protein coupled to a carrier molecule, much in a similar fashion to how PPSGG was constructed.
T48 7526-7677 Sentence denotes Such a “decoy” carbohydrate could block the binding and subsequent internalization of COViD‐19 to its receptor, angiotensin converting enzyme‐2 (ACE2).
T49 7678-7779 Sentence denotes In addition, spike carbohydrate clusters coupled to a carrier might proof to be an effective vaccine.
T50 7780-7912 Sentence denotes Both the pneumococcal vaccine and the meningococcal vaccines target polysaccharides in pneumococcus and meningococcus, respectively.
T51 7913-8033 Sentence denotes They couple the appropriate polysaccharide to a suitable carrier to achieve potent carbohydrate‐specific immunogenicity.
T52 8034-8253 Sentence denotes In a different neuroinflammatory disease antibodies to cryptic mannose containing glycans were observed in the cerebrospinal fluid of individuals with multiple sclerosis, and in its animal model EAE (Wang et al., 2014).
T53 8254-8344 Sentence denotes There again is some precedent for an antigen‐specific therapy for an inflammatory disease.
T54 8345-8496 Sentence denotes Injection of these oligomannose glycans coupled to a protein carrier reduced the clinical severity of paralysis in this animal model (Wang, Bhat et al.
T55 8497-8503 Sentence denotes 2014).
T56 8504-8638 Sentence denotes The success in parlaying the oligomannose glycans in MS and in its EAE model, could be emulated in strategies for therapy of COVID‐19.
T57 8639-8704 Sentence denotes IgM monoclonal gammopathy targeting MAG is indeed a rare disease.
T58 8705-8807 Sentence denotes Lessons from rare diseases often inform us of bold approaches for the treatment of widespread disease.
T59 8808-8986 Sentence denotes The pioneering work of Aliu and colleagues described in this issue, might serve as a guidepost for designing effective therapeutics to the glycan components of the COVID19 virus.
T60 8987-9159 Sentence denotes Such endeavors may produce a sweet ending to a tragedy including both the harsh clinical realities of IgM MAG neuropathy and to the horrors of the deadly CoVID‐19 pandemic.
T61 9161-9182 Sentence denotes CONFLICTS OF INTEREST
T62 9183-9233 Sentence denotes The author has no conflict of interest to declare.
T63 9235-9250 Sentence denotes ACKNOWLEDGMENTS
T64 9251-9298 Sentence denotes This work was supported by NIH 2U01AI101984‐06.
T65 9299-9357 Sentence denotes Editorial advice from Dr Jonathan Steinman is appreciated.
T66 9358-9486 Sentence denotes The figure was re‐drawn in BioRender (https://biorender.com/) by Marco Bazelmans on the basis of a draft provided by the author.