SARS-CoV-2 neutralizing antibodies : longevity, breadth, and evasion by emerging viral variants

The Severe Acute Respiratory Syndrome Coronavirus 2 (SAU ARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus–cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)–confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of “high responders” maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design

Cerebrospinal fluid B-cell expansion in longitudinally extensive transverse myelitis associated with neuromyelitis optica immunoglobulin G

A first episode of central nervous system (CNS) demyelination may represent heterogeneous entities such as acute disseminated encephalomyelitis, clinically isolated syndrome, neuromyelitis optica (NMO), or multiple sclerosis. As new immune therapies become available, it is increasingly important to make an early diagnosis. Autoantibodies such as NMO immunoglobulin G (IgG) and myelin oligodendrocyte glycoprotein IgG are increasingly being employed to define subgroups of CNS demyelination or guide treatment. Similarly, cerebrospinal fluid (CSF) immunophenotyping can demonstrate B-lymphocyte subpopulation expansion, which has been used to guide therapy in other autoimmune CNS disorders. We present a report on a 15-year-old male with longitudinally extensive transverse myelitis with magnetic resonance imaging findings of oedema, cavitation, and gadolinium enhancement. NMO-IgG and aquaporin 4 IgG were positive; thus, we diagnosed a limited form of NMO. Acute CSF immunophenotyping revealed a 3.6% expansion of CD19 B-cell populations, whereas a comparison group of five children (4 males, age range 2–15y; mean age 7y) with other neurological disorders showed only a 0.51% expansion (SD 0.25%). In view of the diagnosis of a 'limited form of neuromyelitis optica', we therefore elected to treat him aggressively from the outset with a prolonged steroid regimen and mycophenylate mofetil. This case demonstrates a correlation between autoantibody production and CSF B lymphocyte expansion in an individual with CNS demyelination. These approaches could be used in individuals with a first episode of CNS demyelination to help delineate immunological subgroups and guide treatment.5 page(s

A long-term prospective cohort study on immediately restored single tooth implants inserted in extraction sockets and healed ridges : CBCT analyses, soft tissue alterations, aesthetic ratings, and patient-reported outcomes

Background: Although many studies have been published on single implants, long-term data remain scarce. Purpose: To evaluate immediately restored single implants after at least 8 years of follow-up in terms of buccal bone, soft tissue alterations, aesthetic ratings, and patient-reported outcomes. Materials and Methods: This prospective cohort study included patients who were consecutively treated with an immediately restored single implant installed in an extraction socket (IIT) or a healed ridge (CIT) in the anterior maxilla. Biomaterials were never used. CBCTs were taken at study termination, soft tissue alterations, and Pink Esthetic Score were evaluated between 1 year and study termination using standardized clinical images. Patient satisfaction was also registered. Results: About 11/16 initially treated patients in the IIT cohort (10 men, 6 women; mean age 45) and 18/23 initially treated patients in the CIT cohort (12 men, 11 women; mean age 40) could be evaluated after more than 8 years. A buccal bone wall less than 2 mm was found at all implant sites. A thin buccal bone wall less than 1 mm was found at 42% of the implant sites. In the CIT cohort, 8 patients had a missing buccal bone in the crestal area, although bone was present at the time of surgery. Alveolar process deficiency significantly deteriorated (P .046), whereas vertical soft tissue levels and PES remained stable over time in both cohorts. Patients expressed high overall satisfaction. Conclusions: Substantial dimensional changes may be expected at the buccal aspect of single implants inserted in the premaxilla. As a result, contour augmentation procedures at the time of implant placement should be considered to counteract these bone alterations, even when implants are fully embedded in bone upon insertion

Additional file 1: Figure S1. of Dopamine-2 receptor extracellular N-terminus regulates receptor surface availability and is the target of human pathogenic antibodies from children with movement and psychiatric disorders

a, b Anti-D2R antibody-positive movement and psychiatric disorder (MPD) protein G-purified IgG from patient does not induce a downregulation of surface D2R on live cells compared to IgG purified from control (CTL) after 30 min at room temperature or 37 °C. c Anti-D2R antibody-positive MPD protein G-purified IgG-incubated on live cells have a similar expression of cytoplasmic GFP compared to IgG purified from control (CTL) after 30 min at room temperature or 37 °C. Representative images are shown (scale bar = 25μm). 15-18 different cells for each control and patient out of two independent experiments are shown. Figure S2. Compared to WT D2R-immunoabsorbed MPD sera, NTermD1RχD2R-immunoabsorbed MPD sera had a higher binding to WT D2R-transfected HEK293 cells. Representative data out of two independent experiments is shown. Figure S3. Live L Δ2-22 D2R-transfected HEK293 cells were not immunolabeled, by the commercial antibody (Sigma; clone 1B11). Representative data out of three independent experiments is shown. Figure S4. a Alignment of extracellular N-terminal 37 amino acids of N5Q/N17Q/N23Q and WT D2R. b Confocal images of live and fixed/permeabilized N5Q/N17Q/N23Q-transfected HEK293 cells after immunolabeling with anti-HA antibody. Mutations of all three N-glycosylation sites led to low surface expression and intracellular sequestration of the mutant (scale bar = 50 μm). Figure S5. Amino acids 1-37 of D2R extracellular N-terminus aligned in 12 different animal species to highlight conserved sequences in mammals (yellow). Amino acid sequences derived from Uniprot database and Uniprot code for the different species. Figure S6. Sequence homology between human D2R (20-29) and an unknown protein of the fungus Penicillium roqueforti FM164 (55-64) was identified using the protein–protein Basic Local Alignment Search Tool from National Center for Biotechnology Information. Bolded residues represent identical residues between the two sequences. Underlined residues represent immunodominant amino acids in D2R N-terminus. (PDF 53400 kb

Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton

Objective: To examine the clinical features of pediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies and to examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton. Methods: We measured MOG antibody using a fluorescence-activated cell sorting live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3-15.3) followed for a median of 4 years. We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging. Results: MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p = 0.03), less likely to have brainstem findings (2/31 vs 16/42, p = 0.005), more likely to have a raised erythrocyte sedimentation rate >20 mm/h (9/19 vs 3/21, p = 0.05), less likely to have intrathecal oligoclonal bands (0/16 vs 5/27, p = 0.18), and less likely to be homozygous or heterozygous for human leukocyte antigen DRB1*1501 (3/18 vs 7/22, p = 0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibody-positive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings. Conclusions: MOG antibody may define a separate demyelination syndrome, which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.10 page(s

Antibodies to myelin oligodendrocyte glycoprotein have a demyelination phenotype in children and affect oligodendrocyte cytoskeleton

Objective: To examine the clinical features of paediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies, and examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton. Methods: We measured MOG antibody using a flow cytometry live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3–15.3), followed for a median of 4 years. We used MO3.13 cells to examine IgG effects on oligodendrocyte cytoskeleton using 3-D deconvolution imaging. Results: MOG antibodies were found in 31/73 DEM (42%, n =73), but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral rather than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p= 0.03), less likely to have brainstem findings (2/31 vs 16/42, p= 0.005), more likely to have a raised erythrocyte sedimentation rate N20 mm/h (9/19 vs 3/21, p= 0.05), less likely to have intrathecal oligoclonal band (0/16 v 5/27, p =0.18), and were less likely to be homozygous or heterozygous for HLA-DRB1*1501 (3/18 vs 7/22, p=0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON being most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibodypositive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings. Conclusions: MOG antibody may define a separate demyelination syndrome which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.1 page(s

Infectious and autoantibody-associated encephalitis : clinical features and long-term outcome

Background and objectives: Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. Methods: By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). Results: An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. Conclusions: We have defined clinical and radiologic phenotypes of infectious and immune-mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/autoantibody-associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority.11 page(s