Swine influenza virus strains recognize sialylsugar chains containing the molecular species of sialic acid predominantly present in the swine tracheal epithelium

AbstractWe determined the ratio of N-glycolylneuraminic acid (Neu5Gc) to N-acetylneuraminic acid (Neu5Ac) in swine respiratory epithelia by fluorometric high-performance liquid chromatography, and examined the binding specificity of swine influenza virus strains for gangliosides containing different molecular species of sialic acid (Neu5Ac and Neu5Gc), and for bovine erythrocyte sialoglycoprotein 2 (GP-2) containing Neu5Gc as its predominate sialic acid (96% of total sialic acids). The presence of Neu5Gc, which had not been detected in human tracheal epithelia, and Neu5Ac in swine tracheal epithelia was observed in a 1:1 ratio. The swine influenza virus H1 and H3 isolates tested, except for A/swine/Iowa/15/30 (H1N1), displayed a marked binding ability for sialylsugar chains containing Neu5Gc compared with that of the human influenza virus strains. These results suggest that swine influenza viruses recognize sialylsugar chains containing the molecular species of sialic acid present predominantly in the swine tracheal epithelium.© 1997 Federation of European Biochemical Societies

Serum Antibody Against NY-ESO-1 and XAGE1 Antigens Potentially Predicts Clinical Responses to Anti–Programmed Cell Death-1 Therapy in NSCLC

Introduction: Programmed cell death-1 (PD-1) inhibitors effectively treat NSCLC and prolong survival. Robust biomarkers for predicting clinical benefits of good response and long survival with anti-PD-1 therapy have yet to be identified; therefore, predictive biomarkers are needed to select patients with benefits. Methods: We conducted a prospective study to explore whether serum antibody against NY-ESO-1 and/or XAGE1 cancer-testis antigens predicted primarily good clinical response and secondarily long survival with anti-PD-1 therapy for NSCLC. The serum antibody was detected by enzyme-linked immunosorbent assay, and tumor immune microenvironment and mutation burden were analyzed by immunohistochemistry and next-generation sequencing. Results: In the discovery cohort (n = 13), six antibody-positive NSCLC cases responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC cases did not. Antibody positivity was associated with good response and survival, regardless of tumor programmed death ligand 1 (PD-L1) expression, mutation burden, and CD8+ T-cell infiltration. In the validation cohort (n = 75), 17 antibody-positive NSCLC cases responded well to anti-PD-1 therapy as compared with 58 negative NSCLC cases (objective response rate 65% versus 19%, p = 0.0006) and showed significantly prolonged progression-free survival and overall survival. Antibody titers highly correlated with tumor reduction rates. In the multivariate analysis, response biomarkers were tumor programmed death ligand 1 expression and antibody positivity, and only antibody positivity was a significantly better predictive biomarker of progression-free survival (hazard ratio = 0.4, p = 0.01) and overall survival (hazard ratio = 0.2, p = 0.004). Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers

Augmented TLR9-induced Btk activation in PIR-B–deficient B-1 cells provokes excessive autoantibody production and autoimmunity

Pathogens are sensed by Toll-like receptors (TLRs) expressed in leukocytes in the innate immune system. However, excess stimulation of TLR pathways is supposed to be connected with provocation of autoimmunity. We show that paired immunoglobulin (Ig)-like receptor B (PIR-B), an immunoreceptor tyrosine-based inhibitory motif–harboring receptor for major histocompatibility class I molecules, on relatively primitive B cells, B-1 cells, suppresses TLR9 signaling via Bruton's tyrosine kinase (Btk) dephosphorylation, which leads to attenuated activation of nuclear factor κB p65RelA but not p38 or Erk, and blocks the production of natural IgM antibodies, including anti-IgG Fc autoantibodies, particularly rheumatoid factor. The autoantibody production in PIR-B–deficient (Pirb−/−) mice was further augmented in combination with the Faslpr mutation, which might be linked to the development of autoimmune glomerulonephritis. These results show the critical link between TLR9-mediated sensing and a simultaneously evoked, PIR-B–mediated inhibitory circuit with a Btk intersection in B-1 cells, and suggest a novel way toward preventing pathogenic natural autoantibody production

Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice

We herein provide a thorough description of new transgenic mouse models for dentatorubral–pallidoluysian atrophy (DRPLA) harboring a single copy of the full-length human mutant DRPLA gene with 76 and 129 CAG repeats. The Q129 mouse line was unexpectedly obtained by en masse expansion based on the somatic instability of 76 CAG repeats in vivo. The mRNA expression levels of both Q76 and Q129 transgenes were each 80% of that of the endogenous mouse gene, whereas only the Q129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiological studies of the Q129 mice demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and γ-aminobutyrate type A receptors in CA1 neurons were also observed. Neuropathological studies of the Q129 mice revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyglutamine stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analyses demonstrated age-dependent down-regulation of genes, including those relevant to synaptic functions and CREB-dependent genes. These results suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. Thus, our Q129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions

Antigen Challenge-induced Expression of Amphiregulin by Mast Cells Increases Goblet-Cell Hyperplasia in a Mouse Model of Asthma

Mast cells play important roles in both acute-and late-phase allergic reactions mediated by IgE, such as those in bronchial asthma. Remodeling of the airway wall may contribute to the development of chronic refractory asthma; effective treatment for remodeling is currently lacking. Tryptase released by degranulated mast cells may participate in airway remodeling by stimulating the proliferation of airway smooth-muscle cells and fibroblasts and promoting the production of extracellular matrix. We found that continued antigen challenge produced time-dependent increases in the number of goblet cells, which are essential for sputum production, as well as the number of mast cells. Furthermore, the expression of amphiregulin released from mast cells was up-regulated by after ovalbumin challenges in mice. The number of amphiregulin-positive cells positively correlated with the degree of goblet-cell hyperplasia. Our results suggest that mast cells also play a key role in airway remodeling

ヒフ キンエン ノ ハッショウ オ ケイキ ニ シンダン サレタ ショウサイボウ ハイガン ノ 1レイ

74 歳男性.顔面,四肢,体幹の紅斑に続き,構音障害および嚥下障害,四肢筋肉痛並び脱力が出現し,起立困難となり入院となった.CK, ALD, AST, LDH 等筋原性酵素の著明上昇及び臨床所見により皮膚筋炎と診断された.高用量ステロイド療法その後シクロスポリンの追加にて治療開始し,検査所見に続き,臨床所見も改善傾向にあった.同時にproGRP 高値並びに全身CT 画像上縦隔リンパ節腫大認め,気管支鏡下気管支粘膜生検にて小細胞肺癌の病理診断が得られ,CBDCA+CPT-11 にて化学療法を施行,腫瘍の縮小効果を見た.皮膚筋炎が腫瘍随伴症候として,小細胞癌とほぼ同時期に発病したことを示唆した症例であったA 74-year-old man was admitted because of erythemaon face, extremities and trunk, followed by dysarthria, dysphagia,extremity myalgia accompanied with weakness, andthen difficulty in upstanding. Dermatomyositis (DM) wasdiagnosed on the basis of a marked increase in serum levelof myogenic enzymes, such as creatinin kinase, aldolase, aspartateaminotransferase and lactate dehydrogenase, andthe clinical manifestations. Introduction of high-dose glucocorticoidtherapy, subsequently concurrent administrationof cyclosporin, made laboratory data gradually return tonormal and produced slight symptom improvement. Inscreening for malignancies, high level of proGRP detectedin peripheral blood, computed tomography scan showed mediastinallymphadenopathy, and histopathologial testing ofthe transbronchial biopsy specimens revealed small celllung cancer (SCLC). Chemotherapy (CBDCA+CPT-11)started, resulting in tumor reduction. The current case maysuggest that DM coincided with SCLC around at the sametime, as a mean of paraneoplastic syndrome