Molecular recognition of paired receptors in the immune system

金沢大学医薬保健研究域薬学系Cell surface receptors are responsible for regulating cellular function on the front line, the cell membrane. Interestingly, accumulating evidence clearly reveals that the members of cell surface receptor families have very similar extracellular ligand-binding regions but opposite signaling systems, either inhibitory or stimulatory. These receptors are designated as paired receptors. Paired receptors often recognize not only physiological ligands but also non-self ligands, such as viral and bacterial products, to fight infections. In this review, we introduce several representative examples of paired receptors, focusing on two major structural superfamilies, the immunoglobulin-like and the C-type lectin-like receptors, and explain how these receptors distinguish self and non-self ligands to maintain homeostasis in the immune system.We further discuss the evolutionary aspects of these receptors as well as the potential drug targets for regulating diseases. © 2012 Kuroki, Furukawa and Maenaka

Evaluation of the reactivity and receptor competition of HLA-G isoforms toward available antibodies: Implications of structural characteristics of HLA-G isoforms

金沢大学医薬保健研究域薬学系The human leucocyte antigen (HLA)-G, which consists of seven splice variants, is a tolerogenic immune checkpoint molecule. It plays an important role in the protection of the fetus from the maternal immune response by binding to inhibitory receptors, including leukocyte Ig-like receptors (LILRs). Recent studies have also revealed that HLA-G is involved in the progression of cancer cells and the protection from autoimmune diseases. In contrast to its well characterized isoform, HLA-G1, the binding activities of other major HLA-G isoforms, such as HLA-G2, toward available anti-HLA-G antibodies are only partially understood. Here, we investigate the binding specificities of anti-HLA-G antibodies by using surface plasmon resonance. MEM-G9 and G233 showed strong affinities to HLA-G1, with a nM range for their dissociation constants, but did not show affinities to HLA-G2. The disulfide-linker HLA-G1 dimer further exhibited significant avidity effects. On the other hand, 4H84 and MEM-G1, which can be used for the Western blotting of HLA-G isoforms, can bind to native HLA-G2, while MEM-G9 and G233 cannot. These results reveal that HLA-G2 has a partially intrinsically disordered structure. Furthermore, MEM-G1, but not 4H84, competes with the LILRB2 binding of HLA-G2. These results provide novel insight into the functional characterization of HLA-G isoforms and their detection systems. © 2019 by the authors. Licensee MDPI, Basel, Switzerland

Molecular mechanism of the recognition of bacterially cleaved immunoglobulin by the immune regulatory receptor LILRA2

金沢大学医薬保健研究域薬学系Human leukocyte immunoglobulin-like receptors (LILRs) typically regulate immune activation by binding to the human leukocyte antigen class I molecules. LILRA2, a member of the LILR family, was recently reported to bind to other unique ligands, the bacterially degraded Igs (N-truncated Igs), for the activation of immune cells. Therefore, LILRA2 is currently attracting significant attention as a novel innate immune receptor. However, the detailed recognition mechanisms required for this interaction remain unclear. In this study, using several biophysical techniques, we uncovered the molecular mechanism of N-truncated Ig recognition by LILRA2. Surface plasmon resonance analysis disclosed that LILRA2 specifically binds to N-truncated Ig with weak affinity (Kd = 4.8 mM) and fast kinetics. However, immobilized LILRA2 exhibited a significantly enhanced interaction with N-truncated Ig due to avidity effects. This suggests that cell surface-bound LILRA2 rapidly monitors and identifies bi- or multivalent abnormal N-truncated Igs through specific cross-linking to induce immune activation. Van\u27t Hoff analysis revealed that this interaction is enthalpy-driven, with a small entropy loss, and results from differential scanning calorimetry indicated the instability of the putative LILRA2-binding site, the Fab region of the N-truncated Ig. Atomic force microscopy revealed that N truncation does not cause significant structural changes in Ig. Furthermore, mutagenesis analysis identified the hydrophobic region of LILRA2 domain 2 as the N-truncated Ig-binding site, representing a novel ligand-binding site for the LILR family. These results provide detailed insights into the molecular regulation of LILR-mediated immune responses targeting ligands that have been modified by bacteria. © 2020 Yamazaki et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc

Molecular phylogeny of the rotifers with two Indonesian Brachionus lineages

The rotifer Brachionus plicatilis is an ecologically and commercially important species, and has been studied in various fields such as population dynamics, ecotoxicology and aging. However, recent studies have revealed that the B. plicatilis lineages involve an unknown number of cryptic species, and the group has been regarded as the Brachionus complex. One cause of this complicated taxonomy is the lack of surveys in the tropical zone, which is characterized by enormous species-richness. Accordingly, in this study we collected two Brachionus rotifers from the Sumatra and Sulawesi Islands, Indonesia, and determined their partial nucleotide sequences of mitochondrial DNA cytochrome c oxidase subunit I gene. Subsequently, we constructed molecular phylogenetic trees with fourteen species/lineages from four genera including the two Indonesian rotifers. The two Indonesian Brachionus rotifers were respectively found to be phylogenetically close to B. ibericus and B. rotundiformis. On the other hand, Japanese B. plicatilis was suggested to be phylogenetically closer to B. Manjavacas, which is proposed to be a new species, than to Spanish B. plicatilis. These results imply that the current taxonomy of the Brachionus is problematic, and a major revision is necessary to establish a reliable taxonomy of this group

Erratum: Synthesis of glycerolipids containing simple linear acyl chains or aromatic rings and evaluation of their Mincle signaling activity (Chem. Commun. (2019) 55 (711–714) DOI: 10.1039/C8CC07322H)

金沢大学医薬保健研究域薬学系The authors regret that the structures of brartemicin and compounds 6a and b presented in Fig. 2 of the article were incorrect. The correct structures are depicted below. In addition, explanations of the R’ groups have been added below each compound. (Figure Presented). This journal is © The Royal Society of Chemistr

Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still’s disease

BackgroundHLA-DRB1 alleles are major determinants of genetic predisposition to rheumatic diseases. We assessed whether DRB1 alleles are associated with susceptibility to particular clinical features of adult onset Still’s disease (AOSD) in a Japanese population by determining the DRB1 allele distributions.MethodsDRB1 genotyping of 96 patients with AOSD and 1,026 healthy controls was performed. Genomic DNA samples from the AOSD patients were also genotyped for MEFV exons 1, 2, 3, and 10 by direct sequencing.ResultsIn Japanese patients with AOSD, we observed a predisposing association of DRB1*15:01 (p = 8.60 × 10−6, corrected p (Pc) = 0.0002, odds ratio (OR) = 3.04, 95% confidence interval (95% CI) = 1.91–4.84) and DR5 serological group (p = 0.0006, OR = 2.39, 95% CI = 1.49–3.83) and a protective association of DRB1*09:01 (p = 0.0004, Pc = 0.0110, OR = 0.34, 95% CI = 0.18–0.66) with AOSD, and amino acid residues 86 and 98 of the DRβ chain were protectively associated with AOSD. MEFV variants were identified in 49 patients with AOSD (56.3%). The predisposing effect of DR5 was confirmed only in patients with AOSD who had MEFV variants and not in those without MEFV variants. Additionally, DR5 in patients with AOSD are associated with macrophage activation syndrome (MAS) and steroid pulse therapy.ConclusionThe DRB1*15:01 and DR5 are both associated with AOSD susceptibility in Japanese subjects. A protective association between the DRB1*09:01 allele and AOSD was also observed in these patients. Our data also highlight the effects of DRB1 alleles in susceptibility to AOSD

Experimental observation of response to Resonant Magnetic Perturbation and its hysteresis in LHD

The magnetic island in the large helical device (LHD) shows the dynamic behaviour of the healing/growth transition withthe hysteretic behaviour. The thresholds of plasma beta and poloidal flow for island healing are larger than that for growth.The threshold of resonant magnetic perturbation (RMP) for healing is smaller than that for growth. Furthermore, thresholds of the amplitude of RMP depend on the magnetic axis position Rax in the LHD. The RMP threshold increases as the magnetic axis position Rax increases. The poloidal viscosity may be considered as a candidate to explain the experimental observation from the viewpoint of the relationship between the electromagnetic torque and the viscous torque

A Report on Overseas Teaching Practicum by Graduate Students in Elementary/Secondary Schools in the United States（Ⅺ）

This paper reports on the 11th overseas teaching practicum in the U.S. 12 students joined this year’s program and they observed and conducted lessons in English in three local public schools in North Carolina after careful and repeated preparation sessions in Japan. Many of them did lessons on crosscultural understandings and a few taught subject contents. Through the trail to convey messages in English, their foreign language, students learned the role of verbal and nonverbal language and the more universal way to explain topics to children who are unfamiliar with what re taught. And they also learned and noticed the cultural differences and similalities between the two countries. It seemed that students realized that the two countries share many things in common such as what chidren are like, teachers’ attitude toward children and challenges they are facing, and people’s kindness. These learning was no substitute experience for the participants and it is hoped that their experience will be passed to the next generation when they become teachers

Serum amyloid A1 (SAA1) gene polymorphisms in Japanese patients with adult-onset Stillʼs disease

Adult-onset Still\u27s disease (AOSD) is a rare systemic inflammatory disorder in which inflammasome activation plays a pathophysiological role. In view of the inflammatory nature of AOSD, we investigated whether serum amyloid A (SAA) gene polymorphisms affect the susceptibility of patients with AOSD.Eighty-seven Japanese patients with AOSD and 200 healthy Japanese subjects were recruited in this study. The genotypes of the -13C/T SNP in the 5′-flanking region of the SAA1 gene (rs12218) and two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined using polymerase chain reaction fragment length polymorphism (PCR-RFLP) assay in all subjects. In AOSD patients, exons 1, 2, 3, and 10 of the MEFV gene were also genotyped by direct sequencing.The frequency of the SAA1.3 allele was increased in AOSD patients compared with that in healthy subjects (43.1% versus 37.5%), but the difference was not significant. The −13T allele was more frequently observed in AOSD patients than in healthy subjects (50.6% versus 41.0%, P = .0336). AOSD patients with the −13T allele had been treated with immunosuppressants more frequently than those without this allele. MEFV mutations were detected in 49 patients with AOSD (49/87, 57.3%). AOSD patients with MEFV variants frequently exhibit macrophage activation syndrome, but the difference was not significant (34.7% versus 18.4%, P = .081). Also, there was no significant difference in SAA1 -13C/T allele frequency between AOSD patients with and without MEFV mutations.Our data shows a significant association between T allele of rs12218 and AOSD in Japanese population