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Start Over Author "Avraham, A." Journal journal of biological chemistry
313 results on '"Avraham, A."'

44. An Immunomodulating Motif of the HIV-1 Fusion Protein Is Chirality-independent

Author

Avraham Ashkenazi, Nathali Kaushansky, Avraham Ben-Nun, Omri Faingold, and Yechiel Shai

Subjects
Protein domain, T-cell receptor, Lipid bilayer fusion, Cell Biology, Biology, Gp41, Biochemistry, Fusion protein, Protein–protein interaction, Cell biology, Myelin oligodendrocyte glycoprotein, Transmembrane domain, biology.protein, Molecular Biology
Abstract

An immunosuppressive motif was recently found within the HIV-1 gp41 fusion protein (termed immunosuppressive loop-associated determinant core motif (ISLAD CM)). Peptides containing the motif interact with the T-cell receptor (TCR) complex; however, the mechanism by which the motif exerts its immunosuppressive activity is yet to be determined. Recent studies showed that interactions between protein domains in the membrane milieu are not always sterically controlled. Therefore, we utilized the unique membrane leniency toward association between d- and l-stereoisomers to investigate the detailed mechanism by which ISLAD CM inhibits T-cell activation. We show that a d-enantiomer of ISLAD CM (termed ISLAD d-CM) inhibited the proliferation of murine myelin oligodendrocyte glycoprotein (MOG)-(35–55)-specific line T-cells to the same extent as the l-motif form. Moreover, the d- and l-forms preferentially bound spleen-derived T-cells over B-cells by 13-fold. Furthermore, both forms of ISLAD CM co-localized with the TCR on activated T-cells and interacted with the transmembrane domain of the TCR. FRET experiments revealed the importance of basic residues for the interaction between ISLAD CM forms and the TCR transmembrane domain. Ex vivo studies demonstrated that ISLAD d-CM administration inhibited the proliferation (72%) and proinflammatory cytokine secretion of pathogenic MOG(35–55)-specific T-cells. This study provides insights into the immunosuppressive mechanism of gp41 and demonstrates that chirality-independent interactions in the membrane can take place in diverse biological systems. Apart from HIV pathogenesis, the d-peptide reported herein may serve as a potential tool for treating T-cell-mediated pathologies.

Published
2013
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45. Role of a Novel Human Leukocyte Antigen-DQA1*01:02;DRB1*15:01 Mixed Isotype Heterodimer in the Pathogenesis of 'Humanized' Multiple Sclerosis-like Disease

Author

Bjarke E. Hansen, Ron Milo, Avraham Ben-Nun, Miriam Eisenstein, Daniel M. Altmann, Claus Henrik Nielsen, Gabriel Zeilig, Nathali Kaushansky, Sigalit Boura-Halfon, and Hans Lassmann

Subjects
musculoskeletal diseases, Candidate gene, Multiple Sclerosis, Molecular Sequence Data, Immunology, Antigen presentation, Mice, Transgenic, Human leukocyte antigen, Biology, Biochemistry, HLA-DQ alpha-Chains, Epitope, Mice, Antigen, immune system diseases, Animals, Humans, Amino Acid Sequence, Allele, skin and connective tissue diseases, Molecular Biology, Mice, Knockout, Genetics, Sequence Homology, Amino Acid, Haplotype, Epistasis, Genetic, Cell Biology, Molecular biology, Isotype, Haplotypes, Claudins, Dimerization, HLA-DRB1 Chains
Abstract

Gene-wide association and candidate gene studies indicate that the greatest effect on multiple sclerosis (MS) risk is driven by the HLA-DRB1*15:01 allele within the HLA-DR15 haplotype (HLA-DRB1*15:01-DQA1*01:02-DQB1*0602-DRB5*01:01). Nevertheless, linkage disequilibrium makes it difficult to define, without functional studies, whether the functionally relevant effect derives from DRB1*15:01 only, from its neighboring DQA1*01:02-DQB1*06:02 or DRB5*01:01 genes of HLA-DR15 haplotype, or from their combinations or epistatic interactions. Here, we analyzed the impact of the different HLA-DR15 haplotype alleles on disease susceptibility in a new "humanized" model of MS induced in HLA-transgenic (Tg) mice by human oligodendrocyte-specific protein (OSP)/claudin-11 (hOSP), one of the bona fide potential primary target antigens in MS. We show that the hOSP-associated MS-like disease is dominated by the DRB1*15:01 allele not only as the DRA1*01:01;DRB1*15:01 isotypic heterodimer but also, unexpectedly, as a functional DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. The contribution of HLA-DQA1/DRB1 mixed isotype heterodimer to OSP pathogenesis was revealed in (DRB1*1501xDQB1*0602)F1 double-Tg mice immunized with hOSP(142-161) peptide, where the encephalitogenic potential of prevalent DRB1*1501/hOSP(142-161)-reactive Th1/Th17 cells is hindered due to a single amino acid difference in the OSP(142-161) region between humans and mice; this impedes binding of DRB1*1501 to the mouse OSP(142-161) epitope in the mouse CNS while exposing functional binding of mouse OSP(142-161) to DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. This study, which shows for the first time a functional HLA-DQA1/DRB1 mixed isotype heterodimer and its potential association with disease susceptibility, provides a rationale for a potential effect on MS risk from DQA1*01:02 through functional DQA1*01:02;DRB1*15:01 antigen presentation. Furthermore, it highlights a potential contribution to MS risk also from interisotypic combination between products of neighboring HLA-DR15 haplotype alleles, in this case the DQA1/DRB1 combination.

Published
2015
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