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2.
J Exp Med ; 211(7): 1465-83, 2014 Jun 30.
Article in English | MEDLINE | ID: mdl-24935259

ABSTRACT

Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN-dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG-DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.


Subject(s)
Brain/immunology , Cell Adhesion Molecules/immunology , Immune Tolerance/physiology , Inflammasomes/immunology , Lectins, C-Type/immunology , Myelin-Oligodendrocyte Glycoprotein/immunology , Receptors, Cell Surface/immunology , Th17 Cells/immunology , Animals , Brain/cytology , CHO Cells , Cell Adhesion Molecules/genetics , Cell Proliferation , Cricetinae , Cricetulus , Female , Humans , Inflammasomes/genetics , Inflammation Mediators/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Lectins, C-Type/genetics , Male , Myelin-Oligodendrocyte Glycoprotein/genetics , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins c-raf/immunology , Receptors, Cell Surface/genetics , Th17 Cells/cytology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology
3.
Cancer Res ; 65(15): 6891-900, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-16061673

ABSTRACT

The HER-2 oncoprotein is commonly overexpressed in a variety of human malignancies and has become an attractive antitumor target. A number of strategies to inhibit the HER-2 receptor tyrosine kinase are currently the focus of intensive preclinical and clinical research. In the present study, we have engineered a bifunctional peptide, BHAP, which consists of two modular domains: a HER-2-targeting/neutralizing domain and a mitochondriotoxic, proapoptotic domain. The chimeric peptide is biologically active and capable of selectively triggering apoptosis of HER-2-overexpressing cancer cells in culture, even those previously described as Herceptin resistant. Furthermore, BHAP slows down growth of HER-2-overexpressing human mammary xenografts established in SCID mice. This approach can be extended to the development of tailored targeted chimeric peptides against a number of overexpressed cellular receptors implicated in the development and progression of cancer.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Mitochondria/drug effects , Peptides/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Amino Acid Sequence , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Growth Processes/drug effects , Cell Line, Tumor , Female , Humans , Mice , Mice, SCID , Mitochondria/physiology , Molecular Sequence Data , Peptides/genetics , Peptides/pharmacokinetics , Protein Engineering , Protein Structure, Tertiary , Receptor, ErbB-2/biosynthesis , Receptor, ErbB-2/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/pharmacokinetics , Recombinant Fusion Proteins/pharmacology , Xenograft Model Antitumor Assays
4.
Tissue Antigens ; 58(6): 351-62, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11929585

ABSTRACT

HLA-B*2702 is an ankylosing spondylitis-associated allotype that differs from the more common B*2705 at residues 77, 80, and 81, in the peptide-binding site. The diversity and fine specificity of alloreactive cytolytic T-lymphocyte (CTL) raised against B*2702 were analyzed at the clonal level. Significant crossreaction with B*2705 and B*2709 indicated that the three subtypes share numerous T-cell epitopes. However, some epitopes shared by B*2702 and B*2705 were lost in B*2709, which correlates with weaker association of this subtype to disease. Clonal specificities were donor-dependent, indicating that allo-immunogenicity is variable among individuals. Anti-B*2702 CTL were little affected by single mutations mimicking B*2702/B*2705 polymorphism, but the double mutant at positions 77 and 81 was recognized worse than B*2705, suggesting a compensatory effect of residue 80. Thus, HLA-B27 polymorphism modulated alloreactivity through cooperative and compensatory effects on T-cell epitope structure. Comparison of B*2705- and B*2702-bound peptide repertoires revealed that they overlapped by 73% and 81%, respectively. This was larger than B*2702/B*2705 cross-reaction, indicating that HLA-B27 allospecificity is only partially determined by the nature of peptide repertoires. The large sharing of natural ligands and T-cell epitopes is consistent with a pathogenetic role of B*2702 and B*2705 in spondyloarthritis based on antigen presentation.


Subject(s)
Epitopes, T-Lymphocyte/immunology , HLA-B27 Antigen/immunology , Spondylarthritis/immunology , Spondylitis, Ankylosing/immunology , Antigen Presentation/immunology , Cell Line , Cross Reactions , Epitopes , Epitopes, T-Lymphocyte/genetics , Genetic Predisposition to Disease , HLA-B27 Antigen/analysis , HLA-B27 Antigen/genetics , Humans , Mutagenesis, Site-Directed , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Spondylarthritis/genetics , Spondylitis, Ankylosing/genetics
5.
Actas Urol Esp ; 16(1): 35-8, 1992 Jan.
Article in Spanish | MEDLINE | ID: mdl-1590072

ABSTRACT

Report on 2 cases of urological neoplasia in HIV positive patients. The first one is a renal adenocarcinoma in a heroin-abuser patient, of a type we have only found mentioned in the literature in 4 other cases. The second case was a disseminated Kaposi's sarcoma, the first symptom being a scrotum impairment and the biopsy suggested the diagnosis. This is believed to be an interesting communication considering the increasing number of anti-HIV antibodies carriers seen in our Units.


Subject(s)
Acquired Immunodeficiency Syndrome/complications , Adenocarcinoma/complications , Genital Neoplasms, Male/etiology , Kidney Neoplasms/complications , Sarcoma, Kaposi/etiology , Scrotum , Adult , Humans , Male
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