title: Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis.
abstract: C-type lectins are key players in immune regulation by driving distinct functions of antigen-presenting cells. The C-type lectin CLEC16A gene is located at 16p13, a susceptibility locus for several autoimmune diseases, including multiple sclerosis. However, the function of this gene and its potential contribution to these diseases in humans are poorly understood. In this study, we found a strong upregulation of CLEC16A expression in the white matter of multiple sclerosis patients (n = 14) compared to non-demented controls (n = 11), mainly in perivascular leukocyte infiltrates. Moreover, CLEC16A levels were significantly enhanced in peripheral blood mononuclear cells of multiple sclerosis patients (n = 69) versus healthy controls (n = 46). In peripheral blood mononuclear cells, CLEC16A was most abundant in monocyte-derived dendritic cells, in which it strongly co-localized with human leukocyte antigen class II. Treatment of these professional antigen-presenting cells with vitamin D, a key protective environmental factor in multiple sclerosis, downmodulated CLEC16A in parallel with human leukocyte antigen class II. Knockdown of CLEC16A in distinct types of model and primary antigen-presenting cells resulted in severely impaired cytoplasmic distribution and formation of human leucocyte antigen class II-positive late endosomes, as determined by immunofluorescence and electron microscopy. Mechanistically, CLEC16A participated in the molecular machinery of human leukocyte antigen class II-positive late endosome formation and trafficking to perinuclear regions, involving the dynein motor complex. By performing co-immunoprecipitations, we found that CLEC16A directly binds to two critical members of this complex, RILP and the HOPS complex. CLEC16A silencing in antigen-presenting cells disturbed RILP-mediated recruitment of human leukocyte antigen class II-positive late endosomes to perinuclear regions. Together, we identify CLEC16A as a pivotal gene in multiple sclerosis that serves as a direct regulator of the human leukocyte antigen class II pathway in antigen-presenting cells. These findings are a first step in coupling multiple sclerosis-associated genes to the regulation of the strongest genetic factor in multiple sclerosis, human leukocyte antigen class II.
authors.affiliation: 1 Department of Immunology and MS Center ErasMS, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Marvin M
authors.initials: MM
authors.lastname: van Luijn
authors.affiliation: 2 Department of Neurology and MS Center ErasMS, Erasmus MC, University Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Karim L
authors.initials: KL
authors.lastname: Kreft
authors.affiliation: 3 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Marlieke L
authors.initials: ML
authors.lastname: Jongsma
authors.affiliation: 1 Department of Immunology and MS Center ErasMS, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Mes
authors.affiliation: 1 Department of Immunology and MS Center ErasMS, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Annet F
authors.initials: AF
authors.lastname: Wierenga-Wolf
authors.affiliation: 1 Department of Immunology and MS Center ErasMS, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Marjan
authors.initials: M
authors.lastname: van Meurs
authors.affiliation: 1 Department of Immunology and MS Center ErasMS, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Melief
authors.affiliation: 3 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Rik van
authors.initials: Rv
authors.lastname: der Kant
authors.affiliation: 3 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Lennert
authors.initials: L
authors.lastname: Janssen
authors.affiliation: 3 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.affiliation: 4 Department of Pathology, Sidra Medical and Research Center, Doha, Qatar 5 BC Children's Hospital and Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Rusung
authors.initials: R
authors.lastname: Tan
authors.affiliation: 5 BC Children's Hospital and Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Priatel
authors.affiliation: 3 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.affiliation: 1 Department of Immunology and MS Center ErasMS, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.affiliation: 2 Department of Neurology and MS Center ErasMS, Erasmus MC, University Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands r.hintzen@erasmusmc.nl.
authors.forename: Rogier Q
authors.initials: RQ
authors.lastname: Hintzen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000502:physiology*; D009103:Multiple Sclerosis / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000494:pharmacology; D066127:White Matter / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C522505:CLEC16A protein, human; D000949:Histocompatibility Antigens Class II; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins; C423317:RILP protein, human; D034741:RNA, Small Interfering; D014807:Vitamin D
keywords: C-type lectin; antigen presentation; autoimmune disease; human leukocyte antigen; immunogenetics
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