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Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis
- Source :
- Brain, 138(6), 1531-1547. Oxford University Press, Brain, 138, 1531-1547. Oxford University Press
- Publication Year :
- 2015
-
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.
- Subjects :
- Male
DENDRITIC CELL-RECEPTOR
RNA, Small Interfering
Vitamin D
HOPS COMPLEX
VITAMIN-D
Cells, Cultured
Late endosome
biology
Antigen processing
RISK ALLELES
Middle Aged
White Matter
SUSCEPTIBILITY GENE CLEC16A
HLA-B
Up-Regulation
Protein Transport
Gene Knockdown Techniques
Female
Adult
CHOLESTEROL SENSOR ORP1L
Multiple Sclerosis
Adolescent
Monosaccharide Transport Proteins
Antigen presentation
Antigen-Presenting Cells
autoimmune disease
Endosomes
CLEC16A
Human leukocyte antigen
Major histocompatibility complex
Young Adult
MHC CLASS-II
SDG 3 - Good Health and Well-being
human leukocyte antigen
Humans
Genetic Predisposition to Disease
Lectins, C-Type
GENOME-WIDE ASSOCIATION
Adaptor Proteins, Signal Transducing
Aged
MHC class II
Histocompatibility Antigens Class II
Dendritic Cells
Original Articles
MAJOR HISTOCOMPATIBILITY COMPLEX
C-type lectin
immunogenetics
antigen presentation
Case-Control Studies
Immunology
Leukocytes, Mononuclear
biology.protein
Neurology (clinical)
Subjects
Details
- ISSN :
- 00068950
- Volume :
- 138
- Database :
- OpenAIRE
- Journal :
- Brain
- Accession number :
- edsair.doi.dedup.....afb18f061e04bd97d7a50507e9f765ff