Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis
Open accessAbstract
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.
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The mutations in the gene analyzed here are likely more disruptive of Clec16a function than alleles associated with human disease risk.
“Importantly, the mutations in the gene analyzed here are likely more disruptive of Clec16a function than alleles associated with human disease risk12163342.”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [33]
The Introduction identifies CLEC16A-region SNPs associated with human disease risk, and the knockdown results show that substantially reducing CLEC16A expression disrupts late-endosome biogenesis. The paper does not assess the mutations analyzed in the citing document or compare their effects with those of human risk alleles, so it does not support the claimed relative severity. (LLM, conf=0.82)
Experimental — accuracy not yet measuredKnock-down or loss of Clec16a in human and murine cells has been described to alter the morphology of late endosomes.
“Knock-down or loss of Clec16a in human and murine cells has been described to alter the morphology of late endosomes1633 but we did not observe alterations in the endosomal network as detected by staining of endosomes for Rab5, Rab7 or EEA1 in Clec16a-deficient cells (Fig. 5a, Supplementary Fig. 5a).”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [33]
In the section on CLEC16A knockdown and late-endosomal biogenesis (page unavailable), electron microscopy shows altered multivesicular-body morphology after CLEC16A knockdown in human MelJuSo cells. The paper also reports dispersed late endosomes in those cells, but the passages do not establish the claimed effect in murine cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA two- to four-fold increase in CLEC16A mRNA was detected in multiple sclerosis patients compared to controls in peripheral blood mononuclear cells and white matter, though this was not related to the multiple sclerosis risk-associated SNP rs7200786.
“a two- to four-fold increase in CLEC16A mRNA was detected in multiple sclerosis patients compared to controls in peripheral blood mononuclear cells and white matter, though this was not related to the multiple sclerosis risk-associated SNP rs720078633.”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [33]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSNPs in CLEC16A associated with autoimmunity may correlate with either increased or decreased CLEC16A protein expression in humans.
“single nucleotide polymorphisms (SNPs) in CLEC16A that are associated with autoimmunity may correlate with either increased or decreased CLEC16A protein expression in humans”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [33]
The Introduction (page unavailable) links SNPs at the CLEC16A locus to multiple sclerosis and other autoimmune diseases. The Discussion (page unavailable) reports that some studies found risk-genotype effects on CLEC16A expression, but it does not establish increased versus decreased protein expression. The paper's own blood analysis found no association between the tested risk SNP and CLEC16A mRNA levels. (LLM, conf=0.85)
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- Authors
- van Luijn, M. M., Kreft, K. L., Jongsma, M. L., Mes, S. W., Wierenga-Wolf, A. F., van Meurs, M., Melief, M.-J., der Kant, R. V., Janssen, L., Janssen, H., Tan, R., Priatel, J. J., Neefjes, J., Laman, J. D., & Hintzen, R. Q.
- Affiliations
- Erasmus MC (NL)
- The Netherlands Cancer Institute (NL)
- University of British Columbia (CA)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-03-29
- Volume
- 138
- Issue
- 6
- Pages
- 1531-1547
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4614123
- OpenAlex
- W2120298753
- Cited by
- 68
- References
- 64
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 7 · 2019: 8 · 2018: 3 · 2017: 11 · 2016: 9 · 2015: 5
- FWCI
- 7.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- Child and Family Research Institute
- Stichting Zabawas
- Canadian Institutes of Health Research (MOP-10266)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- CLEC16A, multiple sclerosis, HLA class II, antigen-presenting cells, dendritic cells, C-type lectin, vitamin D, RILP, HOPS complex, dynein motor complex, white matter
- MeSH terms
- Adolescent, Adult, Aged, Antigen-Presenting Cells, Histocompatibility Antigens Class II, Cells, Cultured, Dendritic Cells, Female, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Monosaccharide Transport Proteins, Multiple Sclerosis, Endosomes, Vitamin D, Up-Regulation, Case-Control Studies, Genetic Predisposition to Disease, Protein Transport, RNA, Small Interfering, Lectins, C-Type, Adaptor Proteins, Signal Transducing, Gene Knockdown Techniques, Young Adult, White Matter
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