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The Act1 D10N missense variant impairs CD40 signaling in human B-cells
Univ Michigan, MI 48109 USA; Shanghai Skin Dis Hosp, Peoples R China.
Univ Michigan, MI 48109 USA.
Univ Michigan, MI 48109 USA.
Univ Michigan, MI 48109 USA.
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2019 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 20, no 1, p. 23-31Article in journal (Refereed) Published
Abstract [en]

The TRAF3IP2 gene resides within one of at least 63 psoriasis susceptibility loci and encodes Act1, an adapter protein involved in IL-17 receptor and CD40 signaling pathways. TRAF3IP2 is distinctive (among amp;lt; 10% of candidate susceptibility genes) in that a strongly disease-associated variant encodes a missense SNP predicted to be functionally relevant (SNP rs33980500 C/T encoding Act1 pD10N). As assessed by flow cytometry, Act1 protein was expressed at the highest levels in monocytes, with lower levels in T-cells and B-cells. However, monocytes, T-cells and B-cells failed to respond to IL-17A stimulation of PBMC, as measured by flow cytometric determination of NF-kappa B phospho-p65. As an alternative stimulus, we treated PBMCs with trimerized recombinant human CD40L and assessed p65, p38 and Erk phosphorylation in CD19(+) B-cells as a function of D10N genotype. The increase of phosphorylated p65, p38, and Erk was well-correlated across individuals, and CD40L-induced phosphorylation of p65, p38, and Erk was significantly attenuated in B-cells from Act1 D10N homozygotes, compared to heterozygotes and nullizygotes. Our results indicate that the Act1 D10N variant is a relevant genetic determinant of CD40L responsiveness in human B-cells, with the risk allele being associated with lower B-cell responses in an acute signaling context.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 20, no 1, p. 23-31
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Immunology in the medical area
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URN: urn:nbn:se:liu:diva-154713DOI: 10.1038/s41435-017-0007-7ISI: 000457464600003PubMedID: 29302052OAI: oai:DiVA.org:liu-154713DiVA, id: diva2:1292286
Note

Funding Agencies|National Institutes of Health (NIH) R01 [AR042742, AR050511, AR054966, AR062382, AR065183]; Dawn and Dudley Holmes Memorial Fund; Babcock Endowment Fund; Ann Arbor Veterans Affairs Hospital

Available from: 2019-02-27 Created: 2019-02-27 Last updated: 2019-02-27

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Enerbäck, Charlotta
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Division of Cell BiologyFaculty of Medicine and Health SciencesDepartment of Dermatology and Venerology
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