Identification of Orch3, a Locus Controlling Dominant Resistance to Autoimmune Orchitis, as Kinesin Family Member 1C

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Identification of Orch3, a Locus Controlling Dominant Resistance to Autoimmune Orchitis, as Kinesin Family Member 1C

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Title: Identification of Orch3, a Locus Controlling Dominant Resistance to Autoimmune Orchitis, as Kinesin Family Member 1C
Author: del Rio, Roxana; McAllister, Ryan D.; Meeker, Nathan D.; Wall, Emma H.; Bond, Jeffrey P.; Kyttaris, Vasileios; Tsokos, George C.; Tung, Kenneth S. K.; Teuscher, Cory

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Citation: del Rio, Roxana, Ryan D. McAllister, Nathan D. Meeker, Emma H. Wall, Jeffrey P. Bond, Vasileios C. Kyttaris, George C. Tsokos, Kenneth S. K. Tung, and Cory Teuscher. 2012. Identification of orch3, a locus controlling dominant resistance to autoimmune orchitis, as kinesin family member 1C. PLoS Genetics 8(12): e1003140.
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Abstract: Experimental autoimmune orchitis (EAO), the principal model of non-infectious testicular inflammatory disease, can be induced in susceptible mouse strains by immunization with autologous testicular homogenate and appropriate adjuvants. As previously established, the genome of DBA/2J mice encodes genes that are capable of conferring dominant resistance to EAO, while the genome of BALB/cByJ mice does not and they are therefore susceptible to EAO. In a genome scan, we previously identified Orch3 as the major quantitative trait locus controlling dominant resistance to EAO and mapped it to chromosome 11. Here, by utilizing a forward genetic approach, we identified kinesin family member 1C (Kif1c) as a positional candidate for Orch3 and, using a transgenic approach, demonstrated that Kif1c is Orch3. Mechanistically, we showed that the resistant Kif1c\(^{D2}\) allele leads to a reduced antigen-specific T cell proliferative response as a consequence of decreased MHC class II expression by antigen presenting cells, and that the L\(^{578}\)→P\(^{578}\) and S\(^{1027}\)→P\(^{1027}\) polymorphisms distinguishing the BALB/cByJ and DBA/2J alleles, respectively, can play a role in transcriptional regulation. These findings may provide mechanistic insight into how polymorphism in other kinesins such as KIF21B and KIF5A influence susceptibility and resistance to human autoimmune diseases.
Published Version: doi:10.1371/journal.pgen.1003140
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531464/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:11181102
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