title: Identification of Orch3, a locus controlling dominant resistance to autoimmune orchitis, as kinesin family member 1C.
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.
authors.affiliation: Department of Medicine/Immunobiology Program, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Roxana
authors.initials: R
authors.lastname: del Rio
authors.forename: Ryan D
authors.initials: RD
authors.lastname: McAllister
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Meeker
authors.forename: Emma H
authors.initials: EH
authors.lastname: Wall
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Bond
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: Kenneth S K
authors.initials: KS
authors.lastname: Tung
authors.forename: Cory
authors.initials: C
authors.lastname: Teuscher
mesh_terms: D000483:Alleles; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D060467:Disease Resistance / Q000235:genetics*; D015870:Gene Expression; D005799:Genes, Dominant; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009920:Orchitis / Q000235:genetics / Q000276:immunology; D040641:Quantitative Trait Loci / Q000235:genetics; D013737:Testis / Q000276:immunology
chemical_list: C485246:Kif1c protein, mouse; D016547:Kinesins