title: Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes.
abstract: DNAX-activation protein 12 (DAP12), a transmembrane adapter, plays a major role in transducing activation signals in natural killer cells and various myeloid cells. Quantitative RT-PCR detected in normal mouse eyes considerable levels of DAP12 and multiple DAP12-coupled receptors, in particular TREM-1, Clec5a and SIRPb1. The role of DAP12 and its receptors in experimental autoimmune diseases has been controversial. Here, we analysed the effect of DAP12 deficiency on the capacity of mice to mount immunopathogenic cellular responses to the uveitogenic ocular antigen and interphotoreceptor retinoid-binding protein (IRBP), and to develop experimental autoimmune uveitis (EAU). Surprisingly, sequential analysis of EAU in mice deficient in DAP12 in two different animal facilities at first revealed enhanced disease as compared with wild-type mice, but when these mice were re-derived into a second, cleaner, animal facility, the response of control mice was essentially unchanged, whereas the DAP12 null mice were markedly hyporesponsive relative to controls in the new facility. Accordingly, when stimulated in vitro with IRBP, lymphocytes from the DAP12-deficient mice housed in the two facilities proliferated and produced opposite profiles of pro-inflammatory and anti-inflammatory cytokines, compared with their controls. These findings therefore demonstrate that the effects of DAP12 deficiency on development of autoimmune disease are dramatically affected by environmental factors.
authors.affiliation: Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Montalvo
authors.forename: Laura
authors.initials: L
authors.lastname: Quigley
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Vistica
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Boelte
authors.forename: Lindsey F
authors.initials: LF
authors.lastname: Nugent
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McVicar
authors.forename: Igal
authors.initials: I
authors.lastname: Gery
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004777:Environment; D005123:Eye / Q000276:immunology / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism; D006799:Housing, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000378:metabolism; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014605:Uveitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D005136:Eye Proteins; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D012177:Retinol-Binding Proteins; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D000099214:Retinol-Binding Proteins, Interstitial; C509772:Clec5a protein, mouse; C517262:TREM1 protein, mouse; C498716:Trem2 protein, mouse; C484963:Tyrobp protein, mouse
keywords: TREM-2; cytokines; lymphoid cells; ocular inflammation
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