title: Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response.
abstract: BACKGROUND
  Mutations in LRRK2 are related to certain forms of Parkinson's disease and, possibly, to the pathogenesis of Crohn's disease. In both these diseases inflammatory processes participate in the pathogenic process. LRRK2 is expressed in lymphoid cells and, interestingly, Lrrk2 (-/-) mice were reported to develop more severe experimental colitis than their wild type (WT) controls. Here, we examined the possible involvement of LRRK2 in the pathogenesis of experimental autoimmune uveitis (EAU), an animal model for human uveitis, by testing Lrrk2 (-/-) mice for their capacity to develop this experimental eye disease and related immune responses.
  
  
  METHODS
  Lrrk2 (-/-) mice and their WT controls (C57Bl/6) were immunized with interphotoreceptor retinoid-binding protein (IRBP) and compared for their development of EAU, delayed type hypersensitivity (DTH) by skin tests, production of cytokines in culture, and expression of interferon (IFN)-γ, interleukin (IL)-17 and FoxP3 by spleen cells, using flow cytometry. Peritoneal macrophages were examined for their production of cytokines/chemokines in culture following stimulation with LPS or the oligodeoxynucleotide CpG. The Lrrk2 (-/-) and WT mice were also compared for their response to bovine serum albumin (BSA).
  
  
  RESULTS
  The Lrrk2 (-/-) mice developed lower levels of EAU, DTH responses and cytokine production by lymphocytes than did their WT controls. Intracellular expression of IFN-γ and IL-17, by spleen cells, and secretion of cytokines/chemokines by activated peritoneal macrophages of Lrrk2 (-/-) mice trended toward diminished levels, although variabilities were noted. The expression levels of FoxP3 by Lrrk2 (-/-) spleen cells, however, were similar to those seen in WT controls. Consistent with their low response to IRBP, Lrrk2 (-/-) mice responded to BSA less vigorously than their WT controls.
  
  
  CONCLUSIONS
  Lrrk2 deficiency in mice diminished the development of EAU and the related adaptive immune responses to IRBP as compared to the WT controls.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Wambui S
authors.initials: WS
authors.lastname: Wandu
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Cuiyan
authors.initials: C
authors.lastname: Tan
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Osato
authors.initials: O
authors.lastname: Ogbeifun
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Vistica
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Guangpu
authors.initials: G
authors.lastname: Shi
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Samuel J H
authors.initials: SJ
authors.lastname: Hinshaw
authors.affiliation: Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.affiliation: Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, United States of America.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.affiliation: Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Igal
authors.initials: I
authors.lastname: Gery
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism / Q000473:pathology*; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006968:Hypersensitivity, Delayed / Q000209:etiology / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D012177:Retinol-Binding Proteins / Q000276:immunology; D012882:Skin Tests; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014605:Uveitis / Q000378:metabolism / Q000473:pathology*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D018925:Chemokines; D005136:Eye Proteins; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D020381:Interleukin-17; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C498833:Foxp3 protein, mouse; C495279:Lrrk2 protein, mouse