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Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response.

Wandu WS, Tan C, Ogbeifun O, Vistica BP, Shi G, Hinshaw SJ, Xie C, Chen X, Klinman DM, Cai H, Gery I - PLoS ONE (2015)

Bottom Line: In both these diseases inflammatory processes participate in the pathogenic process.Peritoneal macrophages were examined for their production of cytokines/chemokines in culture following stimulation with LPS or the oligodeoxynucleotide CpG.The expression levels of FoxP3 by Lrrk2 (-/-) spleen cells, however, were similar to those seen in WT controls.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Lrrk2 (-/-) mice develop less severe EAU and DTH responses than their WT controls.A. A summary of disease histological scores in eye sections of Lrrk2 (-/-) (“KO”) and WT controls in eight repeated experiments, fourteen days post-immunization. Each dot represents the mean score of a mouse group in one experiment and the horizontal bars are the means ± SEM of Lrrk2 (-/-) mice and their WT controls in all eight experiments. B. Representative histological sections of eyes of a WT and an Lrrk2 (-/-) mice. Severe inflammation (scored at 3.5+) in the WT control eye, consisting mainly of intense infiltration of inflammatory cells in all retinal layers, as well as remarkable retinal folding. The eye of the Lrrk2 (-/-) mouse is affected by mild inflammation (scored at 1.0), that consists of inflammatory cells in the vitreous (an open arrow) and loci of infiltration into the retina (arrows). C. A representative DTH experiment demonstrating significantly less intense skin response in the Lrrk2 (-/-) mouse group than in their WT controls. Similar differences between the two groups were observed in two additional experiments.
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pone.0128906.g001: Lrrk2 (-/-) mice develop less severe EAU and DTH responses than their WT controls.A. A summary of disease histological scores in eye sections of Lrrk2 (-/-) (“KO”) and WT controls in eight repeated experiments, fourteen days post-immunization. Each dot represents the mean score of a mouse group in one experiment and the horizontal bars are the means ± SEM of Lrrk2 (-/-) mice and their WT controls in all eight experiments. B. Representative histological sections of eyes of a WT and an Lrrk2 (-/-) mice. Severe inflammation (scored at 3.5+) in the WT control eye, consisting mainly of intense infiltration of inflammatory cells in all retinal layers, as well as remarkable retinal folding. The eye of the Lrrk2 (-/-) mouse is affected by mild inflammation (scored at 1.0), that consists of inflammatory cells in the vitreous (an open arrow) and loci of infiltration into the retina (arrows). C. A representative DTH experiment demonstrating significantly less intense skin response in the Lrrk2 (-/-) mouse group than in their WT controls. Similar differences between the two groups were observed in two additional experiments.

Mentions: Statistical analysis was performed using GraphPad Prism 6 (GraphPad Software Inc. La Jolla, CA). Statistical significance was determined using unpaired t tests with p ≤ 0.05. Where non-normal distributions were compared, the Mann-Whitney test was used. The pathological scores of the WT and the Lrrk2 (-/-) mouse groups (Fig 1A) represent the average score from each group in eight individual experiments. To allow comparison of ELISA results across multiple experiments ELISA results were normalized 0–1 with feature scaling, where:


Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response.

Wandu WS, Tan C, Ogbeifun O, Vistica BP, Shi G, Hinshaw SJ, Xie C, Chen X, Klinman DM, Cai H, Gery I - PLoS ONE (2015)

Lrrk2 (-/-) mice develop less severe EAU and DTH responses than their WT controls.A. A summary of disease histological scores in eye sections of Lrrk2 (-/-) (“KO”) and WT controls in eight repeated experiments, fourteen days post-immunization. Each dot represents the mean score of a mouse group in one experiment and the horizontal bars are the means ± SEM of Lrrk2 (-/-) mice and their WT controls in all eight experiments. B. Representative histological sections of eyes of a WT and an Lrrk2 (-/-) mice. Severe inflammation (scored at 3.5+) in the WT control eye, consisting mainly of intense infiltration of inflammatory cells in all retinal layers, as well as remarkable retinal folding. The eye of the Lrrk2 (-/-) mouse is affected by mild inflammation (scored at 1.0), that consists of inflammatory cells in the vitreous (an open arrow) and loci of infiltration into the retina (arrows). C. A representative DTH experiment demonstrating significantly less intense skin response in the Lrrk2 (-/-) mouse group than in their WT controls. Similar differences between the two groups were observed in two additional experiments.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4465928&req=5

pone.0128906.g001: Lrrk2 (-/-) mice develop less severe EAU and DTH responses than their WT controls.A. A summary of disease histological scores in eye sections of Lrrk2 (-/-) (“KO”) and WT controls in eight repeated experiments, fourteen days post-immunization. Each dot represents the mean score of a mouse group in one experiment and the horizontal bars are the means ± SEM of Lrrk2 (-/-) mice and their WT controls in all eight experiments. B. Representative histological sections of eyes of a WT and an Lrrk2 (-/-) mice. Severe inflammation (scored at 3.5+) in the WT control eye, consisting mainly of intense infiltration of inflammatory cells in all retinal layers, as well as remarkable retinal folding. The eye of the Lrrk2 (-/-) mouse is affected by mild inflammation (scored at 1.0), that consists of inflammatory cells in the vitreous (an open arrow) and loci of infiltration into the retina (arrows). C. A representative DTH experiment demonstrating significantly less intense skin response in the Lrrk2 (-/-) mouse group than in their WT controls. Similar differences between the two groups were observed in two additional experiments.
Mentions: Statistical analysis was performed using GraphPad Prism 6 (GraphPad Software Inc. La Jolla, CA). Statistical significance was determined using unpaired t tests with p ≤ 0.05. Where non-normal distributions were compared, the Mann-Whitney test was used. The pathological scores of the WT and the Lrrk2 (-/-) mouse groups (Fig 1A) represent the average score from each group in eight individual experiments. To allow comparison of ELISA results across multiple experiments ELISA results were normalized 0–1 with feature scaling, where:

Bottom Line: In both these diseases inflammatory processes participate in the pathogenic process.Peritoneal macrophages were examined for their production of cytokines/chemokines in culture following stimulation with LPS or the oligodeoxynucleotide CpG.The expression levels of FoxP3 by Lrrk2 (-/-) spleen cells, however, were similar to those seen in WT controls.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus