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Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease

INTRODUCTION: Scurfy mice are deficient in regulatory T cells (Tregs), develop a severe, generalized autoimmune disorder that can affect almost every organ and die at an early age. Some of these manifestations resemble those found in systemic lupus erythematosus (SLE). In addition, active SLE is ass...

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Autores principales: Hadaschik, Eva N, Wei, Xiaoying, Leiss, Harald, Heckmann, Britta, Niederreiter, Birgit, Steiner, Günter, Ulrich, Walter, Enk, Alexander H, Smolen, Josef S, Stummvoll, Georg H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391674/
https://www.ncbi.nlm.nih.gov/pubmed/25890083
http://dx.doi.org/10.1186/s13075-015-0538-0
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author Hadaschik, Eva N
Wei, Xiaoying
Leiss, Harald
Heckmann, Britta
Niederreiter, Birgit
Steiner, Günter
Ulrich, Walter
Enk, Alexander H
Smolen, Josef S
Stummvoll, Georg H
author_facet Hadaschik, Eva N
Wei, Xiaoying
Leiss, Harald
Heckmann, Britta
Niederreiter, Birgit
Steiner, Günter
Ulrich, Walter
Enk, Alexander H
Smolen, Josef S
Stummvoll, Georg H
author_sort Hadaschik, Eva N
collection PubMed
description INTRODUCTION: Scurfy mice are deficient in regulatory T cells (Tregs), develop a severe, generalized autoimmune disorder that can affect almost every organ and die at an early age. Some of these manifestations resemble those found in systemic lupus erythematosus (SLE). In addition, active SLE is associated with low Treg numbers and reduced Treg function, but direct evidence for a central role of Treg malfunction in the pathophysiology of lupus-like manifestations is still missing. In the present study, we characterize the multiorgan pathology, autoantibody profile and blood count abnormalities in scurfy mice and show their close resemblances to lupus-like disease. METHODS: Scurfy mice have dysfunctional Tregs due to a genetic defect in the transcription factor Forkhead box protein 3 (Foxp3). We analyzed skin, joints, lung and kidneys of scurfy mice and wild-type (WT) controls by conventional histology and immunofluorescence (IF) performed hematological workups and tested for autoantibodies by IF, immunoblotting and enzyme-linked immunosorbent assay. We also analyzed the intestines, liver, spleen and heart, but did not analyze all organs known to be affected in scurfy mice (such as the testicle, the accessory reproductive structures, the pancreas or the eyes). We transferred CD4(+) T cells of scurfy or WT mice into T cell-deficient B6/nude mice. RESULTS: We confirm previous reports that scurfy mice spontaneously develop severe pneumonitis and hematological abnormalities similar to those in SLE. We show that scurfy mice (but not controls) exhibited additional features of SLE: severe interface dermatitis, arthritis, mesangioproliferative glomerulonephritis and high titers of anti-nuclear antibodies, anti-double-stranded DNA antibodies, anti-histone antibodies and anti-Smith antibodies. Transfer of scurfy CD4(+) T cells (but not of WT cells) induced autoantibodies and inflammation of lung, skin and kidneys in T cell-deficient B6/nude mice. CONCLUSION: Our observations support the hypothesis that lupus-like autoimmune features develop in the absence of functional Tregs.
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spelling pubmed-43916742015-04-10 Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease Hadaschik, Eva N Wei, Xiaoying Leiss, Harald Heckmann, Britta Niederreiter, Birgit Steiner, Günter Ulrich, Walter Enk, Alexander H Smolen, Josef S Stummvoll, Georg H Arthritis Res Ther Research Article INTRODUCTION: Scurfy mice are deficient in regulatory T cells (Tregs), develop a severe, generalized autoimmune disorder that can affect almost every organ and die at an early age. Some of these manifestations resemble those found in systemic lupus erythematosus (SLE). In addition, active SLE is associated with low Treg numbers and reduced Treg function, but direct evidence for a central role of Treg malfunction in the pathophysiology of lupus-like manifestations is still missing. In the present study, we characterize the multiorgan pathology, autoantibody profile and blood count abnormalities in scurfy mice and show their close resemblances to lupus-like disease. METHODS: Scurfy mice have dysfunctional Tregs due to a genetic defect in the transcription factor Forkhead box protein 3 (Foxp3). We analyzed skin, joints, lung and kidneys of scurfy mice and wild-type (WT) controls by conventional histology and immunofluorescence (IF) performed hematological workups and tested for autoantibodies by IF, immunoblotting and enzyme-linked immunosorbent assay. We also analyzed the intestines, liver, spleen and heart, but did not analyze all organs known to be affected in scurfy mice (such as the testicle, the accessory reproductive structures, the pancreas or the eyes). We transferred CD4(+) T cells of scurfy or WT mice into T cell-deficient B6/nude mice. RESULTS: We confirm previous reports that scurfy mice spontaneously develop severe pneumonitis and hematological abnormalities similar to those in SLE. We show that scurfy mice (but not controls) exhibited additional features of SLE: severe interface dermatitis, arthritis, mesangioproliferative glomerulonephritis and high titers of anti-nuclear antibodies, anti-double-stranded DNA antibodies, anti-histone antibodies and anti-Smith antibodies. Transfer of scurfy CD4(+) T cells (but not of WT cells) induced autoantibodies and inflammation of lung, skin and kidneys in T cell-deficient B6/nude mice. CONCLUSION: Our observations support the hypothesis that lupus-like autoimmune features develop in the absence of functional Tregs. BioMed Central 2015-02-23 2015 /pmc/articles/PMC4391674/ /pubmed/25890083 http://dx.doi.org/10.1186/s13075-015-0538-0 Text en © Hadaschik et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Hadaschik, Eva N
Wei, Xiaoying
Leiss, Harald
Heckmann, Britta
Niederreiter, Birgit
Steiner, Günter
Ulrich, Walter
Enk, Alexander H
Smolen, Josef S
Stummvoll, Georg H
Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease
title Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease
title_full Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease
title_fullStr Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease
title_full_unstemmed Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease
title_short Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease
title_sort regulatory t cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391674/
https://www.ncbi.nlm.nih.gov/pubmed/25890083
http://dx.doi.org/10.1186/s13075-015-0538-0
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