Cox4i2, Ifit2, and Prdm11 Mutant Mice: Effective Selection of Genes Predisposing to an Altered Airway Inflammatory Response from a Large Compendium of Mutant Mouse Lines.
We established a selection strategy to identify new models for an altered airway inflammatory response from a large compendium of mutant mouse lines that were systemically phenotyped in the German Mouse Clinic (GMC). As selection criteria we included published gene functional data, as well as immunological and transcriptome data from GMC phenotyping screens under standard conditions. Applying these criteria we identified a few from several hundred mutant mouse lines and further characterized the Cox4i2tm1Hutt, Ifit2tm1.1Ebsb, and Prdm11tm1.1ahl lines following ovalbumin (OVA) sensitization and repeated OVA airway challenge. Challenged Prdm11tm1.1ahl mice exhibited changes in B cell counts, CD4+ T cell counts, and in the number of neutrophils in bronchoalveolar lavages, whereas challenged Ifit2tm1.1Ebsb mice displayed alterations in plasma IgE, IgG1, IgG3, and IgM levels compared to the challenged wild type littermates. In contrast, challenged Cox4i2tm1Hutt mutant mice did not show alterations in the humoral or cellular immune response compared to challenged wild type mice. Transcriptome analyses from lungs of the challenged mutant mouse lines showed extensive changes in gene expression in Prdm11tm1.1ahl mice. Functional annotations of regulated genes of all three mutant mouse lines were primarily related to inflammation and airway smooth muscle (ASM) remodeling. We were thus able to define an effective selection strategy to identify new candidate genes for the predisposition to an altered airway inflammatory response under OVA challenge conditions. Similar selection strategies may be used for the analysis of additional genotype-envirotype interactions for other diseases.
Helmholtz Zentrum München GmbH, German Mouse Clinic, Institute of Experimental Genetics, D-85764 Neuherberg, Germany.
Marion
M
Horsch
Helmholtz Zentrum München GmbH, German Mouse Clinic, Institute of Experimental Genetics, D-85764 Neuherberg, Germany; Department of Dermatology and Allergy, TUM and Clinical Research Division of Molecular and Clinical Allergotoxicology, Munich, Germany.
Juan Antonio
JA
Aguilar-Pimentel
Helmholtz Zentrum München GmbH, German Mouse Clinic, Institute of Experimental Genetics, D-85764 Neuherberg, Germany.
Clemens
C
Bönisch
Biotech Research and Innovation Centre, Lund Group, University of Copenhagen, Ole Maaloes vej 5, DK-2200 Copenhagen, Denmark.
Christophe
C
Côme
Biotech Research and Innovation Centre, Lund Group, University of Copenhagen, Ole Maaloes vej 5, DK-2200 Copenhagen, Denmark.
Cathrine
C
Kolster-Fog
Biotech Research and Innovation Centre, Lund Group, University of Copenhagen, Ole Maaloes vej 5, DK-2200 Copenhagen, Denmark.
Klaus T
KT
Jensen
Biotech Research and Innovation Centre, Lund Group, University of Copenhagen, Ole Maaloes vej 5, DK-2200 Copenhagen, Denmark.
Anders H
AH
Lund
College of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do, 330-714, Republic of Korea.
Icksoo
I
Lee
Wayne State University, Center for Molecular Medicine and Genetics, 540 E. Canfield Avenue, Detroit, Michigan 48201, United States of America.
Lawrence I
LI
Grossman
Wayne State University, Center for Molecular Medicine and Genetics, 540 E. Canfield Avenue, Detroit, Michigan 48201, United States of America.
Christopher
C
Sinkler
Wayne State University, Center for Molecular Medicine and Genetics, 540 E. Canfield Avenue, Detroit, Michigan 48201, United States of America.
Maik
M
Hüttemann
Universitätsklinikum Tübingen, Institut für Medizinische Mikrobiologie, Elfriede-Aulhorn-Strasse 6, D-72076 Tübingen, Germany.
Erwin
E
Bohn
Helmholtz Zentrum München GmbH, German Mouse Clinic, Institute of Experimental Genetics, D-85764 Neuherberg, Germany.
Helmut
H
Fuchs
Center of Allergy and Environment Munich (ZAUM), Technische Universität München, Munich, Germany; Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg and Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, Odense, Denmark.
Markus
M
Ollert
Helmholtz Zentrum München GmbH, German Mouse Clinic, Institute of Experimental Genetics, D-85764 Neuherberg, Germany.
Valérie
V
Gailus-Durner
Helmholtz Zentrum München GmbH, German Mouse Clinic, Institute of Experimental Genetics, D-85764 Neuherberg, Germany; Technische Universität München, Chair of Experimental Genetics, D-85354 Freising, Germany; German Center for Diabetes Research (DZD), D-85764 Neuherberg, Germany.
Martin Hrabĕ
MH
de Angelis
Helmholtz Zentrum München GmbH, German Mouse Clinic, Institute of Experimental Genetics, D-85764 Neuherberg, Germany; Technische Universität München, Chair of Experimental Genetics, D-85354 Freising, Germany; German Center for Diabetes Research (DZD), D-85764 Neuherberg, Germany.
Johannes
J
Beckers
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D058977:Molecular Sequence Annotation; D009154:Mutation; D010047:Ovalbumin / Q000276:immunology; D011506:Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins; D012140:Respiratory Tract Diseases / Q000235:genetics / Q000276:immunology; D012641:Selection, Genetic; D014157:Transcription Factors; D059467:Transcriptome
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D016207:Cytokines; C092572:Ifit2 protein, mouse; D007136:Immunoglobulins; C000588732:PRDM11 protein, mouse; D011506:Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D007073:Immunoglobulin E; D010047:Ovalbumin