Scurfy Mice Develop Features of Connective Tissue Disease Overlap Syndrome and Mixed Connective Tissue Disease in the Absence of Regulatory T Cells

Osman K Yilmaz; Stefanie Haeberle; Meifeng Zhang; Marvin J Fritzler; Alexander H Enk; Eva N Hadaschik

doi:10.3389/fimmu.2019.00881

Scurfy Mice Develop Features of Connective Tissue Disease Overlap Syndrome and Mixed Connective Tissue Disease in the Absence of Regulatory T Cells

Front Immunol. 2019 Apr 24:10:881. doi: 10.3389/fimmu.2019.00881. eCollection 2019.

Authors

Osman K Yilmaz¹, Stefanie Haeberle¹, Meifeng Zhang¹, Marvin J Fritzler², Alexander H Enk¹, Eva N Hadaschik^{1

3}

Affiliations

¹ Department of Dermatology, University of Heidelberg, Heidelberg, Germany.
² Mitogen Advanced Diagnostics Laboratory, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³ Department of Dermatology, University Hospital of Essen, Essen, Germany.

Abstract

Due to a missense mutation in the Foxp3 gene, scurfy mice are deficient in functional regulatory T cells (Treg). The consequent loss of peripheral tolerance manifests itself by fatal autoimmune mediated multi-organ disease. Previous studies have outlined the systemic inflammatory disease and demonstrated production of anti-nuclear antibodies (ANA) in scurfy mice. However, specific autoantibody targets remained to be defined. ANA are immunological markers for several connective tissue diseases (CTD) and target a large number of intracellular molecules. Therefore, we examined scurfy sera for the presence of different ANA specificities and further assessed the organ involvement in these animals. Indirect immunofluorescence was used as a screen for ANA in the sera of scurfy mice and dilutions of 1/100 were considered positive. Addressable laser bead immunoassays (ALBIA) were used to detect specific autoantibody targets. Subsequent histological tissue evaluation was verified by hematoxylin and eosin (H&E) staining. In our study, we observed that nearly all scurfy mice produced ANA. The most prevalent pattern in scurfy sera was nuclear coarse speckled, also known as the AC-5 pattern according to the International Consensus on ANA Patterns. U1-ribonucleoprotein (U1RNP) was found to be the most common target antigen recognized by autoantibodies in scurfy mice. Additionally, scurfy mice exhibited a mild myositis with histological characteristics similar to polymyositis/dermatomyositis. Myopathy-specific autoantibody profile revealed significantly increased levels of anti-SMN (survival of motor neuron) as well as anti-Gemin3 antibodies in scurfy sera. Overall, we demonstrate that the impaired peripheral tolerance in the absence of regulatory T cells in scurfy mice is associated with features of mixed connective tissue disease (MCTD). This includes, along with our previous findings, very high titers of anti-U1RNP antibodies and an inflammatory myopathy.

Keywords: anti-nuclear antibodies; mixed connective tissue disease; overlap syndrome; regulatory T cells; scurfy mouse; skin autoimmunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Antinuclear / immunology
Autoantibodies / immunology
Autoimmune Diseases / diagnosis
Autoimmune Diseases / immunology
Autoimmunity
Connective Tissue Diseases / diagnosis*
Diagnosis, Differential
Disease Models, Animal
Disease Susceptibility
Female
Male
Mice
Mice, Knockout
Mixed Connective Tissue Disease / diagnosis*
Muscle, Skeletal / immunology
Muscle, Skeletal / metabolism
Muscle, Skeletal / pathology
Organ Specificity
Phenotype*
Scurvy / diagnosis*
Scurvy / etiology*
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism

Substances

Antibodies, Antinuclear
Autoantibodies