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.
Highlights
Scurfy mice are characterized by a complete functional deficiency of regulatory T cells (Treg) due to an X-linked frameshift mutation in the Foxp3 gene, resulting in an impairment of peripheral tolerance in hemizygous males
anti-nuclear antibodies (ANA) comprise antibodies directed against intracellular molecules and that are historically linked to several autoimmune disorders including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), PM/DM, and mixed connective tissue disease (MCTD)
We identified the indirect immunofluorescence (IIF) patterns in ANA positive sera according to the nomenclature recently established by International Consensus on ANA Patterns (ICAP) [10]
Summary
Scurfy mice are characterized by a complete functional deficiency of regulatory T cells (Treg) due to an X-linked frameshift mutation in the Foxp gene, resulting in an impairment of peripheral tolerance in hemizygous males. Mixed connective tissue disease (MCTD) as a distinct clinical entity includes some of the clinical features of these three disorders along with high levels of antiU1RNP (U1-ribonucleoprotein) antibodies [8]. We have previously shown that Treg-deficient scurfy mice exhibit SLE-like autoimmune features such as arthritis, pneumonitis, and nephritis as well as anemia and lymphopenia [7]. In line with this observation, we have recently focused on the development of sclerodermatous skin manifestations in scurfy mice by demonstrating that lack of functional Treg in scurfy mice leads to elevated levels of cutaneous collagen and an inflammatory response as it is partly found in SSc [9]. We identified major features of mixed CTD in scurfy mice including very
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