Evidence for autoimmunity in the tight skin mouse model of systemic sclerosis

Abstract

The tight skin mouse strain has been proposed for use as an animal model of systemic sclerosis because this animal exhibits a condition that has biochemical and pathologic similarities to the human disease. To date, however, evidence of inflammatory and immunologic changes in the tight skin mouse has been scarce. We demonstrated the presence of antinuclear antibodies in approximately half of these mice ages 8 months and older. This suggests that there is an autoimmune component in their disease process. The antibodies were identified as anti-topoisomerase I by a characteristic staining pattern on HEp-2 cells and by Western blot analysis. Except for a low incidence of anti-DNA antibodies, none of the other parameters tested, including mitogen responses, lymphokine production, and antierythrocyte antibodies, was indicative of immune system dysregulation.The tight skin (TSK/+) mouse, a mutant strain characterized by the presence of thickened skin which Submitted for publication July 2, 1990; accepted in revised form December 3 1, 1990, is tightly bound to subcutaneous tissue, was originally described by Green et a1 (1). Genetic studies by those investigators identified TSK as an autosomal dominant gene located on chromosome 2. In the homozygous state, the mutation is lethal in utero. Heterozygous TSK/+ mice display alterations that are confined almost exclusively to the connective tissues of skin, retroperitoneum, lungs, and heart. Histologic examination of TSK mouse skin by Green et a1 showed marked thickening, with excessive collagen deposition in the dermis and below the panniculum carnosum (1). Subsequent studies by Menton et a1 (2) and Menton and Hess (3) demonstrated a decrease in skin pliability and an increase in its stiffness. These abnormalities in the mechanical properties of skin were accompanied by changes in collagen fibril arrangement and size, as detected by electron microscopy (3). Biochemical studies of TSK mouse skin by Osborn et a1 (4) and Jimenez et a1 (5) revealed excessive deposition of collagen and glycosaminoglycans and increased collagen biosynthesis in TSK/+ skin organ cultures and in cultured fibroblasts derived from TSK/+ mice. The increased collagen production by TSK/+ fibroblasts was accompanied by elevation of the steady-state levels of messenger RNAs for types I and I11 collagens (6).These morphologic, pathologic, and biochemical characteristics led to the suggestion that this strain of mouse represented an animal model for systemic sclerosis (SSc; scleroderma) (5). There are, however, important differences between the TSK/+ mouse and human SSc. These include a paucity of inflammatory and immunologic changes and an absence of vascular lesions in the animal model. The only reported immunologic abnormalities described in TSK mice are the presence of antinuclear antibodies (ANA) (Osborn

Demonstration of Autoimmunity in the Tight Skin-2 Mouse: A Model for Scleroderma

“…Tsk1/ϩ mice do not have an inflammatory mononuclear cell infiltrate in the dermis. However, Tsk1/ϩ mice develop ANAs including antiScl70 Abs, which were detected in supernatants from hybridomas established from Tsk1/ϩ splenocytes (36). The majority of the autoantibodies which arose in Tsk1/ϩ mice were shown to share a conserved heptapeptide sequence motif, YNEKFKG, in their H chains (37) and B cell clones producing autoantibodies in both the Tsk1/ϩ mouse and in SSc patients have been shown to share an interspecies cross-reactive Id (38).…”

Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma

“…Interestingly, in both species, cells of the immune system appear to play a role in disease pathogenesis and/or expression [3,8]. Autoantibodies against topoisomerase I, for example, are detectable in the sera of individuals with scleroderma as well as in approximately half of Tsk /+ mice over 8 months of age [9]. Adoptive transfer of unfractionated Tsk /+ bone marrow or splenic cells, but not purified B or T lymphocyte populations, into normal syngeneic mice led to a delayed Tsk /+-like cutaneous phenotype [10,11].…”

The Vascular Perspective of Systemic Sclerosis: Of Chickens, Mice and Men

“…The disease starts 1–2 weeks after birth with marked thickening and tightness of the skin. At the age of 8 months and older, they also show positivity for antinucelar antibodies (ANA) [14]. Tsk2 is inherited as an autosomal dominant trait, and homozygous embryos degenerate in utero.…”