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

Synovial fluid (SF) from patients with osteoarthritis (OA), rheumatoid arthritis (RA), and various other arthridites was analyzed to assess the prevalence of interleukin-1 (IL-1) using both radioimmunoassay competitive inhibition specific for the beta form of IL-1 and the D10.G4.1 cell line bioassay which measures both alpha and beta forms of IL-1. Using radioimmunoassay competitive inhibition, IL-1 beta was found in 45% and 60% of individual samples from patients with OA and RA respectively. When RA and OA SF were examined in sequentially obtained samples, IL-1 beta occurred in one or more samples from 8 of 10 patients studied, suggesting the probability that it can be produced at some time in SF by all patients with these conditions. No correlation between SF leukocyte counts and the occurrence of IL-1 beta was noted and no effect of antiinflammatory drug treatment on the prevalence of IL-1 beta was found. When tested for the presence of IL-1 by the D10.G4-1 cell line, 66% and 50% of RA and OA patients respectively were found to contain IL-1. These were not in total concordance with results obtained by RIA. Of all SF tested, seven were negative by RIA but positive by D10.G4.1 and these are considered to contain IL-1 alpha. Seven samples which were RIA positive and D10.G4.1 negative were tested for their ability to inhibit IL-1 responses in the bioassay. Five of these contained inhibitor and one markedly enhanced the proliferative response of D10.G4.1 to a known amount of IL-1.(ABSTRACT TRUNCATED AT 250 WORDS)

NZB mice spontaneously develop autoimmune diseases (1). This fact has promptedextensive studies of all aspects of their immune system. Among other phenomena, it was found that stimulation of normal NZB lymphocytes in vitro with H-2-identical BALB/c or DBA/2 lymphocytes readily induced cytotoxic T cell responses (2, 3). We (4) and others (5) have shown that this primary in vitro response is directed against antigens of the Tla region, where NZB mice differ from other H-2 d strains (6). In the course of that study, we observed that when primed NZB lymphocytes were restimulated with BALB/c cells in vitro, they became cytotoxic to target cells of all strains tested, with the exception of NZB. Here we analyze the specificity of this secondary response. Whereas the response itself is a normal T cell response to an antigen present in nearly all other strains but missing in NZB, the antigen is unusual. Materials and MethodsMice. Adult mice of both sexes were obtained from the sources listed in Table I. The NZB/ Icr × C58/J (NX8) recombinant inbred strains were established and maintained at

The study of NZB x C58 recombinant inbred mouse strains has revealed independent segregation of naturally occurring thymocytotoxic antibody and Coombs' anti-erythrocyte autoantibody. The lack of concordance of either of these autoantibodies with known heavy and light chain markers suggests that the autoantibodies are produced as a result of regulatory gene defects rather than alterations of antibody structural genes. Further, lack of concordance of the various autoimmune traits with each other or with H-2 or virus expression suggests that the autoimmune phenotype is not the result of a single "autoimmunity' gene but rather the outcome of faulty regulation of a number of independently segregating genes.

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