Inhalation of dust containing crystalline silica is associated with a number of acute and chronic diseases including systemic autoimmune diseases. Evidence for the link with autoimmune disease comes from epidemiological studies linking occupational exposure to crystalline silica dust with the systemic autoimmune diseases systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Although little is known regarding the mechanism by which silica exposure leads to systemic autoimmune disease, there is a voluminous literature on silica exposure and silicosis that may help identify immune processes that precede development of autoimmunity. The pathophysiology of silicosis consists of deposition of silica particles in the alveoli of the lung. Ingestion of these particles by macrophages initiates an inflammatory response, which stimulates fibroblasts to proliferate and produce collagen. Silica particles are encased by collagen leading to fibrosis and the nodular lesions characteristic of the disease. The steps in the development of silicosis, including acute and chronic inflammation and fibrosis, have different molecular and cellular requirements, suggesting that silica-induced inflammation and fibrosis may be mechanistically separate. Significantly, it is unclear whether silica-induced inflammation and fibrosis contribute similarly to the development of autoimmunity. Nonetheless, the findings from human and animal model studies are consistent with an autoimmune pathogenesis that begins with activation of the innate immune system leading to proinflammatory cytokine production, pulmonary inflammation leading to activation of adaptive immunity, breaking of tolerance, and autoantibodies and tissue damage. The variable frequency of these immunological features following silica exposure suggests substantial genetic involvement and gene/environment interaction in silica-induced autoimmunity. However, numerous questions remain unanswered.

Objective. To determine the frequency, clinical associations, and any major histocompatibility complex correlations of antifibrillarin antibodies in patients with systemic sclerosis (SSc).Methods. Antifibrillarin antibodies were determined by indirect immunofluorescence, immunoblotting, and immunoprecipitation, and HLA class I1 alleles by DNA oligotyping, in a large cohort of SSc patients.Results. Antifibrillarin was found in 8% of 335 SSc sera and was significantly more common in blacks (16%) than whites (S%), in males (33%) than females (14%), and in patients with cardiac, renal, or gut involvement. The HLA class I1 haplotype DRBZ *Z302, DQBZ*0604 was found significantly more frequently in SSc patients with antifibrillarin compared with racematched normal controls and 260 SSc patients without antifibrillarin. In addition, 1 or more of the HLA-DQB1

Monoclonal antibodies against nuclear antigens, such as DNA, histones, Sm, U1 RNP, and SS-B (La), which are targets of spontaneously occurring autoantibodies in systemic rheumatic diseases, have recently been produced by several investigators (1-5). The significance of using monoclonal antibodies against nuclear autoantigens lies in their monospecificity , as compared with human autoimmune sera, which frequently target more than 1 nuclear antigen (6). Therefore, monoclonal antinuclear antibodies should be important probes not only for standardization of clinical tests, but also for further dissecting the structure and function of reactive antigens. In a recent study, we showed that monoclonal anti-native DNA (anti-nDNA) antibodies also reacted with mitochondrial DNA in tissue culture cells (7). This observation facilitated studies to determine why certain human systemic lupus erythematosus sera that display high titers of anti-nDNA antibodies stain mitochondria in tissue culture cells (7).In the present study, we have shown that a monoclonal autoantibody derived from an autoimmune (New Zealand black X New Zealand white)F1 ([NZB/NZW]F1) mouse reacts with an M , 34,000 nucleolar protein. This protein was demonstrated to share an epitope which is also recognized by scleroderma antibodies reactive with an M , 34,000 nucleolar protein associated with the U3 RNP (8,9). MATERIALS AND METHODSMonoclonal antibodies. Monoclonal antibodies were produced by hybridoma technology as described previously (10). Splenocytes from a 6-month-old female, unmanipulated (NZBMZW)FI mouse were mixed, at a ratio of lO:l, with nonsecreting myeloma cells (P3x63Ag8.653) and fused with 35% polyethylene glycol. Hybrids were selected in hypoxanthine/aminopteridthymidine-containing medium, as described (10). After propagating hybridomas and subcloning