Autoantibodies to RNA polymerases (RNAP) I, II, and III are reported to be highly specific for the diagnosis of scleroderma (systemic sclerosis, SSc). In the present study, the specificity of autoantibodies to RNAP I and III for SSc was confirmed by immunoprecipitation of 35S-labeled proteins. However, we report here the previously unrecognized production of anti-RNAP H autoantibodies by 9-14% of patients with SLE and mixed connective tissue disease/overlap syndrome. 12 out of 32 anti-RNAP H positive sera (group 1) immunoprecipitated a diffuse 220-240-kD band identified as the largest subunit of RNAP H whereas the remaining 20 (group 2) immunoprecipitated preferentially the 240-kD phosphorylated (Ho) form of the large subunit. After pulse labeling, group 1 sera immunoprecipitated only the 220-kD (Ila) RNAP H subunit, whereas the diffuse Ha/Ho band plus the 145-kD second largest RNAP II subunit (Hc) were immunoprecipitated after several hours of cold chase, suggesting that these sera recognized primarily the largest subunit of RNAP H. Group 2 sera recognized the Ilc subunit after pulse labeling, and immunoprecipitated the Ilc and Ho, but not the Ha, subunits after cold chase. Although it has been suggested that autoantibodies to RNAP II are usually accompanied by anti-RNAP I/III in SSc, all but one of the anti-RNAP H positive sera from SLE or mixed connective tissue disease/overlap syndrome patients, as well as most of the SSc sera, were negative for anti-RNAP h/IH. Moreover, in contrast to previous reports suggesting that anti-RNAP antibodies rarely coexist with other SSc subset marker antibodies, anti-RNAP H antibodies were often accompanied by anti-Ku, anti-nRNP, or anti-topoisomerase I autoantibodies in the present study. We conclude that autoantibodies to RNAP H are not a specific marker for SSc, whereas autoantibodies to RNAP I/III are associated primarily with SSc. In addition, we have identified two distinctive patterns of RNAP H antigen recognition by autoanti-

The U1 small nuclear ribonucleoprotein (snRNP), a complex of nine proteins with U1 RNA, is a frequent target of autoantibodies in human and murine systemic lupus erythematosus (SLE). Anti-Sm antibodies recognizing the B Ј /B, D, E, F, and G proteins of U1 snRNPs are highly specific for SLE, and are nearly always accompanied by anti-nRNP antibodies recognizing the U1 snRNP-specific 70K, A, and/or C proteins. Previous studies suggest that human anti-nRNP antibodies recognize primarily the U1-70K and U1-A proteins, whereas recognition of U1-C is less frequent. We report here that autoantibodies to U1-C are more common in human autoimmune sera than believed previously.

The frequent coexistence of anti-Ro and anti-La autoantibodies is well described, however, there is little evidence of sequential development of these two autoantibodies. We report a case of typical Sjogren's syndrome with high titer anti-Ro antibodies, who subsequently developed anti-La antibodies later in the course. This case suggests that the anti-La antibodies may actually follow the anti-Ro antibodies in some cases as hypothesized in the concept of linked set of autoantibodies, analogous to development of anti-Sm in certain anti-nRNP antibody positive SLE patients and animal models.

Autoantibodies to RNA polymerases (RNAP) I and III are highly specific for scleroderma (SSc), whereas autoantibodies to RNAP II are associated with systemic lupus erythematosus (SLE) and overlap syndromes, as well as SSc. The specificities of autoantibodies to RNAP I, II, and III in 129 SSc sera were investigated in the present study. Immunoprecipitation and pulse-chase analysis demonstrated several patterns of autoantibody recognition of RNAPs. Some sera immunoprecipitated RNAP II only after its largest subunit was phosphorylated, suggesting that they contained autoantibodies that recognized an epitope carrying a phosphoamino acid. Autoantibody recognition of all three classes of RNAPs was influenced strongly by race. Although in SLE, autoantibodies to the phosphorylated form of RNAP II (RNAP IIO) were identified in all races, in SSc, these autoantibodies were seen in 21% of Japanese and 5% of Black patients, but never in Caucasians. A striking association of anti-RNAP IIO with anti-topoisomerase I (topo I) autoantibodies was found in Japanese and Black SSc, but not SLE, patients. However, anti-topo I Abs were not associated with anti-RNAP IIO in Caucasians. Japanese SSc patients who were positive for both anti-RNAP IIO and anti-topo I Abs had a significantly higher frequency of diffuse disease, pigmentation changes, flexion contractures, and acro-osteolysis than patients having autoantibodies to topo I alone, and were diagnosed at a younger age (p < 0.05). These data suggest that genetic factors (possibly HLA-linked) influence autoantibody specificity, and that different autoantibody fine specificities may either cause, or be predictive of, different clinical outcomes.

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