Anti-Ku (p70/p80) autoantibodies in patients with scleroderma-polymyositis overlap syndrome recognize a 70-kDa/80-kDa protein heterodimer which binds to terminal regions of double-stranded DNA. In the present study, we isolated full-length cDNAs that encode the 80-kDa Ku subunit.

Object: To examine the role of human leukocyte antigen (HLA) class II genes in the development of systemic sclerosis (SSc) as well as in the clinical and serologic expression of SSc in patients. Methods: HLA-DRB1, DRB3, DRB4, DQB1, and DPB1 alleles were determined by genotyping; and serum antinuclear antibodies were identified using indirect immunofluorescence, double immunodiffusion and immunoprecipitation. Patients: One hundred and five Japanese patients with SSc and 104 race-matched healthy controls. Results: Frequencies of DRB1and DQB1alleles were not different between SSc patients and healthy controls, while DPBl*0901 was marginally increased in SSc patients. In contrast, SSc-related autoantibodies were closely associated with the clinical features. HLAclass II genes were detected as follows: anti-DNA topoisomerase I antibody with diffuse cutaneous involvement, pulmonary fibrosis, and DRBl*1502-DQBl*0601-DPBl*0901 ; anti-UlRNP antibody with overlapping features of lupus and/or myositis and DRBl*0401/*0802-DQBl*0302; and anticentromere antibody with limited cutaneous involvement and DRBl*0101-DQBl*0501-DPBl*0402. In the analysis of the association of HLAclass II and the clinical features in SSc patients significant differences were obtained only for the increased frequencies of arthritis and rheumatoid factor in patients with DRBl*0405 compared to those without. Conclusion: HLAclass II genes strongly influence the production of SSc-related autoanti-bodies rather than the development of SSc. In addition, SSc is a composite disease of distinctive subsets defined by serum autoantibodies, which have specific clinical and HLAclass II associations. (Internal Medicine 38: 336-344, 1999)

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The Sm snRNPs play a central role in the processing of pre-mRNA. Anti-Sm antibodies, the diagnostic hallmark of systemic lupus erythematosus, target the B/B and D polypeptides of these snRNPs. We have used patient autoantibodies to clone a cDNA from a human fibroblast cDNA library that encodes the full length of a polypeptide identical with, or closely related to, polypeptide B. This cDNA is comprised of 1139 bases and contains an open reading frame of 855 nucleotides that is capable of encoding 285 amino acids. The first 223 amino acids at the NH2 terminus exhibit nearly complete homology with polypeptide N, a newly recognized brain-and heart-specific component of Sm snRNPs. The derived amino acid sequence for B differs from that of the N polypeptide primarily by a 50-amino acid insert 12 residues upstream from the homologous COOH termini of these polypeptides. The structural differences in these cDNAs for B and N may regulate tissue-specific alternative splicing mechanisms for mRNA. In addition, these clones make it possible to map in fine detail the most characteristic autoimmune responses of systemic lupus erythematosus.The Sm group of small nuclear ribonucleoproteins (the U1, U2, U5, and U4/U6 snRNPs) have a central role in the splicing of pre-mRNA (1-3). These particles are also dominant targets for autoimmune responses in systemic lupus erythematosus (SLE) (4,5). For example, previous studies have demonstrated that anti-Sm autoantibodies, which are diagnostic markers for SLE (6), are directed against the B/B and D polypeptides of these particles (7). Similarly, anti-Ul RNP autoantibodies, which occur in SLE and other connective tissue diseases, are directed against the 70-kDa, A, B/B, and C polypeptides of the U1 snRNP (7-10). The other U1 snRNP polypeptides known as E, F, and G are rarely targets for autoimmune responses. These studies have made it clear that the B/B polypeptides are pivotal in the autoimmune responses of SLE.Recent studies have provided some insights into the structure of the B polypeptides and their relationship to the Sm snRNPs. Only a single B polypeptide is apparent in rodent tumor cell lines, whereas human cells contain the B/B doublet described above (11-13). These latter polypeptides are closely related and possibly represent variants of a single protein (14). In studies based on immunoblots, anti-Sm antibodies were noted to recognize a polypeptide in rat brain tissue referred to as N, which appeared slightly larger than polypeptide B' in NaDodSO4 polyacrylamide gels. Subsequent studies showed that N is an Sm snRNP component specific to brain and heart tissue of both humans and rodents (15). It is currently thought that such unique snRNP polypeptides might provide a basis for tissue-specific mRNA splicing mechanisms (15). Other studies have shown that the B7/B polypeptides likely associate with the U-series small RNAs indirectly through binding to the D, E, F, and G polypeptides (16).In the present study we have cloned and sequenced the entire length of the cDNA that enco...