Systemic lupus erythematosus (SLE) is characterized by the production of high-titer IgG-class antinuclear antibodies (ANA). The principal targets of ANA in SLE include chromatin (DNA, histones, and other associated proteins) and ribonucleoproteins, such as small nuclear RNPs (snRNPs) that process precursor messenger RNAs (mRNAs) to produce mature mRNAs, Ro/La particles (also targets in Sjogren’s syndrome) that help process subsets of small RNAs, and ribosomes, the central cellular machine for translation of mature mRNA to proteins. At least a portion of ANA in lupus are directly pathogenic, for example, those directed against chromatin components, which can induce immune complex glomerulonephritis with renal injury. Certain inbred mice develop a syndrome that closely resembles human lupus, including the generation of affinity-matured autoantibodies of similar specificities, with concomitant immune complex glomerulonephritis. Autoantibodies in SLE and in mice with lupus often arise in grouped, or linked, sets that target macromolecular complexes, such as chromatin, snRNPs, or RoiLa (SS-A/SS-B) particles. Northway and Tan (1) and Mattioli and Reichlin (2) first made this observation about a quarter of a century ago, when they demonstrated that the nRNP (nuclear “RNA protein”) and Sm antigens were physically associated and that autoantibodies to these antigens often were found together in patient sera. The molecular characterization of these antigens occurred in 1979, when Lerner and Steitz found