Patients with systemic autoimmune diseases of-ten develop autoantibodies directed against largeintracellular complexes composed of a number ofproteins that are non-covalently associated withnucleic acid components. For example, antibod-ies against nucleosomes, a complex of doublestranded DNA and histones,are typically foundin Systemic Lupus Erythematosus (SLE) pa-tients. Antibodies targeting spliceosomes, thecomplex of small nuclear RNAs (snRNAs) or uri-dine rich RNAs (URNAs) with (Sm) and (RNP)proteins involved in the processing of RNA, arefound in SLE and Mixed Connective Tissue Dis-ease (MCTD) patients. Similarly, antibodiesagainst the Ro ribonucleoprotein complex thatconsist of Ro and La proteins bound to small cy-toplasmic RNAs (YRNAs) are most commonlydetected in primary Sjogrenis Syndrome (pSS)and SLE; whereas, antibodies to topoisomerase I,an enzyme involved in the DNA duplicationprocess, are found in patients with SystemicScleroderma (SCL) (1,2).Despite the heterogeneity of systemic au-toimmune diseases, the autoantibody responseagainst these complexes shares common char-acteristics. First, the response is antigen–driven, so the antibodies are immunoglobulinG (IgG) in class and undergo affinity matura-tion (3,4). Second, autoantibodies usually existin linked sets. For example, anti-La antibodiesalmost always coexist with anti-Ro antibodiesin SS sera, while the anti-Sm autoantibodyusually accompanies anti-U