Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity

Serum amyloid P component (SAP), a highly conserved plasma protein named fo r its universal presence in amyloid deposits', is the single normal circula ting protein that shows specific calcium-dependent binding to DNA and chrom atin in physiological conditions(2,3). The avid binding of SAP displaces Hi -type histones and thereby solubilizes native long chromatin, which is othe rwise profoundly insoluble at the physiological ionic strength of extracell ular fluids(4). Furthermore, SAP binds in vivo both to apoptotic cells(5), the surface blebs of which bear chromatin fragments(6), and to nuclear debr is released by necrosis(7). SAP may therefore participate in handling of ch romatin exposed by cell death(2-4,7). Here we show that mice with targeted deletion of the SAP genes spontaneously develop antinuclear autoimmunity an d severe glomerulonephritis, a phenotype resembling human systemic lupus er ythematosus, a serious autoimmune disease. The SAP(-/-) mice also have enha nced anti-DNA responses to immunization with extrinsic chromatin, and we de monstrate that degradation of long chromatin is retarded in the presence of SAP both in vitro and in vivo. These findings indicate that SAP has an imp ortant physiological role, inhibiting the formation of pathogenic autoantib odies against chromatin and DNA, probably by binding to chromatin and regul ating its degradation.