Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity.
Serum amyloid P component (SAP), a highly conserved plasma protein named for its universal presence in amyloid deposits, is the single normal circulating protein that shows specific calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly insoluble at the physiological ionic strength of extracellular fluids. Furthermore, SAP binds in vivo both to apoptotic cells, the surface blebs of which bear chromatin fragments, and to nuclear debris released by necrosis. SAP may therefore participate in handling of chromatin exposed by cell death. Here we show that mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoimmunity and severe glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune disease. The SAP-/- mice also have enhanced anti-DNA responses to immunization with extrinsic chromatin, and we demonstrate 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 important physiological role, inhibiting the formation of pathogenic autoantibodies against chromatin and DNA, probably by binding to chromatin and regulating its degradation.
Bickerstaff
M C
MC
Immunological Medicine Unit, Rheumatology Section, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Botto
M
M
Hutchinson
W L
WL
Herbert
J
J
Tennent
G A
GA
Bybee
A
A
Mitchell
D A
DA
Cook
H T
HT
Butler
P J
PJ
Walport
M J
MJ
Pepys
M B
MB
D000818:Animals; D034961:Antigens, Nuclear; D001323:Autoantibodies / Q000378:metabolism; D015551:Autoimmunity / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002843:Chromatin / Q000276:immunology / Q000378:metabolism*; D015922:Complement C1q / Q000235:genetics / Q000276:immunology; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology; D006801:Humans; D007114:Immunization; D047908:Intracellular Signaling Peptides and Proteins; D007962:Leukocytes / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000276:immunology; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein
D034961:Antigens, Nuclear; D001323:Autoantibodies; D002352:Carrier Proteins; D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C114953:SH2D1A protein, human; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D015922:Complement C1q