Macrophages activated by C-reactive protein through Fc gamma RI transfer suppression of immune thrombocytopenia.
C-reactive protein (CRP) is an acute-phase protein with therapeutic activity in mouse models of systemic lupus erythematosus and other inflammatory and autoimmune diseases. To determine the mechanism by which CRP suppresses immune complex disease, an adoptive transfer system was developed in a model of immune thrombocytopenic purpura (ITP). Injection of 200 microg of CRP 24 h before induction of ITP markedly decreased thrombocytopenia induced by anti-CD41. CRP-treated splenocytes also provided protection from ITP in adoptive transfer. Splenocytes from C57BL/6 mice were treated with 200 microg/ml CRP for 30 min, washed, and injected into mice 24 h before induction of ITP. Injection of 10(6) CRP-treated splenocytes protected mice from thrombocytopenia, as did i.v. Ig-treated but not BSA-treated splenocytes. The suppressive cell induced by CRP was found to be a macrophage by depletion, enrichment, and the use of purified bone marrow-derived macrophages. The induction of protection by CRP-treated cells was dependent on FcRgamma-chain and Syk activation, indicating an activating effect of CRP on the donor cell. Suppression of ITP by CRP-treated splenocytes required Fc gamma RI on the donor cell and Fc gamma RIIb in the recipient mice. These findings suggest that CRP generates suppressive macrophages through Fc gamma RI, which then act through an Fc gamma RIIb-dependent pathway in the recipient to decrease platelet clearance. These results provide insight into the mechanism of CRP regulatory activity in autoimmunity and suggest a potential new therapeutic approach to ITP.
Marjon
Kristopher D
KD
University of New Mexico, Albuquerque, NM 87108, USA.
Marnell
Lorraine L
LL
Mold
Carolyn
C
Du Clos
Terry W
TW
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002097:C-Reactive Protein / Q000008:administration & dosage / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007105:Immune Complex Diseases / Q000276:immunology / Q000517:prevention & control; D007275:Injections, Intravenous; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011696:Purpura, Thrombocytopenic / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017452:Receptors, IgG; D002097:C-Reactive Protein