title: Macrophage-derived complement component C4 can restore humoral immunity in C4-deficient mice.
abstract: Mice with a disrupted C4 locus (C4(-/-)) have an impaired immune response to thymus-dependent Ags. To test the role of bone marrow-derived C4 in humoral immunity, we reconstituted deficient animals with wild-type bone marrow or an enriched fraction of bone marrow-derived macrophages. C4 chimeras were immunized with 4-hydroxy-3-nitrophenyl(5) conjugated to keyhole limpet hemocyanin (NP(5)- KLH) or infected with HSV-1, and the Ab response was evaluated. Wild-type bone marrow rescued the humoral immune response to both Ags, i.e., the soluble Ag and HSV-1, demonstrating that local C4 production is sufficient for humoral responses. Although the C4 chimeric animals lacked detectable C4 in their sera, C4 mRNA was identified in splenic sections by in situ hybridization, and C4 protein deposits were identified in the germinal center areas of splenic follicles by immunofluorescence staining. Macrophages derived from bone marrow produced sufficient C4 protein to restore the humoral response to NP(5)-KLH in C4-deficient animals when administered along with Ag. Cell-sorting experiments, followed by C4-specific RT-PCR, identified splenic macrophages (CD11b(+), CD11c(-)) as a cellular source for C4 synthesis within the spleen.
authors.affiliation: Center for Blood Research, 221 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gadjeva
authors.forename: Admar
authors.initials: A
authors.lastname: Verschoor
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Heather
authors.initials: H
authors.lastname: Jezak
authors.forename: Li Ming
authors.initials: LM
authors.lastname: Shen
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D003181:Complement C4 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D006241:Haptens; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D007275:Injections, Intravenous; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009596:Nitrophenols / Q000008:administration & dosage / Q000276:immunology; D010648:Phenylacetates; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: C098951:4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin; D003181:Complement C4; D006241:Haptens; D007074:Immunoglobulin G; D009596:Nitrophenols; D010648:Phenylacetates; C026242:4-hydroxy-5-nitrophenyl acetic acid; D006433:Hemocyanins