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IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells.

ABSTRACT: Natural Abs, which arise without known immune exposure, have been described that specifically recognize cells dying from apoptosis, but their role in innate immunity remains poorly understood. Herein, we show that the immune response to neoantigenic determinants on apoptotic thymocytes is dominated by Abs to oxidation-associated Ags, phosphorylcholine (PC), a head group that becomes exposed during programmed cell death, and malondialdehyde (MDA), a reactive aldehyde degradation product of polyunsaturated lipids produced following exposure to reactive oxidation species. While natural Abs to apoptotic cells in naive adult mice were dominated by PC and MDA specificities, the amounts of these Abs were substantially boosted by treatment of mice with apoptotic cells. Moreover, the relative amounts of PC and MDA Abs was affected by V(H) gene inheritance. Ab interactions with apoptotic cells also mediated the recruitment of C1q, which enhanced apoptotic cell phagocytosis by immature dendritic cells. Significantly, IgM Abs to both PC and MDA were primary factors in determining the efficiency of serum-dependent apoptotic cell phagocytosis. Hence, we demonstrate a mechanism by which certain natural Abs that recognize neoantigens on apoptotic cells, in naive mice and those induced by immune exposure to apoptotic cells, can enhance the functional capabilities of immature dendritic cells for phagocytic engulfment of apoptotic cells.

SUBMITTER: Chen Y

PROVIDER: S-EPMC4428684 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells.

Chen Yifang Y Park Yong-Beom YB Patel Ekta E Silverman Gregg J GJ

Journal of immunology (Baltimore, Md. : 1950) 20090501 10

Natural Abs, which arise without known immune exposure, have been described that specifically recognize cells dying from apoptosis, but their role in innate immunity remains poorly understood. Herein, we show that the immune response to neoantigenic determinants on apoptotic thymocytes is dominated by Abs to oxidation-associated Ags, phosphorylcholine (PC), a head group that becomes exposed during programmed cell death, and malondialdehyde (MDA), a reactive aldehyde degradation product of polyun ...[more]

PMID: 19414754

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Project description:Natural antibodies, which arise without known immune exposure, have been described that specifically recognize cells dying from apoptosis but their role in innate immunity remains poorly understood. Herein, we show that the immune response to neo-antigenic determinants on apoptotic thymocytes is dominated by antibodies to oxidation-associated antigens, phosphorylcholine (PC), a head group that becomes exposed during programmed-cell death, and malondialdehyde (MDA), a reactive aldehyde degradation product of polyunsaturated lipids produced following exposure to reactive-oxidation species. While natural antibodies to apoptotic cells in naM-CM-/ve adult mice were dominated by PC and MDA specificities, the amounts of these antibodies were substantially boosted by treatment of mice with apoptotic cells. Moreover, the relative amounts of PC and MDA antibodies was affected by VH gene inheritance. Antibody interactions with apoptotic-cells also mediated the recruitment of C1q, which alone can promote apoptotic-cell phagocytosis by immature dendritic cells. Significantly, IgM-antibodies to both PC and MDA were primary factors in determining the efficiency of serum-dependent apoptotic-cell phagocytosis. Hence, we demonstrate a mechanism by which certain natural antibodies that recognize neo-antigens on apoptotic cells, in naM-CM-/ve mice and those induced by immune exposure to apoptotic-cells, can enhance the functional capabilities of immature dendritic cells for phagocytic engulfment of apoptotic cells. Keywords: Natural antibodies, Inflammation, Complement, Apoptosis In the study presented here, a total of 11 custom-spotted protein slides were hybridized with a T15 IgM monoclonal antibody at three different concentrations, an isotype control IgM, 2 slides were hybridized with serum from naM-QM-^Wve mice, 2 slides incubated with serum from mice immunized with apoptotic cells, 2 slides were incubated with serum from mice immunized with saline, and a negative control slide with no antibody hybridized

Project description:Pentraxins and complement defense collagens are soluble recognition proteins that sense pathogens and altered-self elements, and trigger immune responses including complement activation. PTX3 has been shown to interact with the globular recognition domains (gC1q) of the C1q protein of the classical complement pathway, thereby modulating complement activity. The C1q-PTX3 interaction has been characterized previously by site-specific mutagenesis using individual gC1q domains of each of the three C1q chains. The present study is aimed at revisiting this knowledge taking advantage of full-length recombinant C1q. Four mutations targeting exposed amino acid residues in the gC1q domain of each of the C1q chains (LysA200Asp-LysA201Asp, ArgB108Asp-ArgB109Glu, TyrB175Leu, and LysC170Glu) were introduced in recombinant C1q and the interaction properties of the mutants were analyzed using surface plasmon resonance. All C1q mutants retained binding to C1r and C1s proteases and mannose-binding lectin-associated serine proteases, indicating that the mutations did not affect the function of the collagen-like regions of C1q. The effect of these mutations on the interaction of C1q with PTX3 and IgM, and both the PTX3- and IgM-mediated activation of the classical complement pathway were investigated. The LysA200Asp-LysA201Asp and LysC170Glu mutants retained partial interaction with PTX3 and IgM, however they triggered efficient complement activation. In contrast, the ArgB108Asp-ArgB109Glu mutation abolished C1q binding to PTX3 and IgM, and significantly decreased complement activation. The TyrB175Leu mutant exhibited decreased PTX3- and IgM-dependent complement activation. Therefore, we provided evidence that, in the context of the full length C1q protein, a key contribution to the interaction with both PTX3 and IgM is given by the B chain Arg residues that line the side of the gC1q heterotrimer, with a minor participation of a Lys residue located at the apex of gC1q. Furthermore, we generated recombinant forms of the human PTX3 protein bearing either D or A at position 48, a polymorphic site of clinical relevance in a number of infections, and observed that both allelic variants equally recognized C1q.

Dataset Information

IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells.

Publications

IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells.

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