Unknown,Transcriptomics,Genomics,Proteomics

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Mice with FIA develop anti-native and anti-in vitro citrullinated fibrinogen antibodies

ABSTRACT: Synovial antigen arrays were probed with 1:150 dilutions of plasma derived from SJL mice immunized with fibrinogen emulsified in CFA or with CFA alone. Autoantibody binding was detected with a Cy3-conjugated goat-anti-mouse IgG/M secondary antibody. SAM was applied to identify antigens with statistically significant differences in array reactivity between FIA and CFA control plasma (q < 0.01) obtained from mice before boosting. The SAM hits were subjected to hierarchical cluster analysis and are displayed as a heatmap. Synovial array profiling of FIA plasma demonstrated autoreactive B-cell responses against peptides representing native fibrinogen, and B-cell epitope spreading resulting in additional targeting of citrullinated fibrinogen in the samples obtained before boosting. Custom-spotted protein slides were probed with plasma samples from individual mice. Four slides were probed with plasma derived from mice immunized with CFA and six slides were probed with plasma derived from mice immunized with fibrinogen emulsified in CFA.

ORGANISM(S): Mus musculus

SUBMITTER: Ricardo Paniagua

PROVIDER: E-GEOD-18023 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Autoimmunity against fibrinogen mediates inflammatory arthritis in mice.

Ho Peggy P PP Lee Lowen Y LY Zhao Xiaoyan X Tomooka Beren H BH Paniagua Ricardo T RT Sharpe Orr O BenBarak Maya J MJ Chandra Piyanka E PE Hueber Wolfgang W Steinman Lawrence L Robinson William H WH

Journal of immunology (Baltimore, Md. : 1950) 20091130 1

Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the presence of anticitrullinated protein Abs, although the exact targets and role of anticitrullinated protein autoimmunity in the pathogenesis of RA remain to be defined. Fibrinogen, which can be citrullinated, has recently emerged as a candidate autoantigen. To determine whether autoimmunity against fibrinogen can mediate inflammatory arthritis, we immunized a variety of common mouse strains with fibrinogen and found that D ...[more]

PMID: 19949094

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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:Although natural antibodies (NAbs) are present from birth, little is known about what drives their selection, and whether they have housekeeping functions. We now show that the prototypic T15-NAb, first identified because of its protective role in infection, is representative of a previously unknown type of NAb response that specifically recognizes and forms complexes with apoptotic cells, and which promotes cell-corpse engulfment by phagocytes. This T15-NAb-mediated process is dependent on the recruitment of C1q and mannose-binding lectin (MBL), which have known immune modulatory activities that also provide âeat meâ signals for phagocytic clearance. Further investigation revealed that, the addition of T15-NAb significantly suppressed in vitro macrophage LPS-induced TNF-alpha and IL-6 secretion, as well as in vitro Toll-like receptor (TLR)-induced dendritic cell maturation and secretion of pro-inflammatory cytokines and chemokines. Significantly, high doses of this B-1 cell produced NAb also inhibited in vivo TLRâinduced pro-inflammatory responses, and could suppress autoimmune inflammatory arthritis. These studies identify and characterize a previously unknown regulatory circuit by which a NAb product of innate-like B cells aids homeostasis by control of fundamental inflammatory pathways. Keywords: Dendritic cells, Macrophages, Natural Antibodies, Apoptosis, Inflammation, Arthritis In the study presented here, a total of 15 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 naÑve mice, 2 slides incubated with serum from mice immunized with apoptotic cells, 2 slides were incubated with serum from mice immunized with saline, 2 slides were incubated with serum from mice injected with T15 IgM monoclonal antibody, 2 slides were incubated with serum from a lupus-prone mouse disease model and a negative control slide with no antibody hybridized

Dataset Information

Mice with FIA develop anti-native and anti-in vitro citrullinated fibrinogen antibodies

Publications

Autoimmunity against fibrinogen mediates inflammatory arthritis in mice.

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