Biomedical subjects

Raphael Clynes

Publications and source records attributed to Raphael Clynes.

7 recordsLinked to original sources

PubMed2006

FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis.

Lupus glomerulonephritis is initiated by deposition of IgG-containing immune complexes in renal glomeruli. FcR engagement by immune complexes (IC) is crucial to disease development as uncoupling this pathway in FcRgamma(-/-) abrogates inflammatory responses in (NZB x NZW)F1 mice. To define the roles of FcR-bearing hemopoietic cells and of kidney resident mesangial cells in pathogenesis, (NZB x NZW)F1 bone marrow chimeras were generated. Nephritis developed in (NZB x NZW)F1 mice expressing activating FcRs in hemopoietic cells. Conversely, recipients of FcRgamma(-/-) bone marrow were protected from disease development despite persistent expression of FcRgamma in mesangial cell populations. Thus, activating FcRs on circulating hemopoietic cells, rather than on mesangial cells, are required for IC-mediated pathogenesis in (NZB x NZW)F1. Transgenic FcRgamma(-/-) mice expressing FcRgamma limited to the CD11b+ monocyte/macrophage compartment developed glomerulonephritis in the anti-glomerular basement disease model, whereas nontransgenic FcRgamma(-/-) mice were completely protected. Thus, direct activation of circulating FcR-bearing myeloid cells, including monocytes/macrophages, by glomerular IC deposits is sufficient to initiate inflammatory responses.

Animals↗

PubMed2006

Antitumor antibodies in the treatment of cancer: Fc receptors link opsonic antibody with cellular immunity.

Engineered antibody therapeutics have provided new treatment options in cancer. Genetic evidence in man and in the mouse suggests that Fc receptor (FcR) engagement contributes mechanistically to the therapeutic activity of naked antibodies. Preferential activation of activating FcRs and limited engagement of inhibitory FcRs enhance tumor responses in mouse models. Thus, engineered Fc domains with favorable affinities for specific FcR types may prove to be clinically superior.

Animals↗

PubMed2005

Cell surface recycling of internalized antigen permits dendritic cell priming of B cells.

Dendritic cells process internalized antigens to present degradative products on MHC for TCR recognition. Because antigen-exposed DCs also induce humoral immunity, DCs must also retain antigen in its native state for the engagement of BCR on B cells. Here, we demonstrate that antigen endocytosed by the inhibitory Fc receptor, FcgammaRIIB, accesses a non-degradative intracellular vesicular compartment that recycles to the cell surface, enabling interaction of native antigen with BCR on B cells. Immunization with IgG-opsonized, T independent antigens leads to enhanced humoral responses in a FcgammaRIIB and complement dependent manner. IC-loaded DCs trafficking to the splenic marginal zone can prime a T independent response in an FcgammaRIIB-dependent manner. Thus dendritic cells are equipped with both non-degradative and degradative antigen uptake pathways to facilitate antigen presentation to both B and T cells.

Animals↗

PubMed2005

Modulation of the immune response in pristane-induced lupus by expression of activation and inhibitory Fc receptors.

Altered homeostasis in Fcgamma receptor (FcgammaR) expression has been implicated in the induction of both immune complex-mediated glomerulonephritis and autoantibody production in systemic lupus erythematosus. FcgammaRI and III are required for immune complexes to activate inflammatory cells, thereby inciting tissue injury. In contrast, FcgammaRIIB functions as a negative regulator of immune complex-mediated inflammation and autoantibody production. We investigated the role of FcgammaRI/III versus FcgammaRIIB on pristane-induced lupus in mice. FcgammaRI/III and FcgammaRIIB-deficient ((-/-)) and control ((+/+)) BALB/c mice were injected with either pristane or PBS. Proteinuria and glomerular immune deposits were evaluated 9 months after treatment and serial sera were analysed for total IgG levels and lupus-specific autoantibodies. The incidence of nephritis was higher in pristane-treated FcgammaRIIB(-/-) mice than pristane-treated FcgammaRI/III(-/-) and (+/+) mice. Hypergammaglobulinaemia and spontaneous anti-DNA/chromatin autoantibody production were associated with interleukin (IL)-6 over-expression in FcgammaRIIB(-/-) mice and were augmented further by pristane treatment when compared to both FcgammaRI/III(-/-) and (+/+) mice. Lack of either FcgammaRIIB or FcgammaRI/III had little effect on both anti-nRNP/Sm and anti-Su production induced by pristane. Our results confirm that spontaneous autoimmunity occurs in the absence of FcgammaRIIB. Moreover, the lupus-like syndrome induced by pristane in BALB/c mice was regulated by opposing activating and inhibitory FcgammaRs. Activating FcgammaRs were required for significant proteinuria and unbridled activation in the absence of FcgammaRIIB dramatically exacerbated glomerular inflammatory responses. FcgammaRIIB may be a key modulator that suppresses cell activation in the inflammatory immune response in systemic lupus erythematosus in humans.

Animals↗

PubMed2005

Immune complexes as therapy for autoimmunity.

For several decades, intravenous Ig has been used as treatment for a variety of immune-related diseases, including immune thrombocytopenic purpura (ITP), autoimmune neuropathies, systemic lupus erythematosus, myasthenia gravis, Guillain-Barré syndrome, skin blistering syndromes, and Kawasaki disease. Despite years of use, its mechanism of immunomodulation is still unclear. Recent studies using mouse models of ITP and arthritis, including one reported in this issue of the JCI, now provide some insights into this mechanism and the rationale for the development of Fcgamma receptor-targeted therapeutics.

Animals↗

PubMed2003

Nonredundant roles of antibody, cytokines, and perforin in the eradication of established Her-2/neu carcinomas.

Since the mechanisms by which specific immunity destroys Her-2/neu carcinoma cells are highly undetermined, these were assessed in BALB/c mice vaccinated with plasmids encoding extracellular and transmembrane domains of the protein product (p185(neu)) of the rat Her-2/neu oncogene shot into the skin by gene gun. Vaccinated mice rejected a lethal challenge of TUBO carcinoma cells expressing p185(neu). Depletion of CD4 T cells during immunization abolished the protection, while depletion of CD8 cells during the effector phase halved it, and depletion of polymorphonuclear granulocytes abolished all protection. By contrast, Ig mu-chain gene KO mice, as well as Fcgamma receptor I/III, beta-2 microglobulin, CD1, monocyte chemoattractant protein 1 (MCP1), IFN-gamma, and perforin gene KO mice were protected. Only mice with both IFN-gamma and perforin gene KOs were not protected. Although immunization also cured all BALB/c mice bearing established TUBO carcinomas, it did not cure any of the perforin KO or perforin and IFN-gamma KO mice. Few mice were cured that had knockouts of the gene for Ig mu-chain, Fcgamma receptor I/III, IFN-gamma, or beta-2 microglobulin. Moreover, vaccination cured half of the CD1 and the majority of the MCP1 KO mice. The eradication of established p185(neu) carcinomas involves distinct mechanisms, each endowed with a different curative potential.

Animals↗

PubMed2002

Immune complex-mediated antigen presentation induces tumor immunity.

Antigen uptake receptors on dendritic cells (DCs) provide efficient entry for the initiation of antigen-specific adaptive immunity. Here we show that targeting of antigen to Fc receptors on DCs accomplishes combined activation of Th1 CD4 and CD8 effector responses in vivo, namely delayed-type hypersensitivity and tumor immunity. Tumor immunity specific for ovalbumin-expressing tumors was provided by immunization with wild-type but not FcgammaRgamma(-/-) DCs loaded with ovalbumin-containing immune complexes. Tumor protection was eliminated when immune complex-loaded DCs lacked beta(2) microglobulin, TAP, or MHC class II, demonstrating that Fc receptor-targeted antigenic uptake led to both MHC class I- and class II-restricted responses, which together are required for effector tumor immunity. Thus the cross-presentation pathway accessed by antigens acquired endocytically through Fc receptors links humoral and cellular immunity. These data suggest that administration of antitumor antibodies may enhance tumor-specific T cell responses in vivo and provide the rationale for Fc receptor targeting in vaccine development.

Animals↗