The genome of vertebrates contains endogenous retroviruses (ERVs) that are largely nonfunctional relicts of ancestral germline infection by exogenous retroviruses. However, in some mouse strains ERVs are actively involved in disease. Here we report that nucleic acid-recognizing Toll-like receptors 3, 7, and 9 (TLR 3, TLR7, and TLR9) are essential for the control of ERVs. Loss of TLR7 function caused spontaneous retroviral viremia that coincided with the absence of ERV-specific antibodies. Importantly, additional TLR3 and TLR9 deficiency led to acute T cell lymphoblastic leukemia, underscoring a prominent role for TLR3 and TLR9 in surveillance of ERV-induced tumors. Experimental ERV infection induced a TLR3-, TLR7-, and TLR9-dependent group of "acute-phase" genes previously described in HIV and SIV infections. Our study suggests that in addition to their role in innate immunity against exogenous pathogens, nucleic acid-recognizing TLRs contribute to the immune control of activated ERVs and ERV-induced tumors.

Immunglobulin E (IgE) production is tightly regulated at the cellular and genetic levels and is believed to be central to allergy development. At least two cellular pathways exist that lead to systemic anaphylaxis reactions in vivo: IgE-sensitized mast cells and IgG1-sensitized basophils. Passive anaphylaxis, by application of allergen and allergen-specific antibodies in mice, indicates a differential contribution of immunoglobulin isotypes to anaphylaxis. However, analysis of a dynamic immunization-mediated antibody response in anaphylaxis is difficult. Here, we generated IgE knock-in mice (IgE ki ), which express the IgE heavy chain instead of IgG1, in order to analyze the contribution of IgG1 and IgE to active anaphylaxis in vivo. IgE ki mice display increased IgE production both in vitro and in vivo. The sensitization of IgE ki mice by immunization followed by antigen challenge leads to increased anaphylaxis. Homozygous IgE ki mice, which lack IgG1 due to the knock-in strategy, are most susceptible to active systemic anaphylaxis. The depletion of basophils demonstrates their importance in IgE-mediated anaphylaxis. Therefore, we propose that an enhanced, antigen-specific, polyclonal IgE response, as is the case in allergic patients, is probably the most efficient way to sensitize basophils to contribute to systemic anaphylaxis in vivo.Keywords: Active systemic anaphylaxis r Allergy model r Basophils r IgE knock-in Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAllergy has become a major threat to public health in developed countries [1,2]. In particular, systemic anaphylaxis, whichCorrespondence: Dr. Philipp Yu e-mail: Philipp.Yu@staff.uni-marburg.de is a rapid and often fatal allergic reaction to a systemic allergen exposure, e.g. a bee sting into the vascular system, necessitates a fundamental understanding of the immune parameters involved. The causative association of allergen-specific Immunglobulin E (IgE), the high-affinity IgE receptor (FcεRI), and mast cells for immediate type allergy and anaphylaxis has been studied for Eur. J. Immunol. 2013Immunol. . 43: 1231Immunol. -1242 decades [3][4][5]. However, since the discovery of anaphylaxis in IgE-deficient mice [6] and more recently studies on basophil biology, a number of publications have focused on the contribution of alternative pathways to anaphylaxis [7][8][9]. It has become evident that the isotype, quantity, and quality of the sensitizing antibodies are important parameters for anaphylaxis [9]. In summary, at least two mutually nonexclusive pathways exist that employ allergen-mediated cross-linking of either receptor bound IgE and/or receptor bound IgG and lead to activation of mast cells and/or basophils leading to release of inflammatory substances, e.g. histamine or platelet activating factor [7,10].Nevertheless, experiments to examine the role of the active polyclonal antibody response in anaphylaxis are hampered by the low expression of IgE and a low frequency of...

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Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their role as anti-cancer immune targets or drivers of autoimmune disease. Here, we generated mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the murine germline. This enabled us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identified an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on T-bet+ B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the hosts immune response.