14 research outputs found

    Paleo-Immunology: Evidence Consistent with Insertion of a Primordial Herpes Virus-Like Element in the Origins of Acquired Immunity

    Get PDF
    BACKGROUND:The RAG encoded proteins, RAG-1 and RAG-2 regulate site-specific recombination events in somatic immune B- and T-lymphocytes to generate the acquired immune repertoire. Catalytic activities of the RAG proteins are related to the recombinase functions of a pre-existing mobile DNA element in the DDE recombinase/RNAse H family, sometimes termed the "RAG transposon". METHODOLOGY/PRINCIPAL FINDINGS:Novel to this work is the suggestion that the DDE recombinase responsible for the origins of acquired immunity was encoded by a primordial herpes virus, rather than a "RAG transposon." A subsequent "arms race" between immunity to herpes infection and the immune system obscured primary amino acid similarities between herpes and immune system proteins but preserved regulatory, structural and functional similarities between the respective recombinase proteins. In support of this hypothesis, evidence is reviewed from previous published data that a modern herpes virus protein family with properties of a viral recombinase is co-regulated with both RAG-1 and RAG-2 by closely linked cis-acting co-regulatory sequences. Structural and functional similarity is also reviewed between the putative herpes recombinase and both DDE site of the RAG-1 protein and another DDE/RNAse H family nuclease, the Argonaute protein component of RISC (RNA induced silencing complex). CONCLUSIONS/SIGNIFICANCE:A "co-regulatory" model of the origins of V(D)J recombination and the acquired immune system can account for the observed linked genomic structure of RAG-1 and RAG-2 in non-vertebrate organisms such as the sea urchin that lack an acquired immune system and V(D)J recombination. Initially the regulated expression of a viral recombinase in immune cells may have been positively selected by its ability to stimulate innate immunity to herpes virus infection rather than V(D)J recombination Unlike the "RAG-transposon" hypothesis, the proposed model can be readily tested by comparative functional analysis of herpes virus replication and V(D)J recombination

    De novo expression of dopamine D2 receptors on microglia after stroke.

    No full text
    Item does not contain fulltextDopamine is the predominant catecholamine in the brain and functions as a neurotransmitter. Dopamine is also a potent immune modulator. In this study, we have characterized the expression of dopamine receptors on murine microglia. We found that cultured primary microglia express dopamine D1, D2, D3, D4, and D5 receptors. We specifically focused on the D2 receptor (D2R), a major target of antipsychotic drugs. Whereas D2Rs were strongly expressed on striatal neurons in vivo, we did not detect any D2R expression on resident microglia in the healthy brains of wild-type mice or transgenic mice expressing the green fluorescent protein (GFP) under the control of the Drd2 promoter. However, cerebral ischemia induced the expression of D2R on Iba1-immunoreactive inflammatory cells in the infarct core and penumbra. Notably, D2R expression was confined to CD45(hi) cells, and GFP BM chimeras revealed that D2R was expressed on activated resident microglia as well as on peripherally derived macrophages in the ischemic brain. Importantly, the D2/3R agonist, pramipexole, enhanced the secretion of nitrite by cultured microglia in response to proinflammatory stimuli. Thus, dopamine may serve as a modulator of microglia function during neuroinflammation.1 november 201

    Development of CD4(+) T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

    No full text
    Differences in T cell receptor (TCR) signaling initiated by interactions among TCRs, coreceptors, and self-peptide–MHC complexes determine the outcome of CD4 versus CD8 lineage of T cell differentiation. The H-2L(d) and K(bm3) alloreactive 2C TCR is positively selected by MHC class I K(b) and a yet-to-be identified nonclassical class I molecule to differentiate into CD8(+) T cells. Here we describe two mechanisms by which CD4(+) 2C T cells can be generated in 2C TCR-transgenic mice. In the RAG(−/−) background, development of CD4(+) 2C T cells requires the expression of both I-A(b) and the TAP genes, indicating that both MHC class I and II molecules are required for positive selection of these T cells. Notably, only some of the 2C(+)RAG(−/−) mice (≈30%) develop CD4(+) 2C T cells, with frequencies in individual mice varying from 0.5% to as high as ≈50%. In the RAG(+) background, where endogenous TCRα genes are rearranged and expressed, CD4(+) 2C T cells are generated because these cells express the 2C TCR as well as additional TCRs, consisting of the 2C TCRβ and endogenous TCRα chains. Similarly, T cells expressing the OT-1 TCR, which is nominally MHC class I-restricted, can also develop into CD4(+) T cells through the same two mechanisms. Thus, expression of two TCRs by a single thymocyte, TCR recognition of multiple MHC molecules, and heterogeneity of TCR, coreceptors, and peptide–MHC interactions in the thymus all contribute to the outcome of CD4 versus CD8 lineage development

    Perfluoroalkyl-Substituted Thiophenes and Pyrroles from Donor–Acceptor Cyclopropanes and Heterocumulenes: Synthesis and Exploration of their Reactivity

    No full text
    corecore