Overall, my laboratory focuses on the interactions of cognate chemokine ligands and chemokine mimics with G-protein coupled chemokine receptor and the resultant effects on inflammation, autoimmunity, cancer and algesia. We have shown that a variety of antimicrobial peptides mimic chemokines and also have the capacity to rapidly activate host immune responses. We previously identified both a and a types of defensins as alarmins with chemotactic and activating effects on iDC and in vivo immunoadjuvant effects. The a defensins interact with the CCR6 chemokine receptor, while a defensins interact with an as yet unknown GiPCR. Another antimicrobial peptide known as cathelicidin (LL37) and its murine homologue CRAMP are chemotactic for FPRL-1 receptors expressed on monocytes and precursors of iDC, induce the maturation of iDC and are equally as potent adjuvants in vivo as alum. Furthermore, we have shown that even antimicrobial peptides obtained from frogs interact with FPRL1 positive mammalian cells. Apparently the immune functions of these peptides have been evolutionarily conserved.We have also investigated the immune activating and chemotactic effects of another leukocyte granule derived alarmin known as eosinophil derived neurotoxin (EDN), which is a member of the RNAse family, and has antiviral activity including anti-HIV activity. EDN based on its interactions with a pertussis toxin susceptible GiPCR is chemotactic for iDC, and mDC. In addition, EDN based on interactions with TLR2 activates iDC to produce multiple proinflammatory cytokines and to mature into mDC. Preliminary data shows that EDN also has potent in vivo immunostimulating effects. We have also shown that High Mobility Group Box I (HMGB1), a DNA binding protein with antiviral activity, is chemotactic for a GiPCR on iDC. Our collaborators, Dr. Kevin Tracey, et al, have shown HMGB1 to be a potent inducer of proinflammatory cytokines, to induce the maturation of iDC to mDC and to be highly produced at inflammatory sites.We have proposed calling these early warning signals """"""""alarmins"""""""". Alarmins are characterized by having chemotactic activity for leukocytes expressing Gi Protein Coupled Receptors (GiPCR), together with the capacity to induce immature dendritic cells (iDC) to mature into antigen- presenting, T lymphocyte activating mDC with resultant in vivo immunoadjuvant effects. These activities of alarmins, if administered together with an antigen, result in considerable augmentation of both cellular and humoral immune response to the antigen. HMGB1 is therefore also an alarmin. Although these alarmins are structurally distinct, they are rapidly released from granules of leukocytes or secreted in response to proinflammatory stimulants by keratinocytes or epithelial cells lining the GI tract, GU tract and tracheobronchial tree. As such, these and yet to be identified alarmins probably represent the early warning system to alert the host defense to danger signals. Like GM-CSF, a cytokine which is also an alarmin based on its chemotactic effect on dendritic cells and immunoadjuvant effects, these alarmins may prove useful as adjuvants in tumor vaccines.GiPCR not only interact with non-cognate alarmins, but also are responsible for the chemotactic responses of iDC to many autoantigens and some tumor antigens. We previously reported that histidyl tRNA synthetase (HRS) and AsnRS, autoantigens to which some patients with myositis develop auto-antibodies, are chemotactic for cells (including iDC) expressing CCR5 and CCR3 respectively. More recently we have shown that of the antigens that induce experimental autoimmune uveitis (EAU), IRBP uses CXCR3 and CXCR5, while S-antigen uses only CXCR3 to chemoattract iDC. Many other autoantigens associated with type I diabetes, EAE and scleroderma are also chemotactic for iDC.
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