Autoantigens signal through chemokine receptors: uveitis antigens induce CXCR3- and CXCR5-expressing lymphocytes and immature dendritic cells to migrate

Howard, O. M. Zack; Dong, Hui; Su, Shao Bo; Caspi, Rachel R; Chen, Xin; Plötz, Paul H.; Oppenheim, Joost J.

doi:10.1182/blood-2004-07-2697

Cited by 43 publications

(38 citation statements)

References 42 publications

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“…Studies with several autoantigens (ie, histidyl-transfer RNA synthetase, retinal S-antigen, etc) have demonstrated that these autoantigens can initiate an innate immune response and, in sensitive individuals, adaptive immune response by attracting iDCs and T and B cells expressing chemokine receptors. 48 Although the precise (patho)physiologic role of PR3 in the immunopathogenesis and/or autoimmune reaction of WG has yet to be established with certainty, our data suggest that the proteolytic activation of PAR2 on DCs represents a new avenue in the direction to understand the early pathogenic events in WG: DCs can become stimulated to mature by PR3 released by damaged cells through the PAR-2 signaling pathway. These PR3-maturated DCs become fully competent APCs for the stimulation of autoreactive Th1-type CD4 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway

Csernok

Gross

et al. 2006

Blood

103

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Autoantibodies to proteinase 3 (PR3) are involved in the pathogenesis of autoimmune-mediated vasculitis in Wegener granulomatosis (WG). To address the question how the autoantigen PR3 becomes a target of adaptive immunity, we investigated the effect of PR3 on immature dendritic cells (iDCs) in patients with WG, healthy blood donors, and patients with Crohn disease (CD), another granulomatous disease. PR3 induces phenotypic and functional maturation of a fraction of blood monocyte-derived iDCs. PR3-treated DCs express high levels of CD83, a DC-restricted marker of maturation, CD80 and CD86, and HLA-DR. Furthermore, the DCs become fully competent antigen-presenting cells and can induce stimulation of PR3-specific CD4+ T cells, which produce IFN-γ. PR3-maturated DCs derived from WG patients induce a higher IFN-γ response of PR3-specific CD4+ T cells compared with patients with CD and healthy controls. The maturation of DCs mediated through PR3 was inhibited by a serine protease inhibitor, by antibodies directed against the protease-activated receptor-2 (PAR-2), and by inhibition of phospholipase C, suggesting that the interactions of PR3 with PAR-2 are involved in the induction of DC maturation. Wegener autoantigen interacts with a “gateway” receptor (PAR-2) on iDCs in vitro triggering their maturation and licenses them for a T helper 1 (Th1)–type response potentially favoring granuloma formation in WG.

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Section: Discussionmentioning

confidence: 99%

Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway

Csernok

Gross

et al. 2006

Blood

103

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“…The number of cells that migrated to the lower surface was microscopically counted at six randomly chosen high-power fields. IFN-g inducible protein 10 (IP10), previously described, was used as a control, as immature dendritic cells exhibit significant chemotaxis through CXCR3 (28,29). Three replicates were done for each treatment and the experiment was done thrice.…”

Section: Methodsmentioning

confidence: 99%

Immunity against Tumor Angiogenesis Induced by a Fusion Vaccine with Murine β-Defensin 2 and mFlk-1

Wang¹,

Wang²,

Wang³

et al. 2007

Clinical Cancer Research

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Purpose: Previous studies indicated that humoral or cellular immunity against murine vascular endothelial growth factor 2 (mFlk-1) was elicited to inhibit tumor growth. Here we describe a genetic fusion vaccine, pMBD2-mFlk-1, based on the targeting of a modified mFlk-1 to antigenpresenting cells by a murine h-defensin 2 (MBD2) protein to induce both humoral and cellular immunity against mFlk-1, with the targeting especially focused on immature dendritic cells. Experimental Design:The protective and therapeutic antitumor immunity of the fusion vaccine was investigated in mouse models. Antiangiogenesis effect was detected by immunohistochemical staining and alginate-encapsulate tumor cell assay. The mechanisms of the fusion vaccine were primarily explored by detection of autoantibodies and CTL activity and confirmed by the deletion of immune cell subsets. Results: The fusion vaccine elicited a strong protective and therapeutic antitumor immunity through antiangiogenesis in mouse models, and this worked through stimulation of an antigenspecific CD8 + T-cell response as well as a specific B-cell response against mFlk-1. The findings were confirmed by depletion of immune cell subsets and in knockout mice. Conclusion: Our study showed that a fusion vaccine based on self immune peptide (MBD2) and self antigen (mFlk-1) induced autoimmunity against endothelial cells, resulting in inhibition of tumor growth, and could be further exploited in clinical applications of cancer immunotherapy.

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“…34 Because of its pertussis toxin sensitivity, probably the CXCR3A variant, and not CXCR3B, is activated by CXCL4L1 on human leukocytes. Indeed, earlier reports indicated the presence of CXCR3 on DCs, 35,36 NK cells, 37 and activated T cells. 38 .…”

Section: Cxcl4l1 Uses Cxcr3 For Angiostasis and Chemotaxis 485mentioning

confidence: 99%

Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3

Struyf

Salogni

Burdick

et al. 2011

Blood

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We investigated possible cellular receptors for the human CXC chemokine platelet factor-4 variant/CXCL4L1, a potent inhibitor of angiogenesis. We found that CXCL4L1 has lower affinity for heparin and chondroitin sulfate-E than platelet factor-4 (CXCL4) and showed that CXCL10 and CXCL4L1 could displace each other on microvascular endothelial cells. Labeled CXCL4L1 also bound to CXCR3A-and CXCR3B-transfectants and was displaced by CXCL4L1, CXCL4, and CXCL10. The CXCL4L1 anti-angiogenic ac- IntroductionThe chemokine family of chemotactic cytokines consists of rather small proteins (7-12 kDa) that signal via G protein-coupled receptors, designated CC chemokine receptor (CCR) or CXC chemokine receptor (CXCR), and regulate leukocyte recruitment to inflammatory sites, as well as leukocyte traffic between immunological compartments. Other target cells of chemokines include tumor cells and endothelial cells, and consequently, chemokines play a role in tumor development. 1,2 For example, the CXCR3 ligands CXCL9, CXCL10, and CXCL11 are chemotactic for antitumoral lymphocytes and inhibit angiogenesis. However, some members of the chemokine family (eg, the CXCR2 ligands CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, and CXCL8) favor tumor growth by attracting neutrophils, by stimulating the release of matrix metalloproteinases, by acting as growth factors, and by promoting angiogenesis. One of the first chemokines that was investigated as an anticancer therapeutic is CXCL4 or platelet factor-4. [1][2][3] The human CXC chemokine platelet factor-4 (CXCL4) is encoded by 2 genes, located on chromosome 4 and probably arose through duplication. 4,5 The 2 genes are indeed highly related and give rise to mature proteins that differ in only 3 amino acid residues in the carboxylic acid (COOH)-terminal part. Analysis of conditioned media from thrombin-treated platelets revealed that both CXCL4 genes are translated into proteins. 6 Afterward, tumor cells and smooth muscle cells were identified as alternative cellular sources for CXCL4L1 but not for CXCL4, indicating that not every cell type that produces CXCL4 also releases CXCL4L1 and vice versa. 7,8 The fact that tumor cells produce angiostatic CXCL4L1 provides a negative feedback on tumor growth, because CXCL4L1 is more potent than CXCL4 in angiostatic assays. 6 In this manuscript, we confirm that the antitumoral activity of CXCL4L1 is exerted through inhibition of angiogenesis and demonstrate that this angiostatic activity is CXCR3-dependent in human and mouse models. Furthermore, we also show for the first time that CXCL4L1 attracts human and mouse activated T lymphocytes, human dendritic cells (DCs), and human natural killer (NK) cells and that CXCL4L1-induced chemotaxis of immature DCs is mediated by CXCR3, coupling to a G ␣i protein. In addition to CXCR3A and CXCR3B interaction, binding to glycosaminoglycans (GAGs) was explored as well. MethodsA supplemental Methods section is available on the Blood Web site (see the Supplemental Materials link at the top of the online article). All animal...

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Autoantigens signal through chemokine receptors: uveitis antigens induce CXCR3- and CXCR5-expressing lymphocytes and immature dendritic cells to migrate

Cited by 43 publications

References 42 publications

Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway

Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway

Immunity against Tumor Angiogenesis Induced by a Fusion Vaccine with Murine β-Defensin 2 and mFlk-1

Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3

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