Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The marginal zone (MZ) of the spleen is an important site for the capture of blood-borne pathogens and a gateway for lymphocytes entering the white pulp. We have recently reported that Leishmania donovani infection results in a remarkably selective loss of MZ macrophages (MZM) from the MZ. To understand the basis of this observation, we have investigated how MZM maintain their anatomical distribution in the steady state in uninfected mice. We now report that plt/plt mice, which lack functional CCL19 and CCL21, have significantly reduced numbers of MZM compared with normal C57BL/6 (B6) mice. Similarly, in B6.CD45.1-->plt/plt chimeras, donor-derived MZM were rare compared with the number observed in reciprocal plt/plt-->B6.CD45.1 chimeras. Moreover, we show that administration of pertussis toxin, an inhibitor of chemokine receptor signaling, to B6 mice results in exit of MZM from the MZ, that MZM can migrate in response to CCL19 and CCL21 in vitro, and that MZM colocalize with CD31+CCL21+ endothelial cells. Collectively, these data indicate that CCL21 and, to a lesser extent, CCL19 play significant roles in the distinctive localization of MZM within the splenic MZ. Deficiency of CCL19 and CCL21, as also previously observed in mice infected with L. donovani, may thus account for the selective loss of MZM seen during this infection.
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PMID:Localization of marginal zone macrophages is regulated by C-C chemokine ligands 21/19. 1547 21

The nervous systems affect immune functions by releasing neurohormones and neurotransmitters. A neurotransmitter dopamine signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. The secondary lymphoid tissues are highly innervated by sympathetic nerve fibers that store dopamine at high contents. Lymphocytes also produce dopamine. In this study, we examined expression and function of dopamine receptors in lymphocytes. We found that D3 was the predominant subtype of dopamine receptors in the secondary lymphoid tissues and selectively expressed by naive CD8+ T cells of both humans and mice. Dopamine induced calcium flux and chemotaxis in mouse L1.2 cells stably expressing human D3. These responses were almost completely inhibited by pertussis toxin, indicating that D3 was coupled with the Galphai class of G proteins. Consistently, dopamine selectively induced chemotactic responses in naive CD8+ T cells of both humans and mice in a manner sensitive to pertussis toxin and D3 antagonists. Dopamine was highly synergistic with CCL19, CCL21, and CXCL12 in induction of chemotaxis in naive CD8+ T cells. Dopamine selectively induced adhesion of naive CD8+ T cells to fibronectin and ICAM-1 through activation of integrins. Intraperitoneal injection of mice with dopamine selectively attracted naive CD8+ T cells into the peritoneal cavity. Treatment of mice with a D3 antagonist U-99194A selectively reduced homing of naive CD8+ T cells into lymph nodes. Collectively, naive CD8+ T cells selectively express D3 in both humans and mice, and dopamine plays a significant role in migration and homing of naive CD8+ T cells via D3.
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PMID:Dopamine selectively induces migration and homing of naive CD8+ T cells via dopamine receptor D3. 1639 68

The encounter between APC and T cells is crucial for initiating immune responses to infectious microorganisms. In the spleen, interaction between dendritic cells (DC) and T cells occurs in the periarteriolar lymphoid sheath (PALS) into which DC and T cells migrate from the marginal zone (MZ) along chemokine gradients. However, the importance of DC migration from the MZ into the PALS for immune responses and host resistance to microbial infection has not yet been elucidated. In this study, we report that following Leishmania donovani infection of mice, the migration of splenic DC is regulated by the CCR7 ligands CCL19/CCL21. DC in plt/plt mutant mice that lack these chemokines are less activated and produce less IL-12, compared with those in wild-type mice. Similar findings are seen when mice are treated with pertussis toxin, which blocks chemokine signaling in vivo. plt/plt mice had increased susceptibility to L. donovani infection compared with wild-type mice, as determined by spleen and liver parasite burden. Analysis of splenic cytokine profiles at day 14 postinfection demonstrated that IFN-gamma and IL-4 mRNA accumulation was comparable in wild-type and plt/plt mice. In contrast, accumulation of mRNA for IL-10 was elevated in plt/plt mice. In addition, plt/plt mice mounted a delayed hepatic granulomatous response and fewer effector T cells migrated into the liver. Taken together, we conclude that DC migration from the MZ to the PALS is necessary for full activation of DC and the optimal induction of protective immunity against L. donovani.
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PMID:Loss of dendritic cell migration and impaired resistance to Leishmania donovani infection in mice deficient in CCL19 and CCL21. 1662 17

Among all chemokine receptors CXCR4 possesses a unique response profile and distinguishes itself through a prolonged signaling capacity. Here, we investigated the signaling capacity of CXCR4 to its so far known unique ligand CXCL12 in B cell lines and primary CD19(+) B lymphocytes. During lymphopoiesis, CXCR4 is continuously expressed on the surface of B cells. However, its signaling profile changes inasmuch preB and proB cells migrate towards CXCL12, mobilize intracellular calcium and activate the small GTPases Rac1 and Cdc42, whereas mature B cells do not show these responses, albeit the cells retain the capability to migrate in response to CXCL13 and CCL21. By contrast, stimulation of B cells with CXCL12 at all stages of development results in the activation of the MAP-kinase cascade and in rapid CXCR4 internalization. The pathways leading to ERK1/2 activation are different in preB and mature B cell lines. In either case, ERK1/2 activation is pertussis toxin sensitive, but only in mature B-cells inhibition of PI3-kinase causes an almost complete block of ERK1/2 activation. Taken together, the results show that CXCR4 changes its coupling to downstream signal-transduction pathways in B cells, suggesting that receptor activity may depend on accessory proteins.
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PMID:Differences in CXCR4-mediated signaling in B cells. 1671 7

High mobility group box-1 (HMGB1) protein is a nonhistone, DNA-binding protein that plays a critical role in regulating gene transcription. Recently, HMGB1 has also been shown to act as a late mediator of endotoxic shock and to exert a variety of proinflammatory, extracellular activities. Here, we report that HMGB1 simultaneously acts as a chemoattractant and activator of dendritic cells (DCs). HMGB1 induced the migration of monocyte-derived, immature DCs (Mo-iDCs) but not mature DCs. The chemotactic effect of HMGB1 on iDCs was pertussis toxin-inhibitable and also inhibited by antibody against the receptor of advanced glycation end products (RAGE), suggesting that HMGB1 chemoattraction of iDCs is mediated by RAGE in a Gi protein-dependent manner. In addition, HMGB1 treatment of Mo-iDCs up-regulated DC surface markers (CD80, CD83, CD86, and HLA-A,B,C), enhanced DC production of cytokines (IL-6, CXCL8, IL-12p70, and TNF-alpha), switched DC chemokine responsiveness from CCL5-sensitive to CCL21-sensitive, and acquired the capacity to stimulate allogeneic T cell proliferation. Based on its dual DC-attracting and -activating activities as well as its reported capacity to promote an antigen-specific immune response, we consider HMGB1 to have the properties of an immune alarmin.
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PMID:High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. 1696 86

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is the severest form of idiopathic interstitial pneumonia for which therapeutic targets are needed. Surgical lung biopsy specimens from IPF/UIP patients exhibit focal expression of CC chemokine receptor (CCR) 7, but the identity of these CCR7-positive cells is unknown. The purpose of the present study was to examine the functional and signalling significance of CCR7 expression of primary fibroblasts grown from IPF/UIP and normal surgical lung biopsy specimens. Primary fibroblasts were cultured from surgical lung biopsy specimens from IPF/UIP and normal patients. Fibroblasts treated with or without CC chemokine ligand (CCL) 21 were analysed for functional, transcriptional and proteomic differences using immunocytochemical analysis, gene arrays, Taqman real-time PCR, and migration, proliferation and Western blot assays. CCR7 was expressed by IPF/UIP fibroblasts, but not normal fibroblasts. IPF/UIP fibroblasts, but not normal fibroblasts, showed significant migratory and proliferative responses when exposed to CCL21, which were inhibited by pertussis toxin or neutralising antibodies to CCR7. Exposure of IPF/UIP fibroblasts to CCL21 altered the phosphorylation status of mitogen-activated protein kinase kinase 1/2, extracellular signal-regulated kinase 1/2 and ribosomal S6 kinase (90 kDa) in these cells; this was abrogated by pertussis toxin or CCR7-specific small interfering RNA. Together, these data demonstrate that CC chemokine ligand 21 modulates the functional properties of idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblasts, but not normal fibroblasts.
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PMID:Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21. 1733 65

CCL19 and CCL21 are thought to be critical for experimental autoimmune encephalomyelitis (EAE) induction, but their precise role is unknown. We examined the role of these chemokines in inducing EAE. C57BL/6 mice lacking expression of these chemokines (plt/plt mice) or their receptor CCR7 were resistant to EAE induced with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)) and pertussis toxin. However, passive transfer of pathogenic T cells from wild-type mice induced EAE in plt/plt mice, suggesting a defect independent of the role of CCR7 ligands in the migration of immune cells. Examination of draining lymph node (DLN) cells from MOG(35-55)-immunized plt/plt mice found decreased IL-23 and IL-12 production by plt/plt dendritic cells (DCs) and a concomitant defect in Th17 cell and Th1 cell generation. In contrast, production of the Th17 lineage commitment factors IL-6 and TGF-beta were unaffected by loss of CCR7 ligands. The adoptive transfer of in vitro-generated Th17 cells from DLN cells of MOG(35-55)-immunized plt/plt mice developed EAE in wild-type recipient mice, whereas that of Th1 cells did not. Pathogenic Th17 cell generation was restored in plt/plt DLNs with the addition of exogenous IL-23 or CCL19/CCL21 and could be reversed by inclusion of anti-IL-23 mAb in cultures. Exogenous CCL19/CCL21 induced IL-23p19 expression and IL-23 production by plt/plt or wild-type DCs. Therefore, CCR7 ligands have a novel function in stimulating DCs to produce IL-23 and are important in the IL-23-dependent generation of pathogenic Th17 cells in EAE induction.
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PMID:CCR7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells. 1962 43

It is unclear where within tissues subsets of effector and memory CD8 T cells persist during viral infection and whether their localization affects function and long-term survival. Following lymphocytic choriomeningitis virus infection, we found most killer cell lectin-like receptor G1 (KLRG1)(lo)IL-7R(hi) effector and memory cells, which are long-lived and high proliferative capacity, in the T cell zone of the spleen. In contrast, KLRG1(hi)IL-7R(lo) cells, which appear terminally differentiated and have shorter life spans, were exclusively localized to the red pulp. KLRG1(lo)IL-7R(hi) T cells homed to the T cell zone using pertussis toxin-sensitive chemokine receptors and appeared to contact gp38(+) stromal cells, which produce the chemokines CCL19 and CCL21 and the T cell survival cytokine IL-7. The transcription factors T-bet and B lymphocyte-induced maturation protein-1 controlled effector CD8 T cell splenic migration. Effector CD8 T cells overexpressing T-bet homed to the red pulp, whereas those lacking B lymphocyte-induced maturation protein-1 homed to the T cell zone. Upon memory formation, CD62L(+) memory T cells were predominantly found in the T cell zone, whereas CD62L(-) cells were found in the red pulp. Thus, effector and memory CD8 T cell subset localization within tissues is linked to their differentiation states, and this may identify anatomical niches that regulate their longevity and homeostasis.
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PMID:Differential localization of effector and memory CD8 T cell subsets in lymphoid organs during acute viral infection. 2092 25

Dendritic cells (DCs) respond to chemotactic signals to migrate from sites of infection to secondary lymphoid organs where they initiate the adaptive immune response. The key chemokines directing their migration are CCL19, CCL21, and CXCL12, but how signals from these chemokines are integrated by migrating cells is poorly understood. Using a microfluidic device, we presented single and competing chemokine gradients to murine bone-marrow derived DCs in a controlled, time-invariant microenvironment. Experiments performed with counter-gradients revealed that CCL19 is 10-100-fold more potent than CCL21 or CXCL12. Interestingly, when the chemoattractive potencies of opposing gradients are matched, cells home to a central region in which the signals from multiple chemokines are balanced; in this region, cells are motile but display no net displacement. Actin and myosin inhibitors affected the speed of crawling but not directed motion, whereas pertussis toxin inhibited directed motion but not speed. These results provide fundamental insight into the processes that DCs use to migrate toward and position themselves within secondary lymphoid organs.
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PMID:Dendritic cells distinguish individual chemokine signals through CCR7 and CXCR4. 2110 54

New vaccines against pertussis are needed to evoke full protection and long-lasting immunological memory starting from the first administration in neonates--the major target of the life-threatening pertussis infection. A novel live attenuated Bordetella pertussis vaccine strain, BPZE1, has been developed by eliminating or detoxifying three important B. pertussis virulence factors: pertussis toxin, dermonecrotic toxin, and tracheal cytotoxin. We used a human preclinical ex vivo model based on monocyte-derived dendritic cells (MDDCs) to evaluate BPZE1 immunogenicity. We studied the effects of BPZE1 on MDDC functions, focusing on the impact of Bordetella-primed dendritic cells in the regulation of Th and suppressor T cells (Ts). BPZE1 is able to activate human MDDCs and to promote the production of a broad spectrum of proinflammatory and regulatory cytokines. Moreover, conversely to its parental wild-type counterpart BPSM, BPZE1-primed MDDCs very efficiently migrate in vitro in response to the lymphatic chemokine CCL21, due to the inactivation of pertussis toxin enzymatic activity. BPZE1-primed MDDCs drove a mixed Th1/Th17 polarization and also induced functional Ts. Experiments performed in a Transwell system showed that cell contact rather than the production of soluble factors was required for suppression activity. Overall, our findings support the potential of BPZE1 as a novel live attenuated pertussis vaccine, as BPZE1-challenged dendritic cells might migrate from the site of infection to the lymph nodes, prime Th cells, mount an adaptive immune response, and orchestrate Th1/Th17 and Ts responses.
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PMID:Attenuated Bordetella pertussis vaccine candidate BPZE1 promotes human dendritic cell CCL21-induced migration and drives a Th1/Th17 response. 2143 Feb 19


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