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)

We investigated whether pertussis toxin (PT)-sensitive heterotrimeric Gi proteins (Gi1, Gi2, Gi3) are involved in the regulation of TCR-induced activation of human T cells. First, Gi proteins were inactivated by PT: pretreatment with PT of purified blood T lymphocytes before CD3 cross-linking inhibited cell proliferation (-71.1 +/- 22.0%, P < 0.001), production of interleukin-2 (IL-2; -47.3 +/- 12.6%, P = 0.008), and expression of CD25 (-24.6 +/- 11.7%, P < 0.001) and CD69 (-25.7 +/- 9.0%, P < 0.001). Then, to identify which of the three Gi was involved, Gi1, Gi2, and Gi3 proteins were specifically inactivated by stably transfecting dominant-negative mutated forms of their alpha subunit in Jurkat cells. After activation, IL-2 production and CD69 expression were inhibited only in cells expressing inactive Gi2. We then studied the effects of interleukin-8 (IL-8), a CXC-chemokine with receptors coupled to Gi2 and produced in an autocrine fashion by activated T cells. Although its effects varied among donors, exogenous IL-8 stimulated proliferation and CD25 expression (up to, respectively, 200 and 77%) of PB T lymphocytes in response to CD3 activation, in a PT-sensitive manner. IL-8 also stimulated IL-2 production (by up to 42%) and CD69 expression, although weakly (+27%). Anti-human IL-8 antibody inhibited proliferation (-43%) and CD25 up-regulation (-45%) of activated T lymphocytes. In summary, several major responses of human T lymphocytes to TCR-mediated activation are regulated by Gi2 proteins, which for this function can be activated by IL-8 in an autocrine manner.
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PMID:Positive regulation of human T cell activation by Gi2 proteins and interleukin-8. 1081 Oct 16

T cells that emigrate from the thymus have primarily been studied in vivo using fluorescent dye injection of the thymus. This study examined the properties of thymocytes that emigrate from cultured thymic lobes in organ culture. Under these conditions, thymic emigrants displayed the expected phenotype, that of mature thymocytes expressing high levels of T-cell receptor (TCR-alphabeta) and either CD4 or CD8, and were observed to emigrate within 24 hours of positive selection. Emigration was inhibited by cytochalasin D, pertussis toxin, or Clostridium difficile toxin B, implicating an active motility process. Most of the surface markers on alphabeta-thymic emigrants (Thy1, CD44, CD69, CD25, leukocyte functional antigen-1, intercellular adhesion molecule-1, alpha(4)-integrin, alpha(5)-integrin, CD45, and CD28) were expressed at a surface density similar to that on mature intrathymic cells and peripheral splenic T cells. Heterogeneous expression of L-selectin and heat-stable antigen (HSA) suggested that subsets emerge from the thymus with a commitment to different migration patterns. The only marker on emigrants not found on either intrathymic cells or mature spleen T cells was CTLA-4, which could dampen the response of emigrants to peripheral antigens. Antigen responsivenes measured in vitro against allogeneic dendritic cells showed a proliferative response comparable to that of splenic T cells. In vivo, however, thymic emigrants failed to induce an acute graft-versus-host reaction in allogeneic severe combined immunodeficiency recipients. This suggests that a mechanism operating in vivo, perhaps tolerance or migration pattern, attenuates the response of emigrants against antigens that did not induce their deletion in the thymus.
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PMID:Thymic emigrants isolated by a new method possess unique phenotypic and functional properties. 1122 81

In myelin basic protein (MBP)-specific TCR-transgenic (Tg) mice, peripheral T cells express the Valpha2.3/Vbeta8.2-Tg TCR, demonstrate vigorous proliferative responses to MBP in vitro, and can exhibit experimental autoimmune encephalomyelitis (EAE) within 5 days of pertussis toxin injection. We explored the effects of oral administration of MBP on the cellular trafficking of the MBP-specific TCR-Tg cells and the ability of oral MBP to protect Tg mice from EAE. Tg mice were fed MBP, OVA or vehicle and sacrificed at various times after feeding. An immediate and dramatic decrease in Valpha2.3/Vbeta8.2(+)-Tg cells was observed in the periphery within 1 h after feeding. By 3 days after feeding, the percentage of Tg cells increased to near control levels, but decreased again by 10 days. When MBP or vehicle-fed Tg mice were challenged for EAE at this point, disease was severe in the vehicle-fed mice and reduced in the MBP-fed mice over the 40-day observation period. In vitro studies revealed a biphasic pattern of MBP proliferative unresponsiveness and an induction of Th1 cytokines. Immunohistochemical staining showed that the number of Tg cells found in the intestinal lamina propria increased dramatically as the number of Tg cells in the periphery decreased. There was no apparent proliferation of Tg cells in the lamina propria, indicating that Tg cells trafficked there from the periphery. Taken together, these results suggest that T cell trafficking into the site of Ag deposition acts to protect the TCR-Tg mouse from EAE.
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PMID:Rapid depletion of peripheral antigen-specific T cells in TCR-transgenic mice after oral administration of myelin basic protein. 1131 21

Lewis rats immunized with guinea pig myelin basic protein (GPBP) emulsified with incomplete Freund's adjuvant (IFA) do not develop experimental autoimmune encephalomyelitis (EAE). However, we found that GPBP/IFA with pertussis toxin (PT) administration induced full-blown EAE. By comparing the immunological status of rats immunized with GPBP/IFA plus PT [PT (+) rats] with that of rats immunized with GPBP/IFA alone [PT (-) rats], we tried to elucidate the pathomechanisms of EAE. Analysis of the TCR clonality by CDR3 spectratyping revealed that Vbeta8.2 and Vbeta10 expansion of T cells occurred in both PT (-) and PT (+) rats, indicating that activation of T cells at this level is not sufficient for the development of clinical EAE. Quantitation of cytokine mRNA and protein revealed that PT (-) rats showed a Th2-dominant, while PT (+) rats showed a Th1-dominant, cytokine profile. Furthermore, administration of IL-12, but not of IFN-gamma and TNF-alpha, induced clinical EAE in GPBP/IFA-immunized animals. Taken together, two-step activation, activation of T cells bearing a particular type of TCR by antigen immunization and subsequent overproduction of Th1 cytokines, mainly IL-12 production, induced by appropriate adjuvants is essential for the development of clinical EAE.
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PMID:Two-step activation of T cells, clonal expansion and subsequent Th1 cytokine production, is essential for the development of clinical autoimmune encephalomyelitis. 1138 25

Pertussis toxin (PTx), an exotoxin produced by Bordetella pertussis, has long been used as a mucosal adjuvant. We examined the T cell stimulatory properties of PTx in order to dissect its mechanisms of adjuvanticity. PTx or the B-oligomer of PTx (PTxB) failed to activate purified murine CD4+ or CD8+ T cells, as measured by a lack of proliferation or expression of early T cell activation markers. However, these T cells proliferated extensively in response to the toxin in the presence of syngeneic DC, and proliferation was accompanied by a high level of IFN-gamma production in the absence of IL-12. Interestingly, such responses were independent of signals mediated by MHC-TCR interaction. Both PTx and PTxB were found to bind stably to the surface of DC, and increased the adherence of DC to surrounding cells. These data suggest that polyclonal T cell responses mediated by the toxin are likely to be caused by the toxin bound on the surface of APC, either cross-linking cell surface molecules on T cells, or directly stimulating T cells together with the co-stimulatory molecules expressed on APC. B. pertussis may use this toxin as a mechanism to evade a specific immune response.
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PMID:Cell-surface bound pertussis toxin induces polyclonal T cell responses with high levels of interferon-gamma in the absence of interleukin-12. 1281 46

Experimental autoimmune encephalomyelitis was induced in macaques. T cell clones infiltrated into the brain lesion area were compared with those in blood. Intradermal immunization of macaques with brain white matter derived from healthy macaque in combination with pertussis toxin, induced neurological symptoms in two macaques. One died on day 25 after immunization, whereas the other survived. Gross examination of the brain from the dead macaque, showed clear hemorrhagic lesions in the white matter. Hematological analysis showed that drastic T cell response was induced in macaques immunized with white matter, but not in control macaques. Flow cytometric analysis of blood cells from the affected macaques demonstrated an increase of CD4 and CD8 T cell populations expressing the CD69 early activation marker. Single strand conformation polymorphism (SSCP) analysis of T cell receptor beta chain showed T cell clones infiltrated into the brain lesion, which were different from those found in the peripheral blood of the same monkey. The present paper shows that SSCP analysis of TCR is useful in studying clonality of T cells infiltrating into the brain tissue of macaque with EAE.
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PMID:Experimental autoimmune encephalomyelitis in cynomolgus monkeys. 1461 8

The use of HLA class II-transgenic (Tg) mice has facilitated identification of antigenic T cell epitopes that may contribute to inflammation in T cell-mediated diseases such as rheumatoid arthritis and multiple sclerosis (MS). In this study, we compared the encephalitogenic activity of three DR2-restricted myelin determinants [mouse (m) myelin oligodendrocyte glycoprotein (MOG)-35-55, human (h)MOG-35-55 and myelin basic protein (MBP)-87-99] in Tg mice expressing the MS-associated DR2 allele, DRB1*1501. We found that mMOG-35-55 peptide was strongly immunogenic and induced moderately severe chronic experimental autoimmune encephalomyelitis (EAE) with white matter lesions after a single injection in Freund's complete adjuvant followed by pertussis toxin. hMOG-35-55 peptide,which differs from mMOG-35-55 peptide by a proline for serine substitution at position 42, was also immunogenic, but not encephalitogenic, and was only partially cross-reactive with mMOG-35-55. In contrast, MBP-87-99, which can induce EAE in double-Tg mice expressing both HLA-DR2 and a human MBP-specific TCR, was completely non-encephalitogenic in HLA-DR2-Tg mice lacking the human TCR transgene. These findings demonstrate potent encephalitogenic activity of the mMOG-35-55 peptide in association with HLA-DR2, thus providing a strong rationale for further study of hMOG-35-55 peptide as a potential pathogenic determinant in humans.
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PMID:Myelin oligodendrocyte glycoprotein-35-55 peptide induces severe chronic experimental autoimmune encephalomyelitis in HLA-DR2-transgenic mice. 1511 58

The role of gammadelta T cells in the regulation of pulmonary inflammation following Bordetella pertussis infection was investigated. Using a well-characterized murine aerosol challenge model, inflammatory events in mice with targeted disruption of the T-cell receptor delta-chain gene (gammadelta TCR-/- mice) were compared with those in wild-type animals. Early following challenge with B. pertussis, gammadelta TCR-/- mice exhibited greater pulmonary inflammation, as measured by intra-alveolar albumin leakage and lesion histomorphometry, yet had lower contemporaneous bacterial lung loads. The larger numbers of neutrophils and macrophages and the greater concentration of the neutrophil marker myeloperoxidase in bronchoalveolar lavage fluid from gammadelta TCR-/- mice at this time suggested that differences in lung injury were mediated through increased leukocyte trafficking into infected alveoli. Furthermore, flow cytometric analysis found the pattern of recruitment of natural killer (NK) and NK receptor+ T cells into airspaces differed between the two mouse types over the same time period. Taken together, these findings suggest a regulatory influence for gammadelta T cells over the early pulmonary inflammatory response to bacterial infection. The absence of gammadelta T cells also influenced the subsequent adaptive immune response to specific bacterial components, as evidenced by a shift from a Th1 to a Th2 type response against the B. pertussis virulence factor filamentous hemagglutinin in gammadelta TCR-/- mice. The findings are relevant to the study of conditions such as neonatal B. pertussis infection and acute respiratory distress syndrome where gammadelta T cell dysfunction has been implicated in the inflammatory process.
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PMID:gammadelta T cells regulate the early inflammatory response to bordetella pertussis infection in the murine respiratory tract. 1649 58

Only activated and effector memory T cells are thought to access non-lymphoid tissues. In contrast, naive T cells are thought to circulate only between the blood, lymph and secondary lymphoid organs. We examined the phenotype of endogenous T cells in various non-lymphoid organs and showed that a subset of cells exhibited an apparently naive phenotype and were functionally inactive. FTY720 treatment selectively depleted this population from the non-lymphoid tissues. In addition, RAG-deficient TCR transgenic CD4 and CD8 T cells were present in non-lymphoid tissues in bone marrow chimeric mice and in situ imaging analysis revealed their location in the parenchymal tissues. Moreover, migration of TCR transgenic T cells to non-lymphoid tissues after adoptive transfer was pertussis-toxin resistant. Overall, the results suggest that naive T cells may circulate through non-lymphoid tissues as part of their normal migratory pathway.
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PMID:Evidence that a significant number of naive T cells enter non-lymphoid organs as part of a normal migratory pathway. 1670

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are marked by inflammatory demyelinating lesions throughout the central nervous system, including optic nerve. Neuronal loss also occurs in EAE, including retinal ganglion cell (RGC) loss in eyes with optic neuritis, but the finding of RGC loss in relation to optic nerve inflammation differs in different EAE settings. Recently, Myelin oligodendrocyte glycoprotein (MOG)-specific TCR transgenic mice were found to develop spontaneous isolated optic neuritis in the absence of EAE. In the current study, the relationship of inflammation to retinal ganglion cell (RGC) loss during isolated optic neuritis is examined. RGCs of MOG-specific TCR transgenic mice were labeled with Flourogold and then treated with pertussis toxin (PT) or observed untreated. At various time points, RGCs were counted, retinas were TUNEL labeled, and optic nerves were examined for inflammatory cell infiltrates. 29% of untreated MOG-specific TCR transgenic mice developed periocular inflammation by 4 months of age, and 32% of optic nerves of TCR transgenic mice had histological lesions in the optic nerve. Incidence of histological optic neuritis was 20% at day 8 following injection of PT and increased to 48% by day 12, and 68% by day 16. In contrast, no RGC loss or TUNEL staining was detected in eyes with optic neuritis until day 12 in the mice injected with PT. A 28% reduction in RGC numbers at day 12 increased to 39% by day 16, and RGC loss of eyes with severe or massive inflammation was significantly higher than that of eyes with mild or moderate inflammation. No RGC loss occurred in TCR transgenic mouse eyes without optic neuritis. The fact that inflammation precedes RGC loss suggests that neuronal loss during optic neuritis occurs secondary to the inflammatory process in isolated optic neuritis.
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PMID:Retinal ganglion cell damage induced by spontaneous autoimmune optic neuritis in MOG-specific TCR transgenic mice. 1682 69


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