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)

Adenosine triphosphate (ATP) is a signaling molecule for brain cells including astrocytes. In these cells, it has been shown that ATP stimulates myelin basic protein (MBP) kinase activity which is believed to represent the Erk family of MAP kinases. Indeed, we show that ATP activates simultaneously MBP kinase activity and phosphotyrosine incorporation in p42 Erk2 and p44 Erk1. Maximal effect of ATP is obtained at 50 microM after 5 min and disappears after 60 min. Effect of ATP is mimicked by 2-methylthio-ATP whereas alpha beta-methyleneadenosine 5' triphosphate (AMP-CPP) and adenosine do not promote any effect. Uridine triphosphate (UTP) activates also p42 and p44 MAP kinases. These observations indicate that p42-p44 MAP kinases activation can be obtained through P2v and P2u receptors. Purinergic stimulation of Erk is insensitive to pertussis toxin which inactivates heterotrimeric Gi protein. It is not inhibited by a PLA2 inhibitor (4 bromophenacyl bromide [B phi B]) and the PI3 kinase inhibitor, wortmannin. In contrast, purinergic stimulation of Erk is partially inhibited by the PKC inhibitor. GF109203X, at 5 microM and suppressed when extracellular calcium is complexed by ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA).
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PMID:Ca2+ dependent purinergic regulation of p42 and p44 MAP kinases in astroglial cultured cells. 975 13

Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development less compared with their contribution to disorders such as insulin-dependent diabetes mellitus. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene(s) is responsible for the genetic predisposition. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 4102 peptide; and the human CD4 coreceptor. The amino acid sequence of the MBP 84-102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells.
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PMID:A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. 1054 35

To elucidate the factor(s) accelerating the autoimmune disease processes, we induced two types of experimental autoimmune encephalomyelitis (EAE), severe and very mild, in F344 rats by immunization with myelin basic protein (MBP) plus pertussis toxin (PT) (PT+) or with MBP alone (PT-) and compared the differences between the two. Immunohistochemical examinations showed that although the nature of inflammation was essentially the same between the two groups, the proportion of Vbeta8.2(+) T cells in the CNS lesion of PT (+) rats was larger than that of PT (-) rats. Cytokine analysis by competitive PCR revealed that IL-10 mRNA in the lymphoid organ was significantly suppressed in the PT(+) group, whereas levels of IFN-gamma,TNF-alpha and TGF-beta mRNA were insignificantly different after PT administration. In addition, T cells taken from PT (+) rats proliferated well in response to MBP, while those from PT (-) rats showed a marginal response to the same antigen. However, this finding does not indicate the switching of non-encephalitogenic to encephalitogenic T cells upon PT administration because PT (-) rats contained encephalitogenic T cells and/or their precursor cells as revealed by adoptive transfer experiments. Taken together, these findings suggest that suppression of IL-10 by PT administration is the major factor contributing to the exacerbation of EAE in PT(+) rats.
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PMID:Analysis of experimental autoimmune encephalomyelitis induced in F344 rats by pertussis toxin administration. 1068 10

To determine the roles of Fas/Fas ligand (FasL) in autoimmunity, we studied spontaneous and actively induced autoimmune encephalomyelitis in 541 myelin basic protein-specific T cell receptor transgenic mice. We found that spontaneous autoimmune encephalomyelitis, which was initiated by unidentified microbial factors, was dramatically exacerbated in mice carrying Fas or FasL gene mutation. The exacerbation of autoimmune encephalomyelitis was reflected primarily by an increase in disease incidence and a decrease in spontaneous disease recovery. By contrast, actively induced encephalomyelitis, which was initiated by pertussis toxin, was significantly inhibited by Fas or FasL gene mutation. These results suggest that environmental factors that trigger autoimmune disease may determine not only whether disease will occur but also whether an immune molecule such as FasL will promote or inhibit the autoimmune process.
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PMID:Differential roles of Fas ligand in spontaneous and actively induced autoimmune encephalomyelitis. 1086 27

Immunization of common marmosets (Callithrix jacchus) with a single dose of human myelin in CFA, without administration of Bordetella pertussis, induces a form of autoimmune encephalomyelitis (EAE) resembling in its clinical and pathological expression multiple sclerosis in humans. The EAE incidence in our outbred marmoset colony is 100%. This study was undertaken to assess the genetic and immunological basis of the high EAE susceptibility. To this end, we determined the separate contributions of immune reactions to myelin/oligodendrocyte glycoprotein (MOG) and myelin basic protein to the EAE induction. Essentially all pathological features of myelin-induced EAE were also found in animals immunized with MOG in CFA, whereas in animals immunized with myelin basic protein in CFA clinical and pathological signs of EAE were lacking. The epitope recognition by anti-MOG Abs and T cells were assessed. Evidence is provided that the initiation of EAE is based on T and B cell activation by the encephalitogenic phMOG14-36 peptide in the context of monomorphic Caja-DRB*W1201 molecules.
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PMID:Myelin/oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis in common marmosets: the encephalitogenic T cell epitope pMOG24-36 is presented by a monomorphic MHC class II molecule. 1087 88

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

We previously reported that murine experimental allergic encephalomyelitis can be induced by an additional intraperitoneal and intracerebral (i.c.) restimulation in resistant B6 mice after standard immunization with myelin antigens in complete Freund's adjuvant and Bordetella pertussis coadjuvant. Neutrophils infiltrated into perivascular spaces at 12 h, followed by mononuclear cells 24 h after i.c. injection. In this study, we report that the i.c. injection induced the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The kinetic expression of ICAM-1 or VCAM-1 on brain endothelial cells paralleled the infiltration of neutrophils and mononuclear cells, respectively. The infiltrated lymphocytes also expressed very late antigen-4 (VLA-4) molecules. The microvascular endothelial cells were positive for VCAM-1, whereas the surrounding mononuclear cells were VLA-4 positive. Furthermore, we found a unique subpopulation of cells with characteristics of CD4(-)CD8(-)V(beta)8(+) markers. The kinetic studies of this population showed that these cells were transiently depleted from 12 to 24 h after i.c. challenge (before the development of clinical symptoms) in cervical lymph nodes. These CD4(-)CD8(-)V(beta)8(+) cells can be expanded by in vitro culture with myelin basic protein or IL-2. No significant changes of CD4(+)/CD8(+) cells were noted. CD4(+)CD8(-)CD3(+) cells were also found in brain by double histochemical stains and were the major infiltrating cells at 24 or 48 h after i.c. challenge.
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PMID:Infiltrated Cells in Experimental Allergic Encephalomyelitis by Additional Intracerebral Injection in Myelin-Basic-Protein-SensitizedB6 Mice. 1238 77

Experimental autoimmune encephalomyelitis (EAE) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology. EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains. In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin (PT). T cell responses were induced to myelin basic protein. Autoreactive T cells could be totally blocked by the in vitro treatment with CTLA4Ig, a protein that blocks the costimulation of autoreactive T cells. The addition of IL-2 could reverse the inhibition seen in vitro with CTLA4Ig. The effects of inhibition of B7 costimulation were also examined by an analysis of cytokine responses and IL-2 receptor on T cells. CTLA4Ig treatment in vitro reduced the expression of IL-2 receptor on T cells, enhanced T cell apoptosis and decreased the synthesis of IL-2, IFN-gamma and TNF-alpha. CTLA4Ig treatment had no effect on IL-10 synthesis by T cells, a cytokine implicated in the functions of regulatory T cell subsets. Overall, our studies support the rationale of B7 blocking therapies as a potential treatment for models of multiple sclerosis. The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity.
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PMID:Experimental autoimmune encephalomyelitis in the Wistar rat: dependence of MBP-specific T cell responsiveness on B7 costimulation. 1238 44

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


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