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)

There has been considerable interest recently in a genetic component as a causative factor in multiple sclerosis, but the identity of putative susceptibility genes is unknown. In the past decade, the primary amino acid sequences of the four proteins making up 90% of the protein content of central nervous system myelin (proteolipid protein, myelin basic protein, 2',3'-cyclic nucleotide-3'-phosphohydrolase, and myelin-associated glycoprotein) have been determined in several species. Additionally, the structural genes coding for these proteins have been analysed and their human chromosomal localization determined. We have been analysing these genes for possible variants conferring susceptibility to multiple sclerosis. Recent results have shown that cholera and pertussis toxin substrates and low molecular-weight GTP-binding proteins are also present in central nervous system myelin. This implies the presence of signal transducing systems whose purpose is currently obscure. The emerging picture of central nervous system myelin is of a complex dynamic structure composed of many more proteins than was previously thought.
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PMID:Genes coding for proteins in central nervous system myelin. 145 36

We have derived a panel of CD4+, TCR-alpha/beta + T cell clones from SJL (H-2s) mice specific for an encephalitogenic determinant of myelin proteolipid protein (PLP) 139-151 (HSLGKWLGHPDKF). All the clones are Ag specific and IAs restricted, but they show heterogeneity in their ability to induce experimental allergic encephalomyelitis (EAE), i.e., one group induces EAE in naive mice, a second group induces disease only in mice that are pretreated with pertussis and irradiation, whereas a third group is essentially nonencephalitogenic. To determine the basis for this functional heterogeneity, the clones were tested for the expression of adhesion molecules and cytokines and for Ag-specific cytolytic activity. All of the clones expressed comparable levels of LFA-1 and CD44 but lacked expression of Mel 14. However, those clones that induced EAE only in irradiation- and pertussis-treated recipients did not express VLA4. Because pretreatment with pertussis has been suggested to increase permeability of the blood-brain barrier and facilitate migration of T cells into the central nervous system, the absence of VLA4 on this group of clones may account for the need for pretreatment to induce EAE. The nonencephalitogenic clones expressed all of the adhesion molecules tested but were not cytolytic in vitro and failed to produce one or more of the proinflammatory cytokines after Ag-specific stimulation. One nonencephalitogenic clone that did not produce many cytokines on activation with specific Ag, however, could be activated with Con A to express mRNA for most cytokines and this was accompanied by a concomitant change in the encephalitogenic potency of this clone. These results suggest that adhesion molecules and cytokines both play a critical role in the encephalitogenicity of PLP peptide-specific T cell clones. Furthermore, the nonencephalitogenicity of some clones may be related to a defect in Ag-mediated activation.
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PMID:Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T cell clones to mediate experimental allergic encephalomyelitis. 769 46

Linomide (LS-2616, quinoline-3-carboxamide) is a synthetic immunomodulator that stimulates natural killer cell activity and activates several lymphocytic subpopulations in experimental animals and humans. In this study we determined the effect of oral treatment with linomide on the development of experimental autoimmune encephalomyelitis, an animal model for immune-mediated human demyelinating disorders. Experimental autoimmune encephalomyelitis was induced in SJL/J mice and in an outbred strain of rats (Sabra) by subcutaneous injection of spinal cord homogenate in adjuvant followed by inoculation with Bordetella pertussis. Linomide was administered in drinking water, at an estimated dose of 50 to 100 mg/kg/day. None of the linomide-treated mice (0/41) and Sabra rats (0/15) developed any clinical or pathological signs of experimental autoimmune encephalomyelitis, whereas almost all control animals (48/53 and 18/19, respectively) were severely paralyzed and 64.5% died from the disease. Lymphocytes obtained from linomide-treated animals had reduced in vitro proliferative responses to guinea pig myelin basic protein, proteolipid protein of the myelin, and tuberculin-purified protein derivative, unlike antigen-independent proliferation which was rather unaffected. Natural killer cell activity (tested by a cytotoxic assay on radiolabeled YAC-1 target cells) was significantly enhanced in mice treated with linomide. Our results indicate that modulation of the immune system with linomide leads to complete inhibition of experimental autoimmune encephalomyelitis in the absence of systemic immunosuppression. Linomide could therefore be of use in future clinical trials for the treatment of human autoimmune demyelinating disorders.
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PMID:Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide. 823 57

Treatment of SJL mice with 400 ng Bordetella pertussis toxin (PT) either in saline or emulsified in incomplete Freund's adjuvant protected the mice against experimental autoimmune encephalomyelitis (EAE) induced 28 days later by a synthetic peptide of myelin proteolipid protein (PLP139-151) in complete Freund's adjuvant. However, treatment with a genetically inactivated pertussis toxin in which the catalytic and NAD-binding sites of the ADP-ribosyltransferase subunit were modified by site-directed mutagenesis was without effect. In vitro, lymphocyte proliferation was considerably enhanced by both the native and the inactivated toxin, at concentrations of 0.1-1 microgram/ml. However, strong inhibition of proliferation was also observed with the native toxin only, at concentrations that were two to three orders of magnitude lower than that required for the mitogenic effect (0.1-1 ng/ml). The inhibition of proliferation was detectable in the case of high-background proliferation, after stimulation with antigen (PLP139-151) or purified protein derivative of Mycobacterium tuberculosis), or with anti-CD3 monoclonal antibody, but not after stimulation with concanavalin A or phorbol esters and Ca2+ ionophore. These results suggest that the inhibitory effect of PT operates by interfering selectively with a T cell receptor-dependent signaling pathway. The biological significance of the in vitro inhibitory effect of PT was demonstrated by a considerable decrease and/or delay in the ability of lymphocytes grown with PLP139-151 and low concentrations of PT to transfer EAE to naive recipients.
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PMID:Native, but not genetically inactivated, pertussis toxin protects mice against experimental allergic encephalomyelitis. 864 Aug 62

B7-1 and B7-2 are well characterized costimulatory ligands on Ag presentation cells for the CD28 and CTLA4 receptors on T cells. The fusion protein CTLA4Ig can block this interaction and prevent specific T cell activation. The development of fatal CD4+ T cell-mediated experimental allergic encephalomyelitis (EAE) in susceptible female Lewis rats was optimized by immunization with 20 mg of guinea pig spinal cord homogenate in CFA on day 0 with three doses of 1 microgram pertussis toxin given i.v. on days 0, 3, and 7. This immunization regimen uniformly resulted in the development of severe clinical neurologic signs of EAE with 100% mortality by day 17 postimmunization. Treatment with 0.5 mg/dose of rhCTLA4-Ig on days - 2, 0, 3, 6, 9, 12, 15 and 18 significantly decreased the incidence, delayed the onset, and reduced the severity of clinical EAE (p = 0.0002 vs control by the Mann-Whitney U test) enough to completely prevent fatal EAE, whereas treatment with control human IgG had no effect. Histologically, perivascular neutrophilic infiltrates were also dramatically decreased in the spinal cords of animals treated with CTLA4 but not in those treated with control human IgG. The proliferative response to encephalitogenic Ags (guinea pig myelin basic protein and proteolipid protein) by lymph node cells from animals immunized with guinea pig spinal cord 10 days before was also significantly suppressed in vitro by CTLA4Ig (1 microg/ml). However, the protective effect of CTLA4Ig could be completely prevented by the daily i.p. administration, from day 0 to 10, of exogenous human rIL-2 (180,000 IU). These results indicate a critical requirement of the costimulatory B7/CD28 pathway early in the development of CD4+ T cell-mediated EAE in the rat.
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PMID:Inhibition by CTLA4Ig of experimental allergic encephalomyelitis. 864 42

Using experimental allergic encephalomyelitis, EAE, as a model for the study of autoimmune demyelinating disease in the CNS, previous studies have indicated that spread may occur with respect to the specificity of T cell responses during disease. This phenomenon, known as epitope spreading, is central to therapeutic strategies in multiple sclerosis (MS). However, in EAE, the clinical course, neuropathology and immunopathogenesis vary depending upon host factors and the method of disease induction. Since passive EAE in SJL/J mice resembles MS clinically and neuropathologically, this model was chosen to study the immune phenomenon of epitope spreading. T cells specific for whole 18.5 kDa MBP were used to initiate disease since MBP or one of its naturally occurring cleavage fragments may initiate a more physiological immune response than one generated to an artificially designed synthetic peptide. While a progressive increase in T cell responsiveness specific for the immunodominant MBP 87-106 region was observed during disease, there was no evidence of either intermolecular epitope spreading to the immunodominant region of proteolipid protein (PLP) 139-151 or of intramolecular epitope spreading to the exon 2 encoded region of MBP, which is spliced out of 18.5 kDa MBP. In addition there was no shift in immunodominance toward the subdominant MBP 16-35 region during disease. In contrast during active EAE induced by MBP, epitope spreading to the immunodominant epitope of PLP, 139-151, was observed. These data demonstrate that immune responses generated during passive versus active EAE may differ, and suggest that significant epitope spreading does not occur in chronic relapsing demyelinating disease initiated with T cells specific for whole MBP in the absence of exogenous antigen, complete Freund's adjuvant and pertussis. Implications of these findings with regard to epitope spreading in MS are discussed.
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PMID:Epitope spreading occurs in active but not passive EAE induced by myelin basic protein. 889 18

The nature of the autoimmune T cell response to myelin oligodendrocyte glycoprotein (MOG), recently recognized as a potential target antigen in multiple sclerosis (MS), has not yet been characterized, in contrast to the T cell reactivity to other potential target antigens in MS such as myelin basic protein and proteolipid protein. Here, we show that the encephalitogenicity of the recombinant Ig-like domain of human MOG is associated, in H-2 b mice, with an immunodominant T cell reactivity against a single region of MOG spanning amino acids 35-55, accounting for the previously reported strong encephalitogenic activity of pMOG 35-55. A single injection of pMOG 35-55 with or without administration of pertussis toxin was sufficient to induce severe clinical experimental autoimmune encephalomyelitis (EAE) in H-2 b mice. Encephalitogenic pMOG 35-55-specific T cell lines derived from C3H.SW (V beta b) mice were diverse in their TCR V beta gene usage (V beta 1, V beta 6, V beta 8 and V beta 15), although V beta 8.2 was most predominantly expressed (48%). However, V beta 8 + T cells may only be part of the encephalitogenic MOG-specific T cell repertoire in H-2 b mice, as demonstrated by the susceptibility of C57L (V beta a) mice to disease induced by pMOG 35-55. Encephalitogenic T cell lines from V beta a mice were also diverse in their TCR V beta gene usage (V beta 1, V beta 2, V beta 6, V beta 14 and V beta 16). Such a heterogeneous TCT V beta gene expression by pMOG 35-55/I-A b-reactive T cells from both V beta a and V beta b H-2 b mice suggested multiple epitopes within pMOG 35-55. Analysis of the pattern of reactivity by pMOG 35-55-reactive T cells to a set of truncated peptides was not commensurate with independent nested epitopes, but revealed a requirement for recognition of a core sequence, YRSPFSRVV (pMOG 40-48). However, optimal stimulation was obtained with longer peptides, with each additional amino acid flanking either the N or the C terminus differentially increasing the stimulatory capacity of pMOG 40-48. Nonetheless, pMOG 40-48 was the minimal encephalitogenic epitope for both V beta a and V beta b mice. Thus, the T cell reactivity against the immunodominant encephalitogenic region of MOG is characterized by a diverse V beta gene usage and a requirement for the same core epitope. This pattern of reactivity may favor epitope-directed, rather than TCR-targeted, approaches to immunospecific therapy for MOG-related autoimmune disease.
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PMID:Delineation of the minimal encephalitogenic epitope within the immunodominant region of myelin oligodendrocyte glycoprotein: diverse V beta gene usage by T cells recognizing the core epitope encephalitogenic for T cell receptor V beta b and T cell receptor V beta a H-2b mice. 889 62

Experimental autoimmune encephalomyelitis (EAE) is an animal model for human multiple sclerosis (MS). Similar to MS patients, EAE animals can exhibit chronic or relapsing, remitting paralysis; leukocyte infiltration of the central nervous system (CNS); and breakdown of the blood-brain barrier (BBB), allowing access to serum components. EAE pathology in rodents is generally thought to progress from the spinal cord to the more rostral brain. This common notion is based on numerous reports on the severity and progression of cellular infiltration and BBB breakdown during the course of disease. We studied opening of the BBB in EAE mice immunized to the proteolipid protein (PLP) peptide, PLP 139-151, with or without the use of pertussis toxin. Peripherally injected rabbit immunoglobulin G showed significant penetration through a compromised BBB in EAE mice and was observed throughout the parenchyma as well as intracellularly in multiple neuronal types. Results demonstrate the novel finding that the cerebellar BBB is dramatically and briefly comprised, even before breakdown of the BBB in the thoracolumbar spinal cord and prior to symptomatic disease. The demonstration of susceptibility in the cerebellum provides an important target for studying the factors predisposing certain CNS regions to autoimmune-related compromise of the BBB, such as MS.
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PMID:Comparison of the timing of acute blood-brain barrier breakdown to rabbit immunoglobulin G in the cerebellum and spinal cord of mice with experimental autoimmune encephalomyelitis. 1113 50

Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. We developed a novel intravital microscopy model to directly analyze through the skull the interactions between lymphocytes and the endothelium in cerebral venules of mice. No adhesive interactions were observed between lymphocytes and the nonactivated endothelium in the cerebral microcirculation. When brain venules were activated by pretreating mice with TNF-alpha or LPS, proteolipid protein 139-151 autoreactive T lymphocytes rolled and arrested; notably, only a few peripheral lymph node cells rolled and firmly adhered. Abs anti-P-selectin glycoprotein ligand-1 and anti-E- and P-selectin blocked tethering and rolling of autoreactive lymphocytes, suggesting that P-selectin glycoprotein ligand-1/endothelial selectins are critical in the recruitment of lymphocytes in inflamed brain venules. E- and P-selectin were expressed on cerebral vessels upon in vivo activation and had a patchy distribution during the preclinical phase of active and passive experimental autoimmune encephalomyelitis. LFA-1/ICAM-1 and alpha(4) integrins/VCAM-1 supported rolling, but were not relevant to rolling velocity. Firm arrest was mainly mediated by LFA-1 and ICAM-1. Pretreatment of autoreactive lymphocytes with pertussis toxin blocked integrin-dependent arrest, implicating a requirement for G(i) protein-dependent signaling in vessels from nonlymphoid districts. In conclusion, our data unveils the molecular mechanisms controlling the recruitment of autoreactive lymphocytes in inflamed cerebral vessels and suggest new insights into the pathogenesis of autoimmune inflammatory diseases of the CNS.
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PMID:Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors. 1182 30

Chronic relapsing/remitting experimental autoimmune encephalomyelitis (EAE) can be induced in 8-week-old female SJL/J(H-2) mice via inoculation with the p139-151 peptide of myelin proteolipid protein (PLP), Mycobacterium tuberculosis (MT), complete Freund's adjuvant (CFA), and Bordatella pertussis. EAE is a relevant preclinical model of MS that incorporates several aspects of the clinical disease. Chief among these are the inflammatory mediated neurological deficits. While the impact of localized spinal cord demyelination on neurotransmission has been modeled successfully, relatively little work has been done with spinal cord from animals with EAE. The goal of this study was to assess the utility of a grease-gap tissue bath methodology in the detection of transmission deficits in EAE spinal cord tissue. Spinal cords removed from EAE mice at different phases of the neurological deficit were assessed for their response to both lumbar and sacral application of one of several depolarizing agents (veratridine, potassium chloride [KCl], (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]). The main finding of this study is that transmission deficits were detected in EAE mice at the onset of the neurological deficits. They were sustained for a period of approximately 2 to 3 weeks post disease onset followed by a gradual recovery of group function. The other finding is that there is a decrease in the latency to achieve AMPA-mediated depolarization in sacral spinal cord that is independent of the magnitude of the depolarization response. These results suggest that this methodology can be utilized to assess sensory and motor deficits in spinal cord from EAE animals.
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PMID:An electrophysiological model of spinal transmission deficits in mouse experimental autoimmune encephalomyelitis. 1456 7


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