Analysis of the Role of<i>Bphs/Hrh1</i>in the Genetic Control of Responsiveness to Pertussis Toxin

Gao, Jian Feng; Call, Stanford B.; Fillmore, Parley D.; Watanabe, Takeshi; Meeker, Nathan D.; Teuscher, Cory

doi:10.1128/iai.71.3.1281-1287.2003

Cited by 13 publications

(23 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A). Bphs/Hrh1 does not regulate sensitivity to PTX (27), indicating that differences observed were not attributable to ineffective PTX intoxication. Thus, contrary to the current dogma, the results obtained in our model system show that H 1 R overexpression in endothelial cells, in fact, negatively regulates BBB permeability, suggesting that H 1 R signaling in endothelial cells may be important in the maintenance of CNS barrier integrity.…”

Section: Resultsmentioning

confidence: 99%

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Lu¹,

Diehl²,

Noubade³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B. pertussis-induced histamine sensitization (Bphs) T he blood-brain barrier (BBB) involves endothelial cells that line the blood vessels of the central nervous system (CNS) and the tight junction protein complexes between these endothelial cells. The BBB thereby acts as a physical and metabolic barrier by separating the vasculature from the parenchyma of the CNS (1). Breakdown of the BBB is associated with the onset and pathogenesis of multiple sclerosis (MS), a degenerative, demyelinating, inflammatory disease of the CNS (2). In MS and its autoimmune model, experimental autoimmune encephalomyelitis (EAE), activated T cells cross the BBB into the perivascular space of the CNS, causing damage to neurons (2). Surveillance of the CNS by T cells does occur (3), but the paucity of leukocytes found in the CNS under noninflammatory conditions suggests that extravasation of cells across the BBB is tightly regulated. Therefore, identifying factors that modulate BBB permeability may be of therapeutical value in treating inflammatory demyelinating diseases of the CNS.Bordetella pertussis-induced hypersensitivity to histamine (Bphs/ Bphs) is a genetically controlled intermediate phenotype associated with susceptibility to EAE (4). Bphs is a state wherein mice are rendered highly susceptible to histamine after a preceding injection of B. pertussis toxin (PTX) (5). Bphs-susceptible strains of mice die within 30 min after histamine challenge, presumably attributable to hypotensive and hypovolemic shock. The cells targeted during Bphs are not known. Histamine has also been implicated in the pathophysiology of MS and EAE. Increased tissue levels of histamine correlate with the onset of EAE (6-8). Mast cells, the major source of histamine (9), are present in MS lesions (10-12), and evidence of mast cell activation is found in the cerebrospinal fluid (CSF) of patients who have MS (13). In mice, mast cells (14) and their activation (15) are required for early EAE onset and maximal disease severity.The effects of histamine are mediated by four surface histamine receptors: H 1 R, H 2 R, H 3 R, and H 4 R (16). H 1 R protein and mRNA are highly expressed in MS lesions (17), and H 1 antihistamines reduce EAE in mice and rats (17,18). In patients with MS, the use of sedating H 1 antihistamines is correlated with decreased disease incidence and amelioration of symptoms (19,20). Our laboratory has shown that susceptibility to Bphs and EAE requires expression of Hrh1, the gene encoding H 1 R (21).Expression of H 1 R on T cells is required for their full encephalitogenic potential (22), but the contribution of H 1 R signaling in other cell types to the pathogenesis of EAE has not been formally addressed. In this study, w...

show abstract

Section: Resultsmentioning

confidence: 99%

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Lu¹,

Diehl²,

Noubade³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…phenotypes, including blood-brain barrier permeability, antigen presentation, and delayed-type hypersensitivity responses (13,35). To assess whether H 1 R signaling in CD4 + T cells influences EAE by regulating encephalitogenic Th1 responses, we examined the susceptibility of H1RKO and H1RKO-Tg mice to EAE using the classical MOG 35 Analysis of EAE-associated clinical quantitative trait variables (37) revealed that the mean day of onset, cumulative disease score, number of days affected, overall severity index, and peak score were significantly different among the strains immunized with either MOG 35-55 -CFA plus PTX or 2× MOG 35-55 -CFA (Table 1).…”

Section: H 1 R Signaling Directly In Cd4 + T Cells Regulates Encephalmentioning

confidence: 99%

“…To assess whether H 1 R signaling in CD4 + T cells influences EAE by regulating encephalitogenic Th1 responses, we examined the susceptibility of H1RKO and H1RKO-Tg mice to EAE using the classical MOG 35 Analysis of EAE-associated clinical quantitative trait variables (37) revealed that the mean day of onset, cumulative disease score, number of days affected, overall severity index, and peak score were significantly different among the strains immunized with either MOG 35-55 -CFA plus PTX or 2× MOG 35-55 -CFA (Table 1). Bonferroni corrected posthoc multiple comparisons for each trait variable revealed that the values were not significantly different among WT, HIRKO-Tg1, and HIRKO-Tg3 mice, all of which were significantly greater than those in H1RKO mice.…”

Section: H 1 R Signaling Directly In Cd4 + T Cells Regulates Encephalmentioning

confidence: 99%

Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice

Noubade¹,

Milligan²,

Zachary³

et al. 2007

J. Clin. Invest.

Self Cite

115

View full text Add to dashboard Cite

“…Only 2.5 g of pertussis toxin is needed to kill susceptible strains of mice (13), and it is likely that a higher rate of secretion would be counterproductive to the organism's survival.…”

mentioning

confidence: 99%

Temporal Expression of Pertussis Toxin and Ptl Secretion Proteins byBordetella pertussis

Rambow-Larsen

Weiss

2004

J Bacteriol

View full text Add to dashboard Cite

Pertussis toxin is an AB 5 toxin comprised of protein subunits S1 through S5. The individual subunits are secreted by a Sec-dependent mechanism into the periplasm, where the toxin is assembled. The Ptl type IV secretion system mediates secretion of assembled toxin past the outer membrane. In this study, we examined the time course of protein expression, toxin assembly, and secretion as a function of the bacterial growth cycle. Logarithmic growth was observed after a 1-h lag phase. Secreted toxin was first observed at 3 h. Secretion continued throughout the logarithmic growth phase and decreased as the culture entered the stationary phase after about 24 h. On a per cell basis, toxin secretion occurred at a constant rate of 3 molecules/min/cell from 2 to 18 h. More of toxin subunits S1, S2, and S3 were produced than were secreted, resulting in periplasmic accumulation. Periplasmic S1, S2, and S3 were found to be soluble in the periplasm, as well as membrane associated. About one-half of the periplasmic S1, S2 and S3 subunits were incorporated into holotoxin. Secretion component PtlF was present at a low level at time zero, and the level increased between 2 and 24 h from 30 to 1,000 molecules per cell; however, the initial level of PtlF, 30 molecules per cell, supported maximal secretion. The accumulation of both periplasmic toxin and secretion components suggests that translation rates exceed the rate of secretion and that secretion, not toxin and Ptl complex assembly, is rate limiting.Pertussis toxin is an AB 5 toxin comprised of the products of five genes, S1 through S5 (25, 27). The A subunit of the toxin is the S1 polypeptide, while the pentameric B subunit is comprised of S2, S3, S4, and S5, assembled in a ratio of 1:1:2:1 (36). Pertussis toxin is secreted past the outer membrane of Bordetella pertussis by a type IV secretion system comprised of the products of the nine ptl (for "pertussis toxin liberation") genes (8,10,42). The ptl genes are located immediately downstream of the pertussis toxin genes (42) and are transcribed from the same promoter (2, 18, 31).It is not known how many secretion complexes are present in one bacterium during active secretion, nor is the stoichiometry of the proteins in the complex known. The structures of other type IV systems, such as the Agrobacterium tumefaciens virB system (11,38,40), which secretes a tumerogenic T-DNA and effector proteins into host plant cells, and the P-plasmid tra conjugation genes (23), have been more thoroughly studied than the Ptl system. The extensive similarity suggests that the Ptl proteins also form a large complex spanning both the inner and outer membranes. Nevertheless, the Ptl secretion system and the DNA transport systems have substantially different substrates and functions. The most intriguing difference is that the same basic machinery transports protein-coated DNA between the cytoplasm of two cells for the conjugation systems or a periplasmic protein complex across the outer membrane in the case of the Ptl system. Functionally, the DNA t...

show abstract

Analysis of the Role ofBphs/Hrh1in the Genetic Control of Responsiveness to Pertussis Toxin

Cited by 13 publications

References 41 publications

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice

Temporal Expression of Pertussis Toxin and Ptl Secretion Proteins byBordetella pertussis

Contact Info

Product

Resources

About

Analysis of the Role ofBphs/Hrh1in the Genetic Control of Responsiveness to Pertussis Toxin

Cited by 13 publications

References 41 publications

Endothelial histamine H 1 receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Endothelial histamine H 1 receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice

Temporal Expression of Pertussis Toxin and Ptl Secretion Proteins byBordetella pertussis

Contact Info

Product

Resources

About

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis