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Biomedical subjects

A Saxon

Publications and source records attributed to A Saxon.

At least 19 recordsLinked to original sources
PubMed2001

Effect of diesel exhaust particles and their components on the allergen-specific IgE and IgG1 response in mice.

Increased antigen-specific IgE expression is a hallmark of the allergic response in mice. IgG1 may also be involved. Co-injection of mice with diesel exhaust particles (DEP) and ovalbumin three times over a 2 week period lead to a rapid and marked elevation of ovalbumin-specific IgE, IgG1 and also IgG2a, compared with ovalbumin alone. When DEP were injected 1 day before or after ovalbumin on each occasion, their adjuvant effect was considerably muted, suggesting that the adjuvant effect of DEP is short-lived, or that a physical interaction between ovalbumin and DEP is required. DEP were extracted with methylene chloride. Both the resulting core carbon particles and the organic extract enhanced ovalbumin specific IgE and IgG1 levels. Thus the adjuvant effect of DEP in this model is due both to the physical and the chemical attributes of the particles. The tricyclic hydrocarbons phenanthene (the most prevalent polycyclic aromatic hydrocarbon in DEP) and anthracene were both capable of enhancing antigen-specific IgE and IgG1 production. The phenolic antioxidant, butylated hydroxyanisole, which can affect gene expression via the antioxidant responsive element (ARE), had a lesser effect. Two agonists for the aryl hydrocarbon receptor, 3-methychloranthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin, either were without effect or suppressed the response, suggesting that DEP adjuvancy may not be mediated by this receptor.

Adjuvants, Immunologic↗
PubMed2000

Diesel exhaust as a model xenobiotic in allergic inflammation.

We investigated the effects of diesel exhaust particulates on the human allergic response using in vivo human nasal challenges. Diesel particles and phenanthrene, one of their constituent polyaromatic hydrocarbons, were shown to enhance total allergic antibody (IgE) production, enhance allergen-specific IgE in the presence of allergen, and induce sensitization to a neoantigen.

Animals↗
PubMed2000

In vivo nasal challenge with diesel exhaust particles enhances expression of the CC chemokines rantes, MIP-1alpha, and MCP-3 in humans.

Diesel exhaust particles (DEP) enhance allergic inflammation by increasing in vivo IgE and cytokine production in the human upper respiratory mucosa. CC chemokines have been shown to play an important role in inflammation. We examined whether DEP could alter the production of CC chemokines by cells residing in the human nasal mucosa. At both 6 and 24 h following intranasal DEP challenge, the levels of nasal RANTES, MIP-1alpha, and MCP-3 were significantly elevated compared to baseline. In contrast, DEP did not enhance levels of Eotaxin at any time, demonstrating that the action of DEP was not simply a global effect on all CC chemokines. Challenge with saline resulted in no significant change in expression of any chemokine at any time. Challenge with DEP also resulted in an increase in total cell counts in nasal lavage fluids. Increases in lymphocyte, monocyte/macrophage, and neutrophil cells were observed but there was no change in eosinophil cell numbers. In contrast, there was a significant enhancement of ECP protein levels in washes performed 6 to 24 h after DEP challenge. Elevated specific nasal chemokine expression following exposure to DEP likely participates in the inflammation, cellular infiltration, and increase in IgE observed in the absence of allergen.

Adult↗
PubMed2000

The novel human IgE epsilon heavy chain, epsilon tailpiece, is present in plasma as part of a covalent complex.

Several splice variants of the secreted human epsilon heavy chain have previously been identified by reverse transcription-PCR. The heavy chain of one isoform, IgE tailpiece, differs from the originally identified IgE, IgE classic, by the replacement of the 2 carboxy-terminal amino acids by 8 novel amino acids including a carboxy-terminal cysteine residue. Recombinant human epsilon tailpiece and epsilon classic heavy chains were expressed and secreted as H2L2 monomers in Sp2/0 murine myeloma cells. We have investigated the in vitro function and in vivo occurrence of epsilon tailpiece heavy chains using receptor binding assays, granule release assays, flow cytometry, half-life studies, immunoprecipitation, SDS-PAGE, two-dimensional SDS-PAGE, and Western blotting. IgE tailpiece and IgE classic exhibited similar in vivo half-lives in BALB/c mice, bound the human high- and low-affinity IgE receptors with similar affinities and triggered equivalent levels of high affinity IgE receptor induced degranulation. In humans, IgE classic is present as a 190 kD circulating protein in vivo. In contrast, we found that in plasma epsilon tailpiece was primarily present as part of covalent complexes of approximately 300 and 338 kD. Dissociation of the complexes revealed that two species of epsilon tailpiece heavy chains were present therein and surprisingly, these in vivo derived epsilon tailpiece heavy chains were approximately 5 and 10 kD smaller than the recombinant expressed epsilon tailpiece or epsilon classic heavy chains. These results show that epsilon tailpiece is present in novel covalent complexes in humans.

Animals↗
PubMed2000

Prevalence of IgE to natural rubber latex in unselected blood donors and performance characteristics of AlaSTAT testing.

BACKGROUND: The prevalence of IgE to natural rubber latex (NRL) proteins in the general population remains unsettled, both because of the difficulty of obtaining an unbiased population representative of the general population of the United States and because of concerns about the reproducibility of tests for anti-latex IgE antibodies. Establishing the prevalence in the population is important toward defining the potential risks of persons entering areas where latex exposure may occur. OBJECTIVE: The purposes of this study were to determine the prevalence of IgE to latex in a general population and to assess the performance characteristics of the AlaSTAT microtiter plate test for anti-latex IgE when performed independently by different laboratories. METHODS: One thousand nine hundred and ninety-seven consecutive blood samples obtained from the Oklahoma Blood Institute were assayed independently in three laboratories for IgE to NRL using the FDA-approved AlaSTAT ELISA for IgE to NRL. The group consisted of 56% men and 44% women. Ninety percent were Caucasian, 4% African American, and 6% were "other." RESULTS: The prevalence IgE to NRL between the 3 laboratories varied from 5.4% to 7.6% at the designated cut off of 0.35 kU/L. Examination of results for specific individuals demonstrated >90% agreement between the three sites with the most reproducible results at the Class II cutoff of > or =0.7 kU/L. There was no difference in the percent of positive values at the three laboratories. CONCLUSIONS: There is good agreement between laboratories as to NRL IgE reactive and non-reactive sera using the AlaSTAT test. This report of the largest sample of blood donors confirms earlier reports as to the prevalence of IgE NRL in blood donors.

Antibodies, Anti-Idiotypic↗
PubMed2000

Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate.

BACKGROUND: The frequency of reactions reported to occur after the consumption of monosodium glutamate (MSG) is the subject of controversy. OBJECTIVE: We conducted a multicenter, multiphase, double-blind, placebo-controlled study with a crossover design to evaluate reactions reportedly caused by MSG. METHODS: In 3 of 4 protocols (A, B, and C), MSG was administered without food. A positive response was scored if the subject reported 2 or more symptoms from a list of 10 symptoms reported to occur after ingestion of MSG-containing foods within 2 hours. In protocol A 130 self-selected reportedly MSG-reactive volunteers were challenged with 5 g of MSG and with placebo on separate days (days 1 and 2). Of the 86 subjects who reacted to MSG, placebo, or both in protocol A, 69 completed protocol B to determine whether the response was consistent and dose dependent. To further examine the consistency and reproducibility of reactions to MSG, 12 of the 19 subjects who responded to 5 g of MSG but not to placebo in both protocols A and B were given, in protocol C, 2 challenges, each consisting of 5 g of MSG versus placebo. RESULTS: Of 130 subjects in protocol A, 50 (38. 5%) responded to MSG only, 17 (13.1%) responded to placebo only (P <. 05), and 19 (14.6%) responded to both. Challenge with increasing doses of MSG in protocol B was associated with increased response rates. Only half (n = 19) of 37 subjects who reacted to 5 g of MSG but not placebo in protocol A reacted similarly in protocol B, suggesting inconsistency in the response. Two of the 19 subjects responded in both challenges to MSG but not placebo in protocol C; however, their symptoms were not reproducible in protocols A through C. These 2 subjects were challenged in protocol D 3 times with placebo and 3 times with 5 g of MSG in the presence of food. Both responded to only one of the MSG challenges in protocol D. CONCLUSION: The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, neither persistent nor serious effects from MSG ingestion are observed, and the responses were not consistent on retesting.

Adult↗
PubMed2000

Diesel exhaust particles directly induce activated mast cells to degranulate and increase histamine levels and symptom severity.

BACKGROUND: The ability of combustion products, such as diesel exhaust particles (DEPs), to modulate the immune system has now been firmly established. DEPs can synergize with allergen at the human upper respiratory mucosa to enhance allergen-specific IgE production, initiate a T(H)2 cytokine environment, and even promote primary allergic sensitization. Experiments suggest that these effects result from the initial activation of mast cells to produce IL-4. OBJECTIVE: We sought to demonstrate that in vivo mast cell activation by DEPs plus allergen will also affect the release of classic mast cell mediators and consequently enhance the immediate-phase response. METHODS: Dust mite-sensitive subjects were challenged intranasally with allergen, and symptom scores and histamine levels in nasal wash samples were compared after prechallenge with 0.3 mg of DEPs. RESULTS: If the subjects were first sprayed with DEPs, mean symptom scores rose from 3.7 to 9.9; additionally, only one fifth of the amount of intranasal dust mite allergen was required to induce clinical symptoms. DEPs alone had no effect. The changes in symptoms correlated with histamine levels measured in nasal lavage specimens from these subjects. Although challenge with DEPs alone did not induce histamine release, challenge with both DEPs and allergen resulted in 3-fold higher histamine concentrations than those seen with allergen alone. In contrast, carbon black particles (elemental carbon devoid of chemicals) had no effect. The role of chemicals was confirmed because degranulation of a murine mast cell line by FcepsilonRI cross-linking was increased significantly (by 72%) by the soluble organic chemicals extracted from DEPs. CONCLUSIONS: Overall, these results suggest that exposure to DEPs can enhance the severity of clinical symptoms to allergen by enhancing mast cell degranulation.

Adult↗
PubMed2000

Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study.

Monosodium glutamate (MSG) has a long history of use in foods as a flavor enhancer. In the United States, the Food and Drug Administration has classified MSG as generally recognized as safe (GRAS). Nevertheless, there is an ongoing debate exists concerning whether MSG causes any of the alleged reactions. A complex of symptoms after ingestion of a Chinese meal was first described in 1968. MSG was suggested to trigger these symptoms, which were referred to collectively as Chinese Restaurant Syndrome. Numerous reports, most of them anecdotal, were published after the original observation. Since then, clinical studies have been performed by many groups, with varying degrees of rigor in experimental design ranging from uncontrolled open challenges to double-blind, placebo controlled (DBPC) studies. Challenges in subjects who reported adverse reactions to MSG have included relatively few subjects and have failed to show significant reactions to MSG. Results of surveys and of clinical challenges with MSG in the general population reveal no evidence of untoward effects. We recently conducted a multicenter DBPC challenge study in 130 subjects (the largest to date) to analyze the response of subjects who report symptoms from ingesting MSG. The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, the frequency of the responses was low and the responses reported were inconsistent and were not reproducible. The responses were not observed when MSG was given with food.

Animals↗
PubMed1999

Early IL-4 production driving Th2 differentiation in a human in vivo allergic model is mast cell derived.

IL-4 is central to the formation of IgE and the development of Th2 effector cells, both key features of an allergic response. We have examined IL-4 production early in the formation of an allergic response by using a previously established human in vivo model of allergic rhinitis where allergic subjects are challenged internasally with allergen and the particulate pollutant diesel exhaust particles (DEP). This model is characterized by enhanced IgE production and deviation to a Th2-type cytokine profile in nasal lavage fluid from these subjects. In this model, IL-4 protein and IL-4-positive cells could first be detected 4 h after challenge and maximal production was observed after 18 h. Two-color flow cytometric analysis for the detection of intracellular IL-4 and surface markers was performed on nasal cells recovered 4 h after challenge. At this time, CD117(+) (c-kit+) cells constituted between 65 and 100% of the IL-4(+) cells, while 0-12% of the IL-4(+) cells were CD3 positive. No IL-4(+) CD19/CD20(+) or IL-4(+) CD56(+) cells were detected at 4 h. As the allergic response progressed the primary source of IL-4 changed. At the peak of IL-4 production, 18 h after challenge, CD3(+) comprised the majority of cells staining for intracellular IL-4 (73 to 100%). Thus we show an initial role for cells of the mast cell/basophil lineage residing in the nasal mucosa in the initial production of IL-4, which frames the subsequent immune response by expanding the repertoire of TH2 cytokine-producing cells in the local microvicinity.

Adult↗
PubMed1999

Editorial

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Journal Article↗
PubMed1999

Effect of topical fluticasone propionate on the mucosal allergic response induced by ragweed allergen and diesel exhaust particle challenge.

Glucocorticoids block the local allergic response in a variety of ways. However, studies have also shown that glucocorticoids increase in vitro IgE synthesis and that treatment with corticosteroids may result in elevated serum IgE concentrations. The ability of topical glucocorticoids to modulate the mucosal IgE response has not been elucidated. We studied the effect of topical steroid (fluticasone propionate) treatment on the local allergic antibody response induced by challenge with either allergen or diesel exhaust particles (DEP). A parallel group study was performed with ragweed-allergic subjects, each subject serving as his/her own control. Nasal provocation challenges were performed on three groups. One group received ragweed allergen, another diesel exhaust particles, and the third saline. The study was repeated following 1 week of treatment with intranasal fluticasone propionate. Each group received the same challenge as before. The concentrations of total immunoglobulins (IgE, IgG, IgA, and IgM), anti-ragweed antibody, IgE- and IgA-secreting cells, epsilon (epsilon) mRNA, and cytokine mRNAs (IL-2, -4, -5, -6, TNF-alpha, INF-gamma) were measured in nasal lavages performed before and at various time points after challenge. Treatment with fluticasone propionate for 7 days caused a decrease in the concentrations of nasal IgE protein, IgE-producing cells, total epsilon mRNA, and all the cytokine mRNAs tested. Furthermore, treatment with fluticasone propionate inhibited the production of allergen-specific IgE and cytokine mRNAs following challenge with ragweed antigen. However, fluticasone treatment did not significantly inhibit the enhancement of mucosal IgE production or cytokine mRNAs observed following nasal challenge with DEP. These results indicate that 1-week treatment with topical fluticasone propionate was effective in blocking local effects of allergen exposure but was unable to inhibit the adjuvant-like effect of DEP.

Administration, Intranasal↗
PubMed1999

Nasal challenge with diesel exhaust particles can induce sensitization to a neoallergen in the human mucosa.

BACKGROUND: Diesel exhaust particles (DEPs) increase in vivo IgE and cytokine production at the human upper respiratory mucosa, exacerbating allergic inflammation. OBJECTIVE: We examined the ability of DEP exposure to lead to primary sensitization of humans by driving a de novo mucosal IgE response to a neoantigen, keyhole limpet hemocyanin (KLH). METHODS: Ten atopic subjects were given an initial nasal immunization with 1 mg of KLH followed by 2 biweekly nasal challenges with 100 microg of KLH. Identical nasal KLH immunization was then performed on 15 different atopic subjects, but DEPs were administered 24 hours before each KLH exposure. RESULTS: Exposure to KLH alone led to the generation of an anti-KLH IgG and IgA humoral response, which was detected in nasal fluid samples. No anti-KLH IgE appeared in any subjects. In contrast, when challenged with KLH preceded by DEPs, 9 of the 15 subjects produced anti-KLH-specific IgE. KLH-specific IgG and IgA at levels similar to that seen with KLH alone could also be detected. Subjects who received DEPs and KLH had significantly increased IL-4, but not IFN-gamma, levels in nasal lavage fluid, whereas these levels were unchanged in subjects receiving KLH alone. CONCLUSION: These studies demonstrate that DEPs can act as mucosal adjuvants to a de novo IgE response and may increase allergic sensitization.

Adjuvants, Immunologic↗
PubMed1999

Widespread B29 (CD79b) gene defects and loss of expression in chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia (CLL) is the most prevalent form of leukemia in Western countries, and is characterized by a monoclonal proliferation of primarily immature CD5+ B lymphocytes. The molecular biology of chronic leukemias and lymphomas remains largely unresolved. Surface immunoglobulin (Ig) expression, which is often decreased in CLL, requires the protein product of the B29 gene for translocation of the B cell antigen receptor complex (BCR) to the cell surface and for signal transduction. Because B29 is essential for intracellular assembly and transport of the B cell antigen receptor complex to the cell surface, we postulate that a perturbation in B29 could result in the diminished expression and function of surface Ig in leukemic CLL cells. We have found recurrent aberrations affecting the B29 gene in CLL cells. Analyses of 27 unselected cases of CLL demonstrate that over 75% had low to absent B29 expression which correlated directly to their level of surface Ig expression. Half of these surface B29(low/-) cases had either no or barely detectable levels of B29 mRNA by RNAse protection assay. To date, all of the CLL samples with normal B29 mRNA levels have been found to have point mutations or truncations which would significantly effect the structure and/or function of B29 protein. Strategies directed at correcting these B29 mutations are expected to induce increased Ig surface expression in CLL and may improve the sensitivity of CLL cells to conventional cytotoxic chemotherapy.

Aged↗
PubMed1998

Macrophage activation by polycyclic aromatic hydrocarbons: evidence for the involvement of stress-activated protein kinases, activator protein-1, and antioxidant response elements.

Polycyclic aromatic hydrocarbons (PAH) contained in fossil fuel combustion particles enhance the allergic response to common environmental Ags. A key question is: what are molecular pathways in the immune system by which PAH and conversion products drive allergic inflammation? Circumstantial evidence suggests that macrophages are involved in PAH-induced responses. We demonstrate that a representative PAH, beta-napthoflavone (BNF), and a representative quinone metabolite, tert-butylhydroxyquinone (tBHQ), induce Jun kinase and p38 mitogen-activated protein kinase activities in parallel with the generation of activator protein-1 (AP-1) mobility shift complexes in THP-1 and RAW264.7 macrophage cell lines. Activation of mitogen-activated protein kinases was dependent on generation of oxidative stress, and could be inhibited by N-acetylcysteine. Another genetic response pathway linked to PAH is the antioxidant response element (ARE), which regulates expression of detoxifying enzymes. BNF and tBHQ activated a human ARE (hARE) reporter gene in RAW264.7 cells. Interestingly, bacterial lipopolysaccharide also induced hARE/chloramphenicol acetyltransferase activity. While the hARE core, GTGACTCAGC, contains a consensus AP-1 sequence (underlined), AP-1 was not required for hARE activation. This suggests that PAH and their conversion products operate via ARE-specific transcription factors in the immune system. BNF and tBHQ did, however, induce AP-1 binding to the hARE, while constitutively active Jun kinase interfered in hARE/chloramphenicol acetyltransferase activation. This suggests that AP-1 proteins negatively regulate the hARE. These data establish important activation pathways for PAH in the immune system and provide us with targets to modulate the effect of environmental pollutants on allergic inflammation.

Animals↗