Toll-like Receptor 3 (TLR3) Ligand Exacerbates Pre-existing Allergic Airway Inflammation in Murine Asthma Model

S114 Abstracts

Trichophyton Allergy: Role in Asthma, Rhinitis and Urticaria/Angioedema R. D. R. Oliveira1, M. Thiesen1, F. R. Oliveira1, A. S. Zampolo1, M. C. Rodrigues1, L. R. Roberti2, L. Arruda1; 1Medicine, School of Medicine of Ribeirão Preto-University of São Paulo, Ribeirão Preto, BRAZIL, 2Pediatrics, School of Medicine of Ribeirão Preto-University of São Paulo, Ribeirão Preto, BRAZIL. RATIONALE: The association of skin and nail infections with dermatophyte fungi and allergic diseases including asthma and urticaria/angioedema has been described for over 70 years. Treatment of dermatophyte infections has been shown to decrease allergic symptoms. METHODS: We have evaluated a group of 17 patients aged 27 to 77 years (mean 49 years-old), 65% males, presenting with visible dermatophyte skin/nail infection and positive skin tests to Trichophyton. Thirteen patients (76.5%) were positive on prick testing and 4/17 were positive on intradermal testing only. Eleven patients had asthma (5 severe, 6 mild/ moderate), five had chronic urticaria/angioedema, and one had rhinitis. Total IgE and IgE antibodies to Trichophyton rubrum were measured in sera using the CAP system (Pharmacia). RESULTS: Presence of Trichophyton in cultures and/or direct exam was found in 7/17(41%) of the patients. Total IgE levels ranged from 7.1 to 2428 KU/L (Geometric mean GM 270.3 KU/L). IgE antibodies to Trichophyton were detected in 7/17 patients (41%), ranging from 0.36 to 37.8K U/L. Peripheral blood eosinophil counts were 100 to 2000/mm3 (GM 330/mm3). Among the 17 patients, 5 were allergic only to Trichophyton, and 12 had positive skin tests to other allergens, particularly to Dermatophagoides mites. Patients with asthma presented mean percentage of predicted values of FEV1, FVC, and FEF25-75 of 63.2%, 74.9%, and 45.6%, respectively and mean FEV1/FVC of 67.2%. CONCLUSIONS: IgE antibody responses to Trichophyton antigens may play a role in pathogenesis of asthma, rhinitis and urticaria/angioedema. In a proportion of patients otherwise diagnosed as “intrinsic”, Trichophyton may be the only allergen identified. Funding: FAPESP

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Oral Pathogens and Asthma: A Potential Connection

S. J. Arbes, Jr., E. A. Cohen, M. L. Sever, D. C. Zeldin; NIEHS/NIH, Research Triangle Park, NC. RATIONALE: Recent studies have shown a link between gastrointestinal microflora and asthma. We hypothesize that oral microflora may also be associated with asthma. The objective of this study was to evaluate the association between two oral bacteria associated with periodontal disease and the prevalence of asthma. METHODS: Data were obtained from the third National Health and Nutrition Examination Survey (NHANES III). Levels of immunoglobulin G (IgG) antibodies to Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were quantified by enzyme-linked immunoassays in serum samples from 9385 subjects aged 12 years and older. Asthma was subject-reported, doctor-diagnosed, current asthma. Levels of IgG were reported by NHANES III both continuously and categorically (positive, negative, and equivocal). Odds ratios, adjusted by eight potential confounders and weighted to represent the U.S. population, were estimated with multivariable logistic regression. RESULTS: The prevalence of current asthma was 5.2%. For a one-logunit increase in IgG to P. gingivalis, the adjusted odds ratio for current asthma was 0.42 (95% CI: 0.20-0.86). For A. actinomycetemcomitans, that odds ratio was 0.57 (0.18-1.75). Comparing a positive to a negative IgG response, the adjusted odds ratio for current asthma was 0.51 (0.310.85) for P. gingivalis and 0.59 (0.31-1.12) for A. actinomycetemcomitans. CONCLUSIONS: Consistent with the hygiene hypothesis, an antibody response to oral pathogens is associated with a lower prevalence of current asthma in the U.S. population. Funding: NIEHS/NIH

J ALLERGY CLIN IMMUNOL FEBRUARY 2006

Toll-like Receptor 3 (TLR3) Ligand Exacerbates Pre-existing Allergic Airway Inflammation in Murine Asthma Model H. Nagase1, N. Yamashita2, T. Adachi1, J. Nakano1, K. Ohta1; 1Department of Internal Medicine, Teikyo University, Tokyo, JAPAN, 2Department of Pharmacy, Musashino University, Nishi-Tokyo, JAPAN. RATIONALE: Many clinical investigations have revealed that viral infections cause the exacerbation of asthma. Among various viral components, dsRNA and ssRNA are identified as TLR3 and TLR7/8 ligand, respectively. Based on our previous in vitro findings that TLR3 ligand, poly I: C (dsRNA analogue) could induce the chemokine generation and apoptosis in bronchial epithelial cells, we investigated the in vivo role of TLR3 ligand in exacerbation of experimental asthma. METHODS: A/J mice were sensitized and intranasally challenged with ovalubumin (OVA) and further stimulated by poly I: C intranasally for 3 days. 24 hours after the final treatment, airway hyperresponsiveness (AHR) to acetylcholine was evaluated. Bronchoalveolar lavage (BAL) was performed and differential cell counts, the protein levels of eotaxin, RANTES and MIP2, and the levels of IL-4 and IFN-gamma mRNA in BAL cells were determined. TUNEL assay was also performed for the detection of apoptotic cells. RESULTS: BALF eosinophils was increased by OVA challenge and additional poly I: C stimulation significantly increased BALF eosinophils and lymphocytes. The enhanced AHR induced by OVA challenge was further up-regulated by poly I: C. Although the increased level of BALF eotaxin by OVA challenge was not significantly up-regulated by poly I: C, the level of RANTES was significantly up-regulated. IFN-gamma mRNA in BAL cells and the number of apoptotic cells was also increased by poly I: C. CONCLUSIONS: Although dsRNA is one component of virus, it aggravated various aspects of allergic inflammation and enhanced AHR. TLR3/dsRNA interaction might have a potentially important role in the exacerbation of allergic airway inflammation during viral infection. Funding: Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labour and Welfare

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Infection with Rhinovirus Induces a Systemic IP-10 Response

S. Kakumanu, M. Evans, W. W. Busse, J. E. Gern; Allergy/ Immunology, UW Madison, Madison, WI. RATIONALE: Infection with rhinovirus (RV) could cause asthma exacerbation through direct infection of lower airway tissues, or by causing systemic immune activation. It was recently demonstrated that blood monocytes are primed during experimental infection, although the mechanism for this is unknown. We hypothesized that RV infection induces cytokine responses that enter the circulation and cause systemic immune activation. METHODS: Sixteen RV16-seronegative subjects were evaluated prior to and following inoculation with RV16. Serum, clinical symptom scores and viral shedding (TCID50) data were obtained at baseline and at days 2, 7 and 14 post-inoculation. A microsphere multiplex ELISA (Luminex100) was used to determine the serum concentrations (pg/ml) of nine cytokines (IP-10, MCP-1, TNF-alpha, IL-1beta, IL-5, IL-6, IL-8, IFNalpha and IFN-gamma). RESULTS: IP-10 was detected in serum of all individuals at baseline, and levels were significantly increased two days post-inoculation (mean values 2063 and 5826 pg/mL, p = 0.0004), and diminished to baseline levels by one week after inoculation. Serum IP-10 levels did not correlate with either systemic symptoms or viral shedding data during the peak of the cold. There were no significant changes in levels of the other cytokines in the panel. CONCLUSIONS: RV infection causes a significant, but variable, increase in IP-10 during the acute phase of infection. This increase of serum IP-10 during a time of monocytic stimulation suggests that IP-10 is involved in systemic cell activation during acute infection, and could contribute to the enhancement of preexisting airway inflammation in asthma. Funding: Asthma and Allergic Diseases Research Centers P01 AI50500