CCL5 regulation of mucosal chlamydial immunity and infection

<p>Abstract</p> <p>Background</p> <p>Following genital chlamydial infection, an early T helper type 1 (Th1)-associated immune response precedes the activation and recruitment of specific Th1 cells bearing distinct chemokine receptors, subsequently leading to the clearance of <it>Chlamydia</it>. We have shown that CCR5, a receptor for CCL5, is crucial for protective chlamydial immunity. Our laboratory and others have also demonstrated that CCL5 deficiencies found in man and animals can increase the susceptibility and progression of infectious diseases by modulating mucosal immunity. These findings suggest the CCR5-CCL5 axis is necessary for optimal chlamydial immunity. We hypothesized CCL5 is required for protective humoral and cellular immunity against <it>Chlamydia</it>.</p> <p>Results</p> <p>The present study revealed that CCR5 and CCL5 mRNAs are elevated in the spleen, iliac lymph nodes (ILNs), and genital mucosa following <it>Chlamydia muriduram </it>challenge. Antibody (Ab)-mediated inhibition of CCL5 during genital chlamydial infection suppressed humoral and Th1 > Th2 cellular responses by splenic-, ILN-, and genital mucosa-derived lymphocytes. Antigen (Ag)-specific proliferative responses of CD4⁺T cells from spleen, ILNs, and genital organs also declined after CCL5 inhibition.</p> <p>Conclusion</p> <p>The suppression of these responses correlated with delayed clearance of <it>C. muriduram</it>, which indicate chlamydial immunity is mediated by Th1 immune responses driven in part by CCL5. Taken together with other studies, the data show that CCL5 mediates the temporal recruitment and activation of leukocytes to mitigate chlamydial infection through enhancing adaptive mucosal humoral and cellular immunity.</p

Epistemic justification and epistemic luck

Among epistemologists, it is not uncommon to relate various forms of epistemic luck to the vexed debate between internalists and externalists. But there are many internalism/externalism debates in epistemology, and it is not always clear how these debates relate to each other. In the present paper I investigate the relation between epistemic luck and prominent internalist and externalist accounts of epistemic justification. I argue that the dichotomy between internalist and externalist concepts of justification can be characterized in terms of epistemic luck. Whereas externalist theories of justification are incompatible with veritic luck but not with reflective luck, the converse is true for internalist theories of justification. These results are found to explain and cohere with some recent findings from elsewhere in epistemology, and support a surprising picture of justification, on which internalism and externalism are complementary rather than contradictory positions

Second-hand smoke increases bronchial hyperreactivity and eosinophilia in a murine model of allergic aspergillosis.

Involuntary inhalation of tobacco smoke has been shown to aggravate the allergic response. Antibodies to fungal antigens such as Aspergillus fumigatus (Af) cause an allergic lung disease in humans. This study was carried out to determine the effect of environmental tobacco smoke (ETS) on a murine model of allergic bronchopulmonary aspergillosis (ABPA). BALB/c mice were exposed to aged and diluted sidestream cigarette smoke to simulate 'second-hand smoke'. The concentration was consistent with that achieved in enclosed public areas or households where multiple people smoke. During exposure, mice were sensitized to Af antigen intranasally. Mice that were sensitized to Af antigen and exposed to ETS developed significantly greater airway hyperreactivity than did mice similarly sensitized to Af but housed in ambient air. The effective concentration of aerosolized acetylcholine needed to double pulmonary flow resistance was significantly lower in Af + ETS mice compared to the Af + AIR mice. Immunological data that supports this exacerbation of airway hyperresponsiveness being mediated by an enhanced type 1 hypersensitivity response include: eosinophilia in peripheral blood and lung sections. All Af sensitized mice produced elevated levels of IL4, IL5 and IL10 but no IFN-gamma indicating a polarized Th2 response. Thus, ETS can cause exacerbation of asthma in ABPA as demonstrated by functional airway hyperresponsiveness and elevated levels of blood eosinophilia