The relative involvement of Th1 and Th2 associated immune responses in the expulsion of a primary infection of Heligmosomoides polygyrus in mice of differing response phenotype

T helper cell (Th1 and Th2) associated responses were examined following a primary infection with the gastrointestinal nematode Heligmosomoides polygyrus in five inbred strains of mice with different resistance phenotypes. Levels of (i) mast cell protease, (ii) specific IgE, (iii) nitric oxide and (iv) specific IgG2a, as markers of Th2 and Th1 associated responses, respectively, were determined in sera and intestinal fluids and correlated with worm burdens. The ‘fast’ responder (resistant) strains SWR and SJL produced strong Th2 and Th1 associated responses respectively in a mutually exclusive fashion. The F1 hybrid(SWR £ SJL) F1, showed rapid expulsion of the parasite and expressed both intense Th1 and Th2 responses, suggesting synergism between Th1 and Th2 activity in these mice. The results indicate that both Th2 and Th1 responses operate in mice following a primary infection with H. polygyrus and that each Th response may be involved to a greater or lesser degree within certain strains. Resistance to H. polygyrus was found to correlate only to the intensity of either the gut-associated mastocytosis or nitric oxide production in these strains but not to either specific IgE or IgG2a titres. Chronic infections in the ‘slow’ response phenotype mouse strains CBA and C57BL/10, were associated with both poor Th2 and poor Th1-associated responses attributed to a general parasite-mediated immunosuppression of the host immune response to infection

Response heterogeneity of human macrophages to ATP is associated with P2X7 receptor expression but not to polymorphisms in the P2RX7 promoter.

A region 2 kb upstream of exon 1 of the P2X7 gene was sequenced using DNA from nine healthy individuals who exhibited three different ATP response phenotypes (i.e. high, low and interferon gamma-inducible). Five single nucleotide polymorphisms were identified within the nine donor promoter sequences but none were associated with a specific ATP response phenotype. A P2X7 loss of function polymorphism (1513 in exon 13) was also screened for within donor DNA but no response associations were identified. ATP response phenotype was positively associated with P2X(7) receptor expression, as assessed by flow cytometry, but not with any identified receptor or promoter gene polymorphisms

Deregulated production of protective cytokines in response to candida albicans infection in patients with chronic mucocutaneous candidiasis

Patients with chronic mucocutaneous candidiasis (CMC) are selectively unable to clear the yeast Candida, which results in persistent debilitating infections affecting the skin, nails, and mucous membranes. The underlying defect is unknown. Recent animal studies highlighted the importance of type 1 cytokines in protection against Candida, and previous work suggested that CMC patients may exhibit altered cytokine production in response to Candida. Based on these findings, in this study we investigated cytokine production in CMC patients by assessing a range of inflammatory, anti-inflammatory, type 1, and type 2 cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-6, IL-10, IL-12, gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α]) in whole-blood cultures in response to five different fractions of Candida albicans (carbohydrate, purified mannan, and protein-rich fractions, etc.), as well as non-Candida antigens. Our results demonstrate that cytokine production is deregulated in a Candida-specific way for some cytokines (IL-2, IL-10), is deregulated more generally for other cytokines (IL-12, IL-6, IFN-γ), and is not markedly altered for still other cytokines (TNF-α, IL-4, IL-5). The most notable finding in CMC patients was the markedly impaired production of IL-12 in parallel with dramatically increased levels of IL-6 and IL-10 that occurred selectively in response to Candida. These results suggest that patients with CMC have impaired production of type 1-inducing cytokines (possibly a macrophage or dendritic cell defect?), which could result in an inability to mount protective cell-mediated responses and a failure to clear Candida. Continued tissue damage and inflammation may trigger production of high levels of inhibitory cytokines, such as the IL-10 production seen in our study, which would further reduce production of type 1-inducing cytokines in a positive feedback loop leading to persistent infection