Hyper-IgE syndrome (HIES) is characterized by systemic impaired differentiation of TH17 cells caused by signal transducer and activator of transcription 3 deficiency. Patients with HIES are predisposed to Staphylococcus species infections that affect the lung and skin specifically. Minegishi et al reported in the Journal of Experimental Medicine (2009;206:1291-301) a mechanism that explains why patients with HIES have lung- and skin-localized Staphylococcus species infections rather than systemic infections. The authors determined that epithelial cells in patients with HIES were highly dependent on interaction between TH17 cytokines and typical proinflammatory cytokines to induce antistaphylococcal innate defenses, which is in contrast to other constituent cells that required only proinflammatory cytokines.
…a mechanism that explains why HIES patients have lung- and skin-localized Staphylococcus infections
Glucocorticoid-suppressive effects are mediated by glucocorticoid receptor activation, initiating nuclear translocation and interaction with glucocorticoid-responsive elements in sensitive genes. Corticosteroids also downregulate inflammatory cytokine gene expression by means of inhibition of nuclear factor kB. Yet their known effect on TH2 cytokine suppression is puzzling because the genes encoding IL-4, IL-5, and IL-13 do not have glucocorticoid-sensitive elements in their promoter regions and are not wholly regulated by nuclear factor kB. Based on previous research that linked corticosteroid suppression of IL-5 and IL-13 to GATA-3, Maneechotesuwan and colleagues (PLos Med 2009;6:e1000076; published online May 19, 2009) reported that corticosteroids disrupted 2 GATA-3 activation pathways by competing with GATA-3 for the nuclear factor importin α and downregulating GATA-3 phosphorylation, which is required for GATA-3 translocation. The authors also reported that importin α binds preferentially to corticosteroids, enhancing steroid suppression of TH2 gene transcription.
We asked Dr Peter J. Barnes, senior author on the article, to comment on this research: “The… mechanisms of action of corticosteroids described in our article might explain why corticosteroids are so effective in treating allergic inflammation. The… pathways described, which regulate GATA-3 activity, might also lead to novel ways of treating allergic diseases in the future.”
A report by Mahn et al (Proc Natl Acad Sci 2009;106:10775-80) identified a faulty sarco/endoplasmic reticulum Ca2+ pump (SERCA2) in airway smooth muscle of asthmatic subjects. The impaired pump function resulted in lower sarcoplasmic stores of Ca, as well as increased proliferation and secretory function of airway smooth muscle. The authors reported that decreased expression of SERCA2 was correlated to asthma severity.
We asked Dr Tak Lee, senior author on the article, to comment on this research: “These findings provide a vital clue about the mechanism of asthmatic airway remodeling, which is widely believed to contribute to the chronicity of the disease. We hope that it will eventually inform new approaches to the creation of effective new treatments for severe asthma.”
Kawakami et al (J Exp Med 2009;206:1219-25) uncovered an explanation for susceptibility to vaccinia infection in patients with eczema. High levels of TH17, which are associated with acute inflammation in eczema, inhibited the natural killer (NK) cell activity required to mount a defense against vaccinia virus insult in a murine model of eczema vaccinatum. Patients with atopic dermatitis have constitutively low levels of NK cell activity and increased levels of TH17, which establishes a receptive environment for vaccinia virus proliferation.
We asked Dr Yuko Kawakami, lead author on the article, and Dr Toshiaki Kawakami, the senior author, to comment on this research: “This study has revealed the importance of IL-17A–mediated suppression of NK cell activity in vaccinia virus–induced… severe skin lesions in mice.… It not only established a mouse model of eczema vaccinatum but also linked the vulnerability of patients with atopic dermatitis to eczema vaccinatum to the… observation that patients with atopic dermatitis have reduced NK cell activity. Our findings also suggest a novel aspect of TH17 cell biology.”
A new member of the IL-1 family of cytokines, IL-33, has been identified as a strong inducer of anaphylaxis in mice and is associated with anaphylaxis in human subjects. Pushparaj et al (Proc Natl Acad Sci 2009;106:9773-8) demonstrated that IL-33 requires the effect of IgE upregulation of its receptor, ST2, on mast cells to illicit rapid degranulation. The authors reported that IL-33 activation resulted in massive intracellular Ca influx through a novel Ca pathway that involved phospholipase D and sphingosine kinase. The anaphylactic effect was observed to be allergen independent.
We asked Dr Alirio Melendez, senior author on the article, to comment on this research: “IL-33 is a relatively new discovery, and its part in anaphylaxis (or any pathology) has not been greatly understood. Our study suggests that patients with the most severe anaphylactic reactions have very high levels of IL-33 in their systems.… without the IL-33 molecule, the allergic reaction experienced would be far less severe, greatly reducing the risk of death. Thus the breakthrough could lead to a huge reduction in the number of fatal cases of anaphylactic shock across the world.”
A new protease, Mina, was characterized by Okamoto et al recently in Nature Immunology (published online June 28, 2009). The authors examined the mechanisms that contribute to the tendency of naive CD4+ T cells to differentiate into IL-4–producing TH2 cells, which is called TH2 bias. Using genetic profiling, the researchers identified Mina as the only candidate gene directly correlated to IL-4 expression. Mina was determined to be the necessary and sufficient negative regulator of the gene coding for IL-4, which directs TH2 bias. Two haplotypes defined by 21 single nucleotide polymorphisms accounted for variable expression of TH2 bias in mice.
We asked Dr Mark Bix, senior author on the article, to comment on this research: “I think the work we have published is important because it reveals a new cellular pathway in which genetic variation might influence the tendency of different individuals to mount immune responses that predispose toward allergic reactions, including bronchial asthma. Thus Mina might be a good target for small-molecule drugs that could modulate allergic disease susceptibility or even symptoms.”
Mina was determined to be the necessary and sufficient negative regulator of the gene coding for IL-4
Campbell et al presented important findings on immunotherapy-induced tolerance in the Journal of Experimental Medicine (http://jem.rupress.org/cgi/content/abstract/jem.20082901v1?papetoc). The authors generated a murine model that mimicked peptide immunotherapy in human subjects and submitted the mice to the human clinical protocol. They reported that immunologic tolerance was induced to both treatment epitopes and nontreatment epitopes (“linked epitope suppression”) derived from the cat allergen Fel d 1 in sensitized mice. Significantly, tolerance was directly correlated to and dependent on generation of a large population of IL-10–secreting regulatory T cells that was much larger than the population of antigen-specific T cells. Reduced lung inflammation, eosinophilia, and TH2 cytokine levels in response to a single low dose of peptide were demonstrated. The authors also reported that the regulatory T-cell population generated from peptide immunotherapy was capable of reversing existing pathology.
We asked Dr Clare Lloyd, senior author on the article, to comment on this research: “Our studies provide a mechanism for the suppression in allergic pathophysiology observed after treatment with a low dose of a single allergen peptide and show a direct functional role for induced IL-10–secreting regulatory T cells. These data have implications for the design and development of peptide intervention therapies for asthma.”
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