New Paradigms in Type 2 Immunity

Department of Pathology, Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
Science (Impact Factor: 33.61). 07/2012; 337(6093):431-5. DOI: 10.1126/science.1221064
Source: PubMed


Nearly half of the world's population harbors helminth infections or suffers from allergic disorders. A common feature of this population is the so-called "type 2 immune response," which confers protection against helminths, but also promotes pathologic responses associated with allergic inflammation. However, the mechanisms that initiate and control type 2 responses remain enigmatic. Recent advances have revealed a role for the innate immune system in orchestrating type 2 responses against a bewildering array of stimuli, from nanometer-sized allergens to 20-meter-long helminth parasites. Here, we review these advances and suggest that the human immune system has evolved multiple mechanisms of sensing such stimuli, from recognition of molecular patterns via innate immune receptors to detecting metabolic changes and tissue damage caused by these stimuli.

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    • "Although an exacerbated Th1 response may lead to tissue damage and be associated with to the immunopathogenesis of ML (Bacellar et al., 2002), Th1 cytokines, such as interferon (IFN)- and tumor necrosis factor (TNF)-α, are indispensable for the control of Leishmania infection in macrophages (Green et al., 1990), the major host cells for this parasite in their mammalian hosts (Naderer and McConville, 2011). On the other hand, infections with intestinal helminths are associated with type 2 responses (Pulendran and Artis, 2012), which are able to inhibit Th1 responses and IFN- production (Del Prete, 1998). "
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    ABSTRACT: The most severe clinical form of American tegumentary leishmaniasis (ATL) due to Leishmania braziliensis is mucosal leishmaniasis (ML), characterized by destructive lesions in the facial mucosa. We performed a retrospective cohort study of 109 ATL patients from Rio de Janeiro State, Brazil, where ATL is caused by Leishmania braziliensis, to evaluate the influence of intestinal parasite coinfections in the clinical course of ATL. Parasitological stool examination (PSE) was performed with samples from all patients by the sedimentation, Kato-Katz and Baermann-Moraes methods. The diagnosis of ATL was made from lesion biopsies by direct observation of amastigotes in Giemsa-stained imprints, isolation of Leishmania promastigotes or histopathological examination. All patients were treated with meglumine antimoniate. Patients with positive PSE had a frequency of mucosal lesions significantly higher than those with negative PSE (p < 0.005). The same was observed for infections with helminths in general (p < 0.05), with nematodes (p < 0.05) and with Ascaris lumbricoides (p < 0.05), but not for protozoan infections. Patients with intestinal parasites had poor response to therapy (therapeutic failure or relapse) significantly more frequently than the patients with negative stool examination (p < 0.005). A similar difference (p < 0.005) was observed between patients with positive and negative results for intestinal helminths, but not for intestinal protozoa. Patients with positive PSE took significantly longer to heal than those with negative PSE (p < 0.005). A similar difference was observed for intestinal helminth infections (p < 0.005), but not for protozoan infections. Our results indicate a deleterious influence of intestinal helminth infections in the clinical course of ATL and evidence for the first time an association between ML and these coinfections, particularly with nematodes and A. lumbricoides.
    Acta tropica 10/2015; 154. DOI:10.1016/j.actatropica.2015.10.015 · 2.27 Impact Factor
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    • "Despite the overall success of live attenuated vaccines, it is only recently that the immune parameters of this vaccine approach are being unravelled. Increasingly, the importance of cognate innate signalling in the conditioning of appropriate adaptive immune responses is being realised [24]. While safety concerns prevent the direct application of live lentivirus vaccine approaches in humans, defining the protective processes elicited by attenuated SIV may inform the design of novel approaches for a safe, durable and effective vaccine against HIV. "
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    ABSTRACT: Vaccination of Mauritian cynomolgus macaques with the attenuated nef-truncated C8 variant of SIVmac251/32H (SIVmacC8) induces early, potent protection against pathogenic, heterologous challenge before the maturation of cognate immunity. To identify processes that contribute to early protection in this model the pathogenesis, anatomical distribution and viral vaccine kinetics were determined in relation to localised innate responses triggered by vaccination. The early biodistribution of SIVmacC8 was defined by rapid, widespread dissemination amongst multiple lymphoid tissues, detectable after 3 days. Cell-associated viral RNA dynamics identified mesenteric lymph nodes (MLN) and spleen, as well as the gut mucosae, as early major contributors of systemic virus burden. Rapid, localised infection was populated by discrete foci of persisting virus-infected cells. Localised productive infection triggered a broad innate response, with type-1 interferon sensitive IRF-7, STAT-1, TRIM5α and ApoBEC3G genes all upregulated during the acute phase but induction did not prevent viral persistence. Profound changes in vaccine-induced cell-surface markers of immune activation were detected on macrophages, B-cells and dendritic cells (DC-SIGN, S-100, CD40, CD11c, CD123 and CD86). Notably, high DC-SIGN and S100 staining for follicular and interdigitating DCs respectively, in MLN and spleen were detected by 3 days, persisting 20 weeks post-vaccination. Although not formally evaluated, the early biodistribution of SIVmacC8 simultaneously targets multiple lymphoid tissues to induce strong innate immune responses coincident at the same sites critical for early protection from wild-type viruses. HIV vaccines which stimulate appropriate innate, as well as adaptive responses, akin to those generated by live attenuated SIV vaccines, may prove the most efficacious.
    PLoS ONE 08/2014; 9(8):e104390. DOI:10.1371/journal.pone.0104390 · 3.23 Impact Factor
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    • "We first describe the results of our GWAS of allergic rhinitis in 5633 ethnically diverse North American subjects, where we identified genome-wide significant loci that were specific to ethnicity (Figure 1, pink box). We then describe the results of our gene expression profiling of immune cells key to allergy (CD4+ lymphocytes [30]), collected from the peripheral blood of selected subjects who had undergone GWAS (Figure 1, blue box). We share the results for the weighted gene coexpression network [31] we constructed to identify modules of genes expressed together. "
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    ABSTRACT: Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis. We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS. GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72). Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
    BMC Medical Genomics 08/2014; 7(1):48. DOI:10.1186/1755-8794-7-48 · 2.87 Impact Factor
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