CD1a presentation of endogenous antigens by group 2 innate lymphoid cells.

Group 2 innate lymphoid cells (ILC2) are effectors of barrier immunity, with roles in infection, wound healing, and allergy. A proportion of ILC2 express MHCII (major histocompatibility complex II) and are capable of presenting peptide antigens to T cells and amplifying the subsequent adaptive immune response. Recent studies have highlighted the importance of CD1a-reactive T cells in allergy and infection, activated by the presentation of endogenous neolipid antigens and bacterial components. Using a human skin challenge model, we unexpectedly show that human skin-derived ILC2 can express CD1a and are capable of presenting endogenous antigens to T cells. CD1a expression is up-regulated by TSLP (thymic stromal lymphopoietin) at levels observed in the skin of patients with atopic dermatitis, and the response is dependent on PLA2G4A. Furthermore, this pathway is used to sense Staphylococcus aureus by promoting Toll-like receptor-dependent CD1a-reactive T cell responses to endogenous ligands. These findings define a previously unrecognized role for ILC2 in lipid surveillance and identify shared pathways of CD1a- and PLA2G4A-dependent ILC2 inflammation amenable to therapeutic intervention

IL-6 effector function of group 2 innate lymphoid cells (ILC2) is NOD2 dependent

Cutaneous group 2 innate lymphoid cells (ILC2) are spatially and epigenetically poised to respond to barrier compromise and associated immunological threats. ILC2, lacking rearranged antigen-specific receptors, are primarily activated by damage-associated cytokines and respond with type 2 cytokine production. To investigate ILC2 potential for direct sensing of skin pathogens and allergens, we performed RNA sequencing of ILC2 derived from in vivo challenged human skin or blood. We detected expression of NOD2 and TLR2 by skin and blood ILC2. Stimulation of ILC2 with TLR2 agonist alone not only induced interleukin-5 (IL-5) and IL-13 expression but also elicited IL-6 expression in combination with Staphylococcus aureus muramyl dipeptide (MDP). Heat-killed skin-resident bacteria provoked an IL-6 profile in ILC2 in vitro that was notably impaired in ILC2 derived from patients with nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations. In addition, we show that NOD2 signaling can stimulate autophagy in ILC2, which was also impaired in patients with NOD2 mutations. Here, we have identified a role for ILC2 NOD2 signaling in the differential regulation of ILC2-derived IL-6 and have reported a previously unrecognized pathway of direct ILC2 bacterial sensing.<br

A Comprehensive Analysis of the Impact of HIV on HCV Immune Responses and Its Association with Liver Disease Progression in a Unique Plasma Donor Cohort - Fig 4

<p><b>A)</b> Reduced percentage of CD4+ specific T cell responses in HIV co-infected patients. The percentage of HCV specific CD4+ or CD8+ T cell responses were measured in a subset of HIV/HCV co-infected (n = 14) and HCV mono-infected (n = 7) individuals following <i>ex-vivo</i> stimulation of PBMC and IFNγ ELISPOT assay after CD8+ T cell depletion (See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158037#sec006" target="_blank">Materials and methods</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158037#pone.0158037.s006" target="_blank">S5 Fig</a>). The <i>p</i> values calculated by Mann-Whitney U test. Data are presented as median with interquartile range. <b>B)</b> Representative data from HCV NS3 peptide stimulated enriched short-term T cell lines from three patients each of HCV mono-infected (Group HCVc) and HIV/HCV co-infected (group HIV/HCVc) to demonstrate HCV specific IFNγ response. CD4⁺ and CD8⁺ dependency of IFNγ responses were analysed after flow cytometry based sorting. <b>C and D</b> The antiviral activity of enriched HCV NS3 specific T cells. HCV suppression by peptide stimulated <b>(C)</b> bulk CD4+ T cells (n = 4 replicates) and (<b>D)</b> bulk CD8+ T cells (n = 4 replicates). Solid lines represent HCV mono-infected patients; dash lines represent HIV/HCV co-infected patients. The percentage suppression was calculated by measuring luciferase activity after 48 hours of co-culture of enriched HCV NS3 specific T cells with HLA-A2 transfected Huh7.5 HCV replicon cells. Bars represent mean + SD. <b>E)</b> HIV has no impact on HCV neutralizing antibodies. Serum from a subgroup of patients co-infected with HCV and HIV (group HIV/HCVc, HIV/HCVr, HIVt/HCVc & HIVt/HCVr, n = 40) and patients with HCV mono-infection (group HCVc & HCVr, n = 49) were used to neutralize the infectivity of H77 HCVpp. The percentage of neutralization by patient serum was determined for patients positive of HCV viral load (blue symbols) and negative for HCV viral load (red symbols). The data were analyzed by Kruskal-Wallis test, and followed with Dunn’s multiple comparisons test. Each point is representative of the mean of one patient from two independent experiments. Data are presented as mean with SEM.</p

Patient characteristics of 151 individuals infected with HCV and /or HIV.

<p>Patients in Group 1, 2 and 3 are considered infected with HIV/HCV for over 15 years before sampling. Group HCVc was mono-infected, HCV chronic. Group HCVr was mono-infected, HCV spontaneously resolved. Group HIV/HCVc was HIV-1+, HCV chronic, HAART naïve. Group HIV/HCVr was HIV-1+, HCV spontaneously resolved, HAART naïve. Group HIVt/HCVc was HIV-1+, HCV chronic, HAART treated. Group HIVt/HCVr was HIV-1+, HCV spontaneously resolved, HAART naïve. ALT, Alanine transaminase; Tbil, Total bilirubin; ALP, Alkaline phosphatase: γ-GT, gamma glutamyl transferase; VL, viral load; IU, international units; HAART, highly active anti retroviral therapy. Values represent mean ± standard deviation.</p

HCV specific T cell responses are important in the control of HCV viral load and are higher in HCV mono infected patients.

<p><b>A)</b> HCV core and NS protein specific T cell responses were compared between a sub group of HCV mono-infected (Group HCVc (n = 21) and HAART naïve HIV/HCV co-infected patients (group HIV/HCVc (n = 24)). Median is shown. <b>B)</b> HCV specific T cell responses were compared between CD4>200 and CD4<200 in HCV/HIV co-infection group (n = 60). Data are presented as median with interquartile range. The <i>p</i> values calculated by Mann-Whitney U test.</p

HIV/HCV Co-infection affects the progression of chronic liver disease.

<p><b>A)</b> The progression of liver disease was assessed by measuring the degree of liver fibrosis. The progression of liver disease in chronic HIV/HCV co-infected patients (Group HIV/HCVc+ HIVt/HCVc (n = 40)) was faster than chronic HCV mono-infected patients (Group HCVc (n = 12)). <b>B)</b> The ALB/GLB ratio was higher in Group HCVc (n = 24) than chronic HIV/HCV co-infected patients (Group HIV/HCVc + HIVt/HCVc (n = 67)). <b>C)</b> Gamma GT levels were higher in Group HIV/HCV co-infected patients (Group HIV/HCVc + HIVt/HCVc (n = 69) than HCVc (n = 24). <b>D)</b> HCV virus load was lower in Group HCVc (n = 24) than chronic HIV/HCV co-infected patients (Group HIV/HCVc +HIVt/HCVc (n = 70)). <b>E)</b> A higher HCV viral loads were observed in patients with low CD4⁺ T cell counts in HIV/HCV Co-infection (CD4+T<200 n = 12, CD4+T>200 n = 55). The <i>p</i> values calculated by Mann-Whitney U test. Data are presented as median with interquartile range.</p

Short term HAART has no effect on the progression of chronic liver disease in HIV/HCV Co-infection group.

<p><b>A)</b> The degree of liver fibrosis (Group HIV/HCVc (n = 21) vs Group HIVt/HCVc (n = 19) <b>B)</b> ALB/GLB ratio (Group HIV/HCVc (n = 25) vs Group HIVt/HCVc (n = 43) and <b>C)</b> HCV virus load (Group HIV/HCVc (n = 29) vs Group HIVt/HCVc (n = 42) were compared between subgroups of HIV/HCV co-infected treatment naive group and HIV/HCV co-infected group that received short term HAART. The <i>p</i> values calculated by Mann-Whitney U test. Data are presented as median with interquartile range.</p

A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample.

Rationale: Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). Objectives: To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. Methods: We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. Results: The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers. Conclusions: Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population