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Objectives SSc is a devastating autoimmune disease characterized by fibrosis and obliterative vasculopathy affecting the skin and visceral organs. While the processes mediating excessive extracellular matrix deposition and fibroblast proliferation are clear, the exact link between autoimmunity and fibrosis remains elusive. Th17 cells have been proposed as critical drivers of profibrotic inflammation during SSc, but little is known about the immune components supporting their pathogenic role. Our aim was to determine cytokine responses of stimulated monocyte-derived dendritic cells (Mo-DCs) and to determine how they influence T-cell cytokine production in SSc. Material and methods Dendritic cells (DCs) activate and shape T cell differentiation by producing polarizing cytokines. Hence, we investigated the cytokine responses of monocyte-derived DCs (Mo-DCs) from patients with limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc) and healthy controls (HCs) after stimulation with toll-like receptor (TLR) agonists. Also, using co-culture assays, we analysed T cell subpopulations after contact with autologous TLR-activated Mo-DCs. Results In general, we observed an increased production of Th17-related cytokines like IL-1β, IL-17F, IL-21 and IL-22 by SSc compared with HC Mo-DCs, with variations between lcSSc vs dcSSc and early- vs late-stage subgroups. Noticeably, we found a significant increment in IL-33 production by Mo-DCs in all SSc cases regardless of their clinical phenotype. Strikingly, T cells displayed Th2, Th17 and dual Th2–Th17 phenotypes after exposure to autologous TLR-stimulated Mo-DCs from SSc patients but not HCs. These changes were pronounced in individuals with early-stage dcSSc and less significant in the late-stage lcSSc subgroup. Conclusions Our findings suggest that functional alterations of DCs promote immune mechanisms favouring the aberrant T cell polarization and profibrotic inflammation behind clinical SSc heterogeneity.

Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk

Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk IFITM1 and IFITM3 mRNA expression dynamics and their correlation with clinical outcomes have not been extensively addressed in patients with respiratory infections. In this study, we evaluated the expression of IFITM1 and IFITM3 in peripheral leukocytes from healthy controls and individuals with severe pandemic influenza A(H1N1) or coronavirus disease 2019 (COVID-19). Comparisons between participants grouped according to their clinical characteristics, underlying disease, and outcomes showed that the downregulation of IFITM1 was a distinctive characteristic of severe pandemic influenza A(H1N1) that correlated with outcomes, including mortality. Conversely, increased IFITM3 expression was a common feature of severe pandemic influenza A(H1N1) and COVID-19. Using a high-dose murine model of infection, we confirmed not only the downregulation of IFITM1 but also of IFITM3 in the lungs of mice with severe influenza, as opposed to humans. Analyses in the comparative cohort also indicate the possible participation of IFITM3 in COVID-19. Our results add to the evidence supporting a protective function of IFITM proteins against viral respiratory infections in humans. Introduction Methods - Human samples - IFITM expression in humans - Influenza infection in mice - IFITM expression in mice - Cytokine levels in mouse lungs - Study approval - Statistical analysis Results - Participant characteristics - IFITM1 and IFITM3 in patients with severe pandemic influenza A(H1N1) - High-dose influenza A (H1N1) virus infection downregulates IFITM expression in mice - IFITM1 and IFITM3 in severe COVID-19 Discussion

The costs of coronavirus disease 2019 (COVID-19) are devastating. With millions of deaths worldwide, specific serological biomarkers, antiviral agents, and novel therapies are urgently required to reduce the disease burden. For these purposes, a profound understanding of the pathobiology of COVID-19 is mandatory. Notably, the study of immunity against other respiratory infections has generated reference knowledge to comprehend the paradox of the COVID-19 pathogenesis. Past studies point to a complex interplay between cytokines and other factors mediating wound healing and extracellular matrix (ECM) remodeling that results in exacerbated inflammation, tissue injury, severe manifestations, and a sequela of respiratory infections. This review provides an overview of the immunological process elicited after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Also, we analyzed available data about the participation of matrix metalloproteinases (MMPs) and transforming growth factor-beta (TGF-β) in immune responses of the lungs. Furthermore, we discuss their possible implications in severe COVID-19 and sequela, including pulmonary fibrosis, and remark on the potential of these molecules as biomarkers for diagnosis, prognosis, and treatment of convalescent COVID-19 patients. Our review provides a theoretical framework for future research aimed to discover molecular hallmarks that, combined with clinical features, could serve as therapeutic targets and reliable biomarkers of the different clinical forms of COVID-19, including convalescence.

The differentiation between influenza and coronavirus disease 2019 (COVID-19) could constitute a diagnostic challenge during the ongoing winter owing to their clinical similitude. Thus, novel biomarkers are required to enable making this distinction. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in patients with severe pandemic influenza but not those with COVID-19. This finding was validated in a separate cohort of mechanically ventilated patients with COVID-19 who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with death and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.

The mechanisms underlying the immunopathology of tuberculous meningitis (TBM), the most severe clinical form of extrapulmonary tuberculosis (TB), are not understood. It is currently believed that the spread of Mycobacterium tuberculosis (Mtb) from the lung is an early event that occurs before the establishment of adaptive immunity. Hence, several innate immune mechanisms may participate in the containment of Mtb infection and prevent extrapulmonary disease manifestations. Natural killer (NK) cells participate in defensive processes that distinguish latent TB infection (LTBI) from active pulmonary TB (PTB). However, their role in TBM is unknown. Here, we performed a cross-sectional analysis of circulating NK cellCID="C008" value="s" phenotype in a prospective cohort of TBM patients ( n = 10 ) using flow cytometry. Also, we addressed the responses of memory-like NK cell subpopulations to the contact with Mtb antigens in vitro. Finally, we determined plasma levels of soluble NKG2D receptor ligands in our cohort of TBM patients by enzyme-linked immunosorbent assay (ELISA). Our comparative groups consisted of individuals with LTBI ( n = 11 ) and PTB ( n = 27 ) patients. We found that NK cells from TBM patients showed lower absolute frequencies, higher CD69 expression, and poor expansion of the CD45RO+ memory-like subpopulation upon Mtb exposure in vitro compared to LTBI individuals. In addition, a reduction in the frequency of CD56brightCD16- NK cells characterized TBM patients but not LTBI or PTB subjects. Our study expands on earlier reports about the role of NK cells in TBM showing a reduced frequency of cytokine-producing cells compared to LTBI and PTB.

BackgroundCXCL17 is chemotactic for myeloid cells, exhibits broad-spectrum bactericidal activity, and is expressed in mucosal tissues. This chemokine is constitutively expressed in the respiratory tract, suggesting a role for CXCL17 in lung defenses. However, little is known about the possible participation of CXCL17 during respiratory infections in humans. Here, we evaluated the role of CXCL17 as a biomarker in patients with severe pandemic influenza A(H1N1) and coronavirus disease 2019 (COVID-19). MethodsWe conducted a prospective cohort study in hospitalized patients with severe influenza A(H1N1) and COVID-19 admitted to two national reference centers in Mexico City. Peripheral blood samples were obtained on admission for determinations of the serum levels of CXCL17 by enzyme-linked immunosorbent assay (ELISA). The expression of CXCL17 in lung autopsy specimens from patients that succumbed to both diseases was assessed by immunohistochemistry (IHQ). Serum CXCL17 levels were compared between patients grouped according to their disease and clinical outcome. The diagnostic and predictive value of serum CXCL17 levels was evaluated using machine-learning algorithms and regression analyses. ResultsA total of 92 patients were enrolled in the study, from which 68 were infected with influenza and 24 had COVID-19. Their clinical characteristics were similar, although dyspnea, rhinorrhea, and sputum production were more common during influenza, whereas dry cough and vomit were more frequent among COVID-19 patients. Both diseases induced the local expression of CXCL17 in the lung. However, serum levels of CXCL17 were increased only in patients with influenza but not COVID-19. CXCL17 not only differentiates influenza from COVID-19 but serves as a prognostic biomarker associated with mortality and renal failure in influenza patients. Using cell culture assays, we also identified that human alveolar A549 cells and peripheral blood monocyte-derived macrophages produce CXCL17 after influenza A(H1N1) pdm09 virus infection. ConclusionsOur results suggest a possible role for CXCL17 in the pathogenesis of influenza A(H1N1), supporting the use of this molecule as a prognostic biomarker. Future studies on the role of CXCL17 in COVID-19 are warranted.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although clinical descriptions of COVID-19 are currently available, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, a histological pattern of alveolar pneumonia, and higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163 in influenza patients. Conversely, dry cough, gastrointestinal symptoms, interstitial lung pathology, increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1β, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3, were observed in COVID-19 cases. We demonstrated the diagnostic potential of some clinical and immune factors to differentiate COVID-19 from pandemic influenza A(H1N1). Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against influenza. These findings might be relevant for the upcoming 2020-2021 influenza season, which is projected to be historically unique due to its convergence with COVID-19.

Natural killer (NK) cells participate in immunity against several pathogens by exerting cytotoxic and cytokine-production activities. Some NK cell subsets also mediate recall responses that resemble memory of adaptive lymphocytes against antigenic and non-antigenic stimuli. The C-X-C motif chemokine receptor 6 (CXCR6) is crucial for the development and maintenance of memory-like responses in murine NK cells. In humans, several subsets of tissue-resident and circulating NK cells with different functional properties express CXCR6. However, the role of CXCR6+ NK cells in immunity against relevant human pathogens is unknown. Here, we addressed whether murine and human CXCR6+ NK cells respond to antigens of Mycobacterium tuberculosis (Mtb). For this purpose, we evaluated the immunophenotype of hepatic and splenic CXCR6+ NK cells in mice exposed to a cell-wall (CW) extract of Mtb strain H37Rv. Also, we characterized the expression of CXCR6 in peripheral NK cells from active pulmonary tuberculosis (ATB) patients, individuals with latent TB infection (LTBI), and healthy volunteer donors (HD). Furthermore, we evaluated the responses of CXCR6+ NK cells from HD, LTBI, and ATB subjects to the in vitro exposure to CW preparations of Mtb H37Rv and Mtb HN878. Our results showed that murine hepatic CXCR6+ NK cells expand in vivo after consecutive administrations of Mtb H37Rv CW to mice. Remarkably, pooled hepatic and splenic, but not isolated splenic NK cells from treated mice, enhance their cytokine production capacity after an in vitro re-challenge with H37Rv CW. In humans, CXCR6+ NK cells were barely detected in the peripheral blood, although slightly significative increments in the percentage of CXCR6+, CXCR6+CD49a−, CXCR6+CD49a+, and CXCR6+CD69+ NK cells were observed in ATB patients as compared to HD and LTBI individuals. In contrast, the expansion of CXCR6+CD49a− and CXCR6+CD69+ NK cells in response to the in vitro stimulation with Mtb H37Rv was higher in LTBI individuals than in ATB patients. Finally, we found that Mtb HN878 CW generates IFN-γ-producing CXCR6+CD49a+ NK cells. Our results demonstrate that antigens of both laboratory-adapted and clinical Mtb strains are stimulating factors for murine and human CXCR6+ NK cells. Future studies evaluating the role of CXCR6+ NK cells during TB are warranted.

NK cells are crucial antiviral effectors. However, their role against emerging respiratory pathogens has not been extensively addressed in humans. Here, we characterized the phenotype of peripheral NK cells in patients with severe pandemic influenza A(H1N1) and age- and sex-matched healthy controls (HC) using an extended panel of flow cytometry antibodies against markers of activation, cytotoxicity, cytokine production, immune memory, and surface receptors. Enrolled patients were grouped according to their clinical outcome (survival vs. death). The study included 42 influenza patients (73% men) with a median age of 48 years, from which eight (26%) died during the follow-up period. All patients were admitted to the intensive care unit and required mechanical ventilation. Individuals with influenza differentiated from HC by reduced numbers of total, CD56bright, CD56dimCD16+, CD27+ memory-like, NKp46+, and perforin+ NK cell subpopulations, but increased CD69+ NK cells. Notably, lower percentages of CD27+ memory-like NK cells correlated with increased alkaline phosphatase levels, a readout of lung damage in patients with acute respiratory distress syndrome. Strikingly, a higher expression of the senescence marker CD57 in CD27+ memory-like NK cells and expansion of double-positive CD27+CD57+ NK cells was characteristic of deceased influenza patients, but not survivors. Finally, despite being reduced in the overall influenza group with respect to HC, increased percentages of IFN-γ+ NK cells distinguished death vs. survival outcomes. Collectively, our results demonstrate that alterations in the phenotype of NK cells influence with the progression and outcomes of patients with severe pandemic influenza A(H1N1) infection. Supported by grants from CONACyT (FORDECyT/10SE/2020/05/14-06, FORDECyT/10SE/2020/05/14-07) and SECTEI CDMX (SECTEI/050/2020) to JZ. JAR-N received a scholarship from CONACyT (CVU-1097402) for achieving her M.S.

Cancer-associated fibroblasts (CAFs) are the main component of the tumor stroma and promote tumor progression through several mechanisms. Recent evidence indicates that small noncoding RNAs, microRNAs (miRNAs), play key roles in CAF tumor-promoting properties; however, the role of miRNAs in lung cancer-associated fibroblasts remains poorly defined. We characterized the differential miRNA expression profile of fibroblasts isolated from matched tumor front (F-CAFs), inner tumor (In-CAFs), and normal adjacent (NFs) tissues from four lung adenocarcinoma patients (ADs) using microarray analysis. Proliferation and invasion assays of A549 human lung cancer cells in the presence of conditioned medium from F-CAFs, In-CAFs or NFs were performed to assess tumorigenic properties. Ten identified candidate miRNAs in F-CAFs, In-CAFs and NFs from 12 ADs were then validated by RT-PCR. Both F-CAFs and In-CAFs enhanced the proliferation and invasion of A549 cells compared with NFs; moreover, F-CAFs showed a significantly stronger effect than In-CAFs. RT-PCR validation demonstrated three downregulated miRNAs in F-CAFs compared with NFs (miR-145-3p, miR-299-3p, and miR-505-3p), two in F-CAFs compared with In-CAFs (miR-410-3p and miR-485-5p), but no differentially expressed miRNAs between In-CAFs and NFs. Further target-gene prediction and pathway enrichment analysis indicated that deregulated miRNAs in F-CAFs showed significant associations with "pathways in cancer" (miR-145-3p, miR-299-3p and miR-410-3p), "Wnt signaling pathway" (miR-410-3p and miR-505-3p), and "TGF-beta signaling pathway" (miR-410-3p). Importantly, a tumor-promoting growth factor targeted by those miRNAs, VEGFA, was upregulated in F-CAFs compared with NFs, as judged by RT-PCR. In conclusion, deregulated miRNAs in F-CAFs are potentially associated with CAF tumor-promoting properties.

Background. The role of miRNAs in the pathogenesis of cutaneous lupus has not been studied. Objective. It was to assess the levels of a selected panel of circulating miRNAs that could be involved in the regulation of the immune response, inflammation, and fibrosis in cutaneous lupus. Methods. It was a cross-sectional study. We included 22 patients with subacute (SCLE) and 20 with discoid (DLE) lesions, and 19 healthy donors (HD). qRT-PCR for miRNA analysis, flow cytometry in peripheral blood, and skin immunohistochemistry were performed to determine the distribution of CD4 T cells and regulatory cells and their correlation with circulating miRNAs. Results. miR-150, miR-1246, miR-21, miR-23b, and miR-146 levels were downregulated in SCLE vs. HD. miR-150, miR-1246, and miR-21 levels were downregulated in DLE vs. HD. Peripheral CD4+/CD25-/IL-4+ cells and CD4+/CD25hi/Foxp3+ were negatively associated with miR-23b, and CD4+/CD25-/IFN-γ+ with miR-1246 in SCLE, whereas CD123+/CD196+/IDO+ cells were positively associated with miR-150 in DLE. In the tissue, CD4+/IL-4+ and CD20+/IL-10+ cells were positively associated with miR-21 and CD4+/IFN-γ+ with miR-31 in SCLE, whereas CD4+/IL-4+ cells were positively associated with miR-150, and CD20+/IL-10+ cells with miR-1246 and miR-146a in DLE. In the SCLE, lower miR-150 levels were correlated with higher CLASI scores. The KEGG pathway enrichment analysis revealed that cell cycle regulation pathways, p53, TGF-β, thyroid hormone, and cancer signaling pathways were shared between miR-21, miR-31, miR-23b, miR-146a, miR-1246, and miR-150. Conclusions. A downregulation of miR-150, miR-1246, and miR-21 in both CLE varieties vs. HD was determined.

Antecedentes: La respuesta inmune Th1/Th2 es insuficiente para el control de la infeccion por Mycobacterium tuberculosis (Mtb), particularmente contra cepas mas virulentas como W-Beijing. Metodos: Se incluyeron 30 pacientes con tuberculosis activa (TBA) y 30 controles con tuberculosis latente (TBL). Se evaluo la distribucion del polimorfismo rs2275913 por PCR tiempo real. Se estimularon celulas mononucleares (CMN) con antigenos CFP-10 y ESAT-6 y extractos de H37Rv, W-Beijing-HN878. Los niveles de IL-17, IFN-γ se cuantificaron por Luminex. Las diferencias se evaluaron con t de Student y U de Mann-Whitney y valores de p A con la susceptibilidad a TBA. Se observo un efecto de la mutacion -197G>A en la tasa de expresion de IL-17A. Las CMN de pacientes TBA con genotipo A/G mostraron una mayor produccion de IL-17A (185 pg/mL) en relacion con las de pacientes G/G (100 pg/mL, p = 0.008). Esto no se observo en individuos con TBL. Los antigenos de H37Rv y HN878 estimularon mayor produccion de IFN-γ en CMN de pacientes con TBA (p < 0.05). Conclusion: La presencia del alelo A en la posicion -197 del promotor de IL-17A condiciona mayor produccion de esta citocina en respuesta a la cepa hipervirulenta W-Beijing-HN878

BackgroundAround 8–10% of individuals over 50 years of age present interstitial lung abnormalities (ILAs), but their risk factors are uncertain.MethodsFrom 817 individuals recruited in our lung ageing programme at the Mexican National Institute of Respiratory Diseases, 80 (9.7%) showed ILAs and were compared with 564 individuals of the same cohort with normal high-resolution computed tomography to evaluate demographic and functional differences, and with 80 individuals randomly selected from the same cohort for biomarkers. We evaluated MUC5B variant rs35705950, telomere length, and serum levels of matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, interleukin (IL)-6, surfactant protein (SP)-D, α-Klotho and resistin.ResultsIndividuals with ILAs were usually males (pMUC5B rs35705950 (OR 3.5, 95% CI 1.3–9.4; p=0.01), and reduced diffusing capacity of the lung for carbon monoxide and oxygen saturation. Resistin, IL-6, SP-D, MMP-1, MMP-7 and MMP-13 were significantly increased in individuals with ILAs. Resistin (12±5 versus 9±4 ng·mL−1; p=0.0005) and MMP-13 (357±143 versus 298±116 pg·mL−1; p=0.004) were the most increased biomarkers. On follow-up (24±18 months), 18 individuals showed progression which was associated with gastro-oesophageal reflux disease (OR 4.1, 95% CI 1.2–12.9; p=0.02) and in females with diabetes mellitus (OR 5.3, 95% CI 1.0–27.4; p=0.01).ConclusionsAround 10% of respiratory asymptomatic individuals enrolled in our lung ageing programme show ILAs. Increased serum concentrations of pro-inflammatory molecules and MMPs are associated with ILAs.

Introduction Surfactant protein D (SP-D) plays an important role in the innate responses against pathogens and its production is altered in lung disorders. Methods We studied the circulating levels of SP-D in 37 patients with acute respiratory distress syndrome due to the A/H1N1 virus infection and in 40 healthy controls. Cox logistic regression models were constructed to explore the association of SP-D levels and risk of death. Results Mortality rate after a 28-day was 32.42 %. Significant higher levels of SP-D were detected in A/H1N1 patients with fatal outcome (p

Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown etiology. Genetic variation within different major histocompatibility complex (MHC) loci contributes to the susceptibility to IPF. The effect of 70 kDa heat shock proteins (HSP70) gene polymorphisms in the susceptibility to IPF is unknown. The aim of this study was to explore the association between HSP70 polymorphisms and IPF susceptibility in the Mexican population. Methods Four HSP70 single nucleotide polymorphisms (SNPs) were evaluated using real time PCR assays in 168 IPF patients and 205 controls: +2763 C>T of HSPA1L (rs2075800), +2437 of HSP HSPA1L A>G (rs2227956), +190 of HSPA1A G>C (rs1043618) and +1267 of HSPA1B G>A (rs1061581). Results The analysis of the recessive model revealed a significant decrease in the frequency of the genotype HSPA1B AA (rs1061581) in IPF patients (OR = 0.27, 95 % CI = 0.13–0.57, Pc = 0.0003) when compared to controls. Using a multivariate logistic regression analysis in a codominant model the HSPA1B (rs1061581) GA and AA genotypes were associated with a lower risk of IPF compared with GG (OR = 0.22, 95 % CI = 0.07–0.65; p = 0.006 and OR = 0.17, 95 % CI = 0.07–0.41; p =

Overproduction of pro-inflammatory cytokines and chemokines is frequently associated with severe clinical manifestations in patients infected with influenza A/H1N1 virus. Micro-RNAs (miRNAs) are highly conserved small non-coding RNA molecules that post-transcriptionally regulate gene expression and are potential biomarkers and therapeutic targets in different inflammatory conditions.We studied the circulating and miRNA profiles in critically ill A/H1N1 patients, A/H1N1 patients with milder disease, asymptomatic housemates and healthy controls. Cytokine, chemokine and growth factors that were potential targets of differentially expressed miRNAs were assessed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and interactome analysis of these miRNAs were also performed.Critically ill patients exhibited a significant over-expression of circulating miR-150 (p0.005) when compared to patients with milder disease. miR-29c, miR-145 and miR-22 were differentially expressed in patients with severe A/H1N1 disease whereas miR-210, miR-126 and miR-222 were downregulated in individuals exposed to the A/H1N1 virus. Significant correlations (p0.05) between circulating levels of miR-150 with IL-1ra, IL-2, IL-6, CXCL8, IFN-γ, CXCL10 and G-CSF were detected, particularly in critically ill patients.The up-regulation of miR-150 is associated with poorer outcomes of A/H1N1 infection. The differential expression of miRNAs related with immune processes in severe A/H1N1 disease supports the potential role of these miRNAs as biomarkers of disease progression.

Article history:Received 10 February 2010Received in revised form 31 March 2010Accepted 23 April 2010Available online 4 May 2010Keywords:Gene polymorphismsHypersensitivityPneumonitisPDCD1PD1.3PD1.5 Objective: Hypersensitivity pneumonitis (HP) is an immunological disorder caused by antigen exposurein susceptible individuals. ThePDCD1polymorphisms,PD1.3 and PD1.5 have been associated with thesusceptibility to in ammatory disorders. This study was conducted to test whether thePD1.3and PD1.5polymorphisms are associated with HP in Mexican patients and to explore the distribution of thesepolymorphisms in different Mexican ethnic groups.Design and methods: We studied 98 Mexican patients with HP and 92 healthy Mexican controls. Also,156 healthy Amerindian individuals from two ethnic groups were included (96 Mayans and 60 Mayos).Polymorphisms were determined by TaqMan 5 nuclease assays.Results:Signi cant differences in the distribution of thePD1.3andPD1.5genotypes between HP patientsand healthy Mestizo controls were not found. We observed a signi cantly different distribution of thesepolymorphisms in Mexican Mestizos when compared to the Amerindians.Conclusions:We found no association between PD1 polymorphism and HP; however the distribution ofthese polymorphisms was different in Mexican Mestizos and Amerindians.© 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Introduction: Systemic sclerosis (SSc) shows variable clinical expression in different ethnic groups; vascular abnormalities are a prominent feature of this disease and its clinical expression may be influenced by genetic factors. Patients and methods: Herein, we describe 15 polymorphisms of the renin-angiotensin-aldosterone pathway in 170 Mexican admixed SSc patients (defined as patients with Mexican ancestry for at least 3 generations) and 199 healthy controls. We determined the presence of angiotensin II Type 1 receptor (AGTR1), angiotensin converting enzyme (ACE) and Endothelin 1 single nucleotide polymorphisms (SNPs) using 5’ exonuclease TaqMan genotyping assays on a 7900HT real-time fast polymerase chain reaction (PCR) system. Results: These polymorphisms had a similar distribution between SSc patients and controls, but we found that the AGTR1 G-680T (rs275652) ( p = 0.02; OR 3.5; 95%CI 1.2–10.4) and AGTR1 A-119G (rs275653) ( p = 0.008; OR 4.2; 95% CI 1.5–12.1) polymorphisms were associated with severe vascular involvement in our SSc patients. Conclusions: This is the first report of the association of these polymorphisms with vasculopathy in Mexican admixed SSc patients. Our findings suggested that the angiotensin II Type 1 receptor genotype may influence the clinical expression of vasculopathy in these patients. Functional analyses should follow.

Infection with pandemic (pdm) A/H1N1 virus induces high levels of pro-inflammatory mediators in blood and lungs of experimental animals and humans.To compare the involvement of seasonal A/PR/8/34 and pdm A/H1N1 virus strains in the regulation of inflammatory responses, we analyzed the changes in the whole-genome expression induced by these strains in macrophages and A549 epithelial cells. We also focused on the functional implications (cytokine production) of the differential induction of suppressors of cytokine signaling (SOCS)-1, SOCS-3, retinoid-inducible gene (RIG)-I and interferon receptor 1 (IFNAR1) genes by these viral strains in early stages of the infection.We identified 130 genes differentially expressed by pdm A/H1N1 and A/PR/8/34 infections in macrophages. mRNA levels of SOCS-1 and RIG-I were up-regulated in macrophages infected with the A/PR/8/34 but not with pdm A/H1N1 virus. mRNA levels of SOCS-3 and IFNAR1 induced by A/PR/8/34 and pdm A/H1N1 strains in macrophages, as well as in A549 cells were similar. We found higher levels of IL-6, TNF-α, IL-10, CCL3, CCL5, CCL4 and CXCL8 (p0.05) in supernatants from cultures of macrophages infected with the pdm A/H1N1 virus compared to those infected with the A/PR/8/34 strain, coincident with the lack of SOCS-1 and RIG-I expression. In contrast, levels of INF-α were higher in cultures of macrophages 48h after infection with the A/PR/8/34 strain than with the pdm A/H1N1 virus.These findings suggest that factors inherent to the pdm A/H1N1 viral strain may increase the production of inflammatory mediators by inhibiting SOCS-1 and modifying the expression of antiviral immunity-related genes, including RIG-I, in human macrophages.

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by an influx of activated T cells to the lung, in which the CD28/B7 costimulatory signals are essential for the T cell activation and the outcome of the inflammatory response. In this study, we investigated the effect of the CD28/B7 antagonist, CTLA-4Ig, on the lung inflammation and the T cell subset profile in experimental Saccharopolyspora recivirgula (SR)-induced HP. C57BL/6 mice were treated with SR or saline during two and three weeks and in addition of CTLA-4Ig was administrated after either the second or third week and mice were sacrificed seven days later. The extent of the lung inflammation was quantified by histopathology and the lung T cell subsets (Treg, Th17, γδT and NKT) were analyzed by flow cytometry. Mice treated with CTLA-4Ig showed a significant decrease in the extent of lung damage (p

Mycobacterium tuberculosis (Mtb) is a global health threat, compounded by the emergence of drug-resistant strains. A hallmark of pulmonary tuberculosis (TB) is the formation of hypoxic necrotic granulomas, which upon disintegration, release infectious Mtb. Furthermore, hypoxic necrotic granulomas are associated with increased disease severity and provide a niche for drug-resistant Mtb. However, the host immune responses that promote the development of hypoxic TB granulomas are not well described. Using a necrotic Mtb mouse model, we show that loss of Mtb virulence factors, such as phenolic glycolipids, decreases the production of the proinflammatory cytokine IL-17 (also referred to as IL-17A). IL-17 production negatively regulates the development of hypoxic TB granulomas by limiting the expression of the transcription factor hypoxia-inducible factor 1α (HIF1α). In human TB patients, HIF1α mRNA expression is increased. Through genotyping and association analyses in human samples, we identified a link between the single nucleotide polymorphism rs2275913 in the IL-17 promoter (–197G/G), which is associated with decreased IL-17 production upon stimulation with Mtb cell wall. Together, our data highlight a potentially novel role for IL-17 in limiting the development of hypoxic necrotic granulomas and reducing disease severity in TB.