Dendritic cells drive profibrotic inflammation and aberrant T cell polarization in systemic sclerosis.

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-1ß, 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.

Self-reported dietary omega-3 polyunsaturated fatty acids are associated with adipose tissue markers and glucose metabolism in apparently healthy subjects.

BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1) and resistin are associated with dysfunctional adipose tissue (AT)-related metabolic complications. The role of dietary eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids in this relationship is unknown. AIM: To investigate the association of EPA and DHA with PAI-1 and resistin, as well as the role of this association on the glucose metabolism of apparently healthy subjects. SUBJECTS AND METHODS: Thirty-six healthy individuals were included. Validated food frequency questionnaires were used to analyse dietary habits. Inflammatory and glucose metabolism markers were quantified. Subcutaneous AT samples were obtained, and adipocyte number, area, and macrophage content were assessed. RESULTS: In 36 subjects aged 56 ± 8 years and with a body mass index of 26 ± 4 kg/m2, logEPA, and logDHA showed significant association with logresistin and a marginal association with PAI-1. Adipocyte number, area, and lognumber of macrophages per adipocyte significantly correlated with PAI-1 but not with logresistin. Although logEPA and logDHA were independently associated with loginsulin, loginsulin resistance, and C-Peptide, the addition of logresistin, but not of PAI-1, into the multivariable model, abolished the associations. CONCLUSIONS: EPA and DHA could modulate glucose metabolism across AT functional states. Our data indicate that this association is independent of other metabolic risk factors.

Smoke exposure from chronic biomass burning induces distinct accumulative systemic inflammatory cytokine alterations compared to tobacco smoking in healthy women.

Long-term exposure to biomass-burning smoke (BS) is associated with chronic obstructive pulmonary disease (COPD), asthma, and other chronic inflammatory lung diseases. BS results from such processes as the burning of wood for indoor cooking and heating, with women and children having the highest exposure rate. This study aimed to analyze the accumulative alterations in cytokine levels associated with BS (from wood) compared to tobacco smoke (TS) in healthy adult women. The levels of 27 cytokines were analyzed in the serum of 100 women, including 40 tobacco smokers/non-exposed to BS (TS+/BS-), 30 never-smokers/exposed to BS (TS-/BS+) and 30 never-smokers/non-exposed to BS (TS-/BS-) as controls, using 27-Plex immunoassay. The chronic BS exposure index was rated at ≥100 h-years, and the tobacco-smoking index was ≥10 pack-years. Compared to TS-/BS-, TS+/BS- had higher levels of IL-2, IL-9, MCP-1, MIP-1ß, and VEGF, while TS-/BS+ showed higher levels of IL-1ra, IL-6, IL-8, Eotaxin, IP-10, RANTES, and VEGF, presenting a distinct inflammatory profile that may favor an eosinophil-derived inflammatory response to BS exposure. Compared to TS+/BS-, TS-/BS+ expressed higher levels of IP-10 and IL-8, but lower levels of IL-2 and MIP-1ß. Gene-disease database analysis showed that altered cytokines in both TS+/BS- and TS-/BS+ are associated with asthma, COPD, lung fibrosis, and lung cancer. In conclusion, chronic BS exposure induces distinct systemic inflammatory cytokine alterations compared to tobacco smokers in healthy women. These findings provide new insights into how long-term exposure to BS affects the inflammatory response-and potentially the health-of adult women.

Alveolar microbiota profile in patients with human pulmonary tuberculosis and interstitial pneumonia.

BACKGROUND: The presence of the human lung microbiota has been demonstrated in patients with different lung diseases, mainly in sputum samples. However, for study of the alveolar microbiota, a bronchoalveolar lavage (BAL) sample represents the lower respiratory tract (LRT) environment. It is currently unknown whether there is a specific alveolar microbiota profile in human lung diseases, such as pulmonary tuberculosis (TB) and interstitial pneumonia (IP). METHODS: BAL samples from six active TB patients, six IP patients and ten healthy volunteers were used for DNA extraction followed by amplification of the complete bacterial 16S ribosomal RNA gene (16S rDNA). The 16S rDNA was sequenced with a MiSeq Desktop Sequencer, and the data were analysed by QIIME software for taxonomic assignment. RESULTS: The alveolar microbiota in TB and IP patients and healthy volunteers was characterized by six dominant phyla, Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Fusobacteria and Cyanobacteria. A significant reduction in the abundance of Firmicutes was observed in IP patients. In TB and IP patients, the diversity of the alveolar microbiota was diminished, characterized by a significant reduction in the abundance of the Streptococcus genus and associated with increased Mycobacterium abundance in TB patients and diminished Acinetobacter abundance in IP patients with respect to their abundances in healthy volunteers. However, an important difference was observed between TB and IP patients: the Fusobacterium abundance was significantly reduced in TB patients. Exclusive genera that were less abundant in patients than in healthy volunteers were characterized for each study group. CONCLUSIONS: This study shows that the alveolar microbiota profile in BAL samples from TB and IP patients, representing infectious and non-infectious lung diseases, respectively, is characterized by decreased diversity.

Genetic polymorphism of HLA-DRB1 alleles in Mexican mestizo patients with abdominal aortic aneurysms.

BACKGROUND: Multiple factors are implicated in the etiology and pathogenesis of Abdominal Aortic Aneurysms (AAA). Available literature of genetic studies has previously suggested the possible roles of autoimmunity, genetic predisposition and ethnic susceptibility. Due to the association with autoimmune diseases and proven application in population genetics, we aimed to investigate alleles of the Class II Human Leukocyte Antigens (HLA-DRB1) in the Mexican Mestizo population with aortic aneurysms and determine possible associations with susceptibility. METHODS: We performed a case Control Study; the HLA molecular typing was completed for DRB1 loci by LabType Sequence-Specific Oligonucleotide (SSO) SSO-OneLambda kit (Applied Biosystems; Thermo Fisher Scientific. Inc.) in the studied individuals. Allele frequencies (af) were determined, associations were assessed by chi square or fisher exact tests at significance level (< 0.05), and Odds Ratios (OR) were calculated using the STATA software version 14. RESULTS: The genetic polymorphism of HLA-DRB1 of fifty one patients (70% males with a mean age of 71 years) with atherosclerotic or also known as degenerative AAA were compared with 99 unrelated patients (60% males, mean age 65 years) without the disease [Control group (CG)] from the same ethnic group. We examined a total of 102 Class II HLA-DRB1 alleles of AAA patients and 198 from CG. When comparing af, we observed the HLA-DRB1*01 af of 0.139 in the AAA compared to 0.05 in the CG [p = 0.015, OR 3, 95% confidence interval (CI) 1.29-7.08], the HLA-DRB1*16 af were 0.109 in the AAA and 0.025 in CG (p = 0.006, OR 4.7, 95% CI 1.59-13.98). CONCLUSIONS: Our study confirmed increased frequencies of the alleles HLA-DRB1*01 and HLA-DRB1*16 and their association to the development of AAA in Mexican Mestizo patients. The utility of genetic testing may assist in identifying individuals at genetic risk for the development of this disease in different ethnic groups, who might benefit from earlier ultrasound screening and closer imaging surveillance.

Serum surfactant protein D (SP-D) is a prognostic marker of poor outcome in patients with A/H1N1 virus infection.

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 < 0.05). After adjusting for confounding variables, levels of SP-D ≥250 ng/mL were associated with increased the risk of death (HR = 8.27, 95 % CI 1.1-64.1, p = 0.043). CONCLUSIONS: Our results revealed that higher circulating levels of SP-D are associated with higher mortality risk in critically ill A/H1N1 patients. SP-D might be a predictive factor of poor outcomes in viral pneumonia.

Characterization of the lung microbiome and inflammatory cytokine levels in women exposed to environmental risk factors: A pilot study.

INTRODUCTION: Lung microbiome dysbiosis affects the immune system balance and promotes lung inflammation. We aimed to characterize and compare the lung bacteriome composition and the cytokine profile in women with normal lung function exposed to risk factors for chronic lung diseases (tobacco smoking and biomass-burning smoke exposure). METHODS: We included women with biomass-burning smoke exposure (BE, n = 11) and current smokers women (TS, n = 10). The bacteriome composition was performed in induced sputum, sequencing the 16 rRNA gene. Cytokine levels were measured using enzyme-linked immunosorbent assay multiplex assay in the supernatant of induced sputum. For quantitative variables, we used medians and minimum and maxim values. For the amplicon sequence variants (ASV) differential abundance testing between groups. RESULTS: At the taxa level, the phylum Proteobacteria was found in a higher proportion in the TS group concerning BE (p = .045); however, after the false discovery rate adjustment, this difference was not retained (p = .288). We found a higher concentration of IL-1ß in the TS group than in the BE group (248.6 vs. 177.9 pg/mL, p = .010). Women with high biomass-burning smoke exposure in an hour per day had a positive correlation with the abundance of Bacteroidota (ρ = 0.71, p = .014) and Fusobacteriota (ρ = 0.73, p = .011). FEV1/FVC had a positive correlation with an abundance of Bacteroidota, Proteobacteria, and Fusobacteria (ρ = 0.74, p = .009, ρ = 0.85, p = .001, and ρ = 0.83, p = .001, respectively). In tobacco smoking, women had a positive correlation (ρ = 0.77, p = .009) between cigarettes per day and Firmicutes' abundance. CONCLUSION: Compared to biomass-burning smoke-exposed women, current smokers have poor lung function and high levels of IL-1ß in sputum. Women with biomass-burning smoke exposure present an increased abundance of Bacteroidota and Fusobacteriota.

Salivette® Cortisol versus oropharyngeal swabbing for the detection of SARS-CoV-2 infection.

BACKGROUND: Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by naso/oropharyngeal swabbing may expose health-care workers to the virus and is technically challenging. The Salivette® is an alternative saliva-collection device with an oral cotton swab containing citric acid to stimulate saliva production, which may have an unpleasant taste. We present a pilot study comparing the Salivette® Cortisol (SC), which uses a synthetic swab without citric acid, against oropharyngeal swabbing for the detection of SARS-CoV-2 by reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESEARCH DESIGN AND METHODS: Symptomatic SARS-CoV-2-positive patients were sampled at various timepoints. The number of patients positive/negative for SARS-CoV-2 in oropharyngeal swab and SC samples and the percentage of patients testing true positive/true negative for SARS-CoV-2 from SC samples were determined. Positivity was defined by RT-qPCR amplification of 2/3 target SARS-CoV-2 N, ORF1, and S gene sequences. RESULTS: SC demonstrated 100% specificity, 52.2% sensitivity, and positive correlation with oropharyngeal swabbing for the detection of the SARS-CoV-2 S gene. In later-stage disease, lower viral load was observed in SC samples compared with oropharyngeal swabs. CONCLUSIONS: The SC may be an alternative for SARS-CoV-2 detection where naso/oropharyngeal swabbing is not feasible/available. This technique also confirms observations that the detection of SARS-CoV-2 in the upper airway may vary due to viral load over the disease course. TRIAL REGISTRATION: NCT04599959.

Differential Leukocyte Expression of IFITM1 and IFITM3 in Patients with Severe Pandemic Influenza A(H1N1) and COVID-19.

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.

Heterogeneity of Genetic Admixture Determines SLE Susceptibility in Mexican.

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well identified as risk factors. SLE patients present different clinical phenotypes, which are partly explained by admixture patterns variation among Mexicans. Population genetic has insight into the high genetic variability of Mexicans, mainly described through HLA gene studies with anthropological and biomedical importance. A prospective, case-control study was performed. In this study, we recruited 146 SLE patients, and 234 healthy individuals were included as a control group; both groups were admixed Mexicans from Mexico City. The HLA typing methods were based on Next Generation Sequencing and Sequence-Based Typing (SBT). The data analysis was performed with population genetic programs and statistical packages. The admixture estimations based on HLA-B and -DRB1 revealed that SLE patients have a higher Southwestern European ancestry proportion (48 ± 8%) than healthy individuals (30 ± 7%). In contrast, Mexican Native American components are diminished in SLE patients (44 ± 1%) and augmented in Healthy individuals (63 ± 4%). HLA alleles and haplotypes' frequency analysis found variants previously described in SLE patients from Mexico City. Moreover, a conserved extended haplotype that confers risk to develop SLE was found, the HLA-A∗29:02∼C∗16:01∼B∗44:03∼DRB1∗07:01∼DQB1∗02:02, pC = 0.02, OR = 1.41. Consistent with the admixture estimations, the origin of all risk alleles and haplotypes found in this study are European, while the protection alleles are Mexican Native American. The analysis of genetic distances supported that the SLE patient group is closer to the Southwestern European parental populace and farthest from Mexican Native Americans than healthy individuals. Heterogeneity of genetic admixture determines SLE susceptibility and protection in Mexicans. HLA sequencing is helpful to determine susceptibility alleles and haplotypes restricted to some populations.

The role of socioeconomic status in the susceptibility to develop systemic lupus erythematosus in Mexican patients.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well-identified as risk factors. SLE patients have different phenotypes or clinical presentations, which vary among Mexicans. This variation could be explained by ethnicity and admixture. Since socioeconomic status probably limits and change the patterns of migration, this factor could favor inbreeding and homogamy in some geographic areas. Consequently, it could alter or restrict the possibilities of admixture too. Therefore, the socioeconomic status may also have implications in the susceptibility and the clinical heterogeneity of SLE in Mexican patients. METHODS: One hundred twenty-three SLE patients and 234 healthy individuals with Mexican admixed ancestry were recruited. HLA alleles were analyzed using the HLA typing method based on Sequence-based typing (SBT). RESULTS: As expected, it was found an increased frequency of the HLA-DRB1*03:01 allele in all socioeconomic groups when compared with healthy individuals. The susceptibility allele found in the low-income SLE patients was HLA-DRB1*04:05 whereas, the susceptibility alleles for the high-income SLE patients were HLA-DRB1*07:01 (pC = 0.03, OR = 2.0) and HLA-DRB1*11:04 (pC = 0.0004, OR = 5.1). Additionally, the frequencies of two protective alleles HLA-DRB1*14:06 (pC = 0.01, OR = 0.28) and HLA-DRB1*16:02 (pC = 0.04, OR = 0.22) were found diminished. These findings correlate with the admixture differences between low-income and high-income SLE patients. The clinical manifestations showed a different distribution between both groups. Arthritis and neurological disorder were prevalent in low-income SLE patients, while the hematological disorder was prevalent in high-income SLE patients. CONCLUSIONS: These findings suggest that HLA class II DRB1 genes contribute to the susceptibility and protection to develop SLE differently depending on socioeconomic status. Due to this, the clinical manifestations vary among patients and it could be related to different admixture charge.Key Point• HLA class II DRB1 genes contribute to the susceptibility and protection to develop SLE differently depending on socioeconomic status.

A unique immune signature of serum cytokine and chemokine dynamics in patients with Zika virus infection from a tropical region in Southern Mexico.

OBJECTIVES: To describe the kinetics of circulating cytokines and chemokines in humans with ZIKAV infection. METHODS: Serum levels of different immune mediators in patients with ZIKAV infection were measured at distinct stages of the disease, as well as in culture supernatants from human monocytes infected with a clinical ZIKAV isolate. We also looked for clinical features associated with specific immune signatures among symptomatic patients. RESULTS: We evaluated 23 ZIKAV-infected patients. Their mean age was 32 ± 8.3 years and 65% were female. ZIKAV patients showed elevated IL-9, IL-17A, and CXCL10 levels at acute stages of the disease. At day 28, levels of CCL4 and CCL5 were increased, whereas IL-1RA, CXCL8 and CCL2 were decreased. At baseline, IL-7 was increased among patients with headache, whereas CCL2, and CCL3 were decreased in patients with bleeding and rash, respectively. Our clinical ZIKAV isolate induced a broad immune response in monocytes that did not resemble the signature observed in ZIKAV patients. CONCLUSIONS: We showed a unique immune signature in our cohort of ZIKAV-infected patients. Our study may provide valuable evidence helpful to identify immune correlates of protection against ZIKAV.

Surface phase diagrams: evidence of molecular arrangements at the aqueous-solution/solid interface.

Surface state changes described as phase transitions or simple molecular rearrangements have become a key issue in modern science. Indeed, they have an impact on the development of numerous (nano)technologies; they are also involved in biochemical and chemical mechanisms at the molecular level and also in environmental phenomena. At last, they have been at the origin of flourishing statistical descriptions that have illuminated new and very interesting aspects of surface behaviors. Here, to obtain still lacking coherent sets of experimental data on systems in which molecular interactions and thermodynamic properties are different, the adsorption behaviors of three aqueous mixtures in contact with a dense and homogeneous silica were studied versus concentrations and temperatures. Of course, these mixtures displayed very different bulk phase properties. Their stairlike isotherms are interpreted through surface phase diagrams; each of them is very similar to the corresponding bulk phase diagram. Their comparison gives new insights into the different surface states, the role of solvent in the surface, and the probable molecular mobility.