Effect of occupational co-exposure to lead and cadmium on selected immunomodulatory cytokines

Occupational exposure to heavy metals like lead (Pb) and cadmium (Cd) is associated with the development of several diseases. The objective of this study was to determine the effect of occupational co-exposure to Pb and Cd on the blood levels of selected immune-modulatory cytokines related to T helper (Th), that is, Th1, interleukin-2 (IL-2), Th2, (IL-4 and IL-10), and Th17, (IL-17) cells. The study comprised 207 individuals divided into two groups: exposed ( n = 110) and nonexposed ( n = 97). Blood Pb and Cd were determined using Graphite Furnace Atomic Absorption Spectroscopy, and serum levels of cytokines were measured using enzyme-linked immunosorbent assay (ELISA). The study revealed significantly higher blood Pb and Cd levels in the exposed group. A significant decrease in Th1 cytokine-IL-2 and Th2 cytokine-IL-10 was found, while IL-4 (Th2 cytokine) and IL-17 (Th17) levels were higher in the exposed group. In the mixed exposure analysis, among all the selected cytokines, IL-4 levels were significantly different between individuals having higher levels of both Pb and Cd versus lower levels of Pb and Cd. While IL-2 levels were highest among the low Pb and Cd group, the IL-17 levels were highest among individuals with higher Cd levels. The study demonstrated that co-exposure to low levels of Pb and Cd might have an immune-modulatory effect. The data suggested a metal-induced pro-inflammatory immune response.

A Preliminary Study on the Relationship between Parasitaemia and Cytokine Expression of Peripheral Blood Cells in Trypanosoma vivax-Experimentally Infected Cattle

Trypanosoma vivax outbreaks have been reported with increasing frequency worldwide, causing significant economic losses in livestock. Though several studies have suggested that cytokine responses may influence infection caused by Trypanosoma sp., their exact role remains unclear and may vary according to the animal species and parasite strain. The present study aimed to evaluate cytokine expression of peripheral blood cells from three Girolando dairy cows experimentally infected with T. vivax. For this purpose, blood samples were collected prior to the inoculation on the day of inoculation (D0), the day after inoculation (D1), and then every seven days up to 119 days after infection (DAI). Each animal presented a unique pattern of cytokine expression. While a tendency of a Th1 cytokine response was observed during the patent phase (presence of circulating parasites), an increase of Th2 cytokine expression was found at the beginning of the sub-patent phase (low parasitaemia or aparasitaemic periods). In animals that presented a better control of parasitaemia, IL-6 and IFNγ increased during most of the trial period. On the other hand, the cow that presented reduction of IL-1β, IL-2, and TNFα during the entire period did not control parasitaemia properly. A balance between the Th1 and Th2 profile is beneficial for parasite control and animal health. The results found in the present study are a first step towards elucidating the dynamics of cattle’s inflammatory response against T. vivax, requiring future studies focusing on the role of key cytokines on the controlling of parasitaemia in different stages of bovine trypanosomosis.

Identification of Two Subsets of Murine DC1 Dendritic Cells That Differ by Surface Phenotype, Gene Expression, and Function

Classical dendritic cells (cDCs) in mice have been divided into 2 major subsets based on the expression of nuclear transcription factors: a CD8+Irf8+Batf3 dependent (DC1) subset, and a CD8-Irf4+ (DC2) subset. We found that the CD8+DC1 subset can be further divided into CD8+DC1a and CD8+DC1b subsets by differences in surface receptors, gene expression, and function. Whereas all 3 DC subsets can act alone to induce potent Th1 cytokine responses to class I and II MHC restricted peptides derived from ovalbumin (OVA) by OT-I and OT-II transgenic T cells, only the DC1b subset could effectively present glycolipid antigens to natural killer T (NKT) cells. Vaccination with OVA protein pulsed DC1b and DC2 cells were more effective in reducing the growth of the B16-OVA melanoma as compared to pulsed DC1a cells in wild type mice. In conclusion, the Batf3-/- dependent DC1 cells can be further divided into two subsets with different immune functional profiles in vitro and in vivo.

Salvianolic Acid A Suppresses DNCB-Induced Atopic Dermatitis-Like Symptoms in BALB/c Mice

Prevalence of atopic dermatitis (AD), a chronic, pruritic, and relapsing inflammatory skin disorder, is growing. Because available therapeutics is limited, immune regulators from natural resources could be helpful for treating AD symptoms. The root of Salvia miltiorrhiza Bunge (Lamiaceae) has been studied for the treatment of inflammatory diseases, including dermatologic disorders in Korea. This study examined the effect of salvianolic acid A on AD-like symptoms. Sensitization on the dorsal skin and repeated application on the ears with 2,4-dinitrochlorobenzene (DNCB) were performed in BALB/c mice to induce AD-like skin lesions. After induction of atopic dermatitis, salvianolic acid A (5 and 10 mg/kg) or dexamethasone (10 mg/kg) were administrated via intraperitoneal injection for 3 weeks. Salvianolic acid A suppressed DNCB-induced AD-like symptoms like ear skin hypertrophy and decreased mast cell infiltration into skin lesions. Salvianolic acid A not only reduced DNCB-induced increase of serum IgE but also lowered levels of the Th2 cytokines (IL-4 and IL-13), Th1 cytokine (interferon-γ), and Th17 cytokine (IL-17A). Furthermore, salvianolic acid A blocked DNCB-induced lymph node enlargement. In summary, these results suggest that salvianolic acid A might have a therapeutic potential for the treatment of AD.

Bias of the Immune Response to Pneumocystis murina Does Not Alter the Ability of Neonatal Mice to Clear the Infection

Newborn mice are unable to clear Pneumocystis (PC) infection with the same efficiency as adults due, in part, to their inability to develop a robust immune response to infection until three weeks of age. It is known that infants tend develop a Th2 skewed response to antigen so we sought to determine whether a biased cytokine response altered the clearance of PC infection in neonatal mice. P. murina infection in neonatal mice resulted in increased IL-4 expression by CD4 T cells and myeloid cells, augmented IL-13 secretion within the airways and increased arginase activity in the airways, indicative of Th2-type responses. P. murina-infected IL-4Rα−/− neonates had a shift towards Th1 cytokine production and increased numbers of CD4 and CD8 T cells within the lung as well as elevated levels of P. murina-specific IgG. IFNγ−/− and IL-23 p19−/− mice had altered CD4-T cell-dependent cytokine and cell responses. Though we could alter the T helper cell environment in neonatal knockout mice, there was no loss in the ability of these pups to clear infection. It is possible that the Th2 phenotype normally seen in neonatal mice protects the developing lung from pro-inflammatory immune responses without compromising host defense against P. murina.

Th2/Th1 Cytokine Imbalance Is Associated With Higher COVID-19 Risk Mortality

A major component of COVID-19 severe respiratory syndrome is the patient’s immune response to the SARS-CoV-2 virus and the consequential multi-organ inflammatory response. Several studies suggested a potential role of CD4+ T cells in COVID-19 severe respiratory syndrome. We first hypothesized that there is a type 2 helper (Th2)/type 1 helper (Th1) imbalance in older age, male, asthma, smokers, and high ACE2 expression phenotype in the airway of non-infected patients. Next, we hypothesized that a Th2/Th1 imbalance may predict higher mortality in COVID-19 infected hospitalized patients with and without patient reported current asthma. We first analyzed publicly available gene expression from the sputum of 118 moderate-to-severe asthma patients and 21 healthy controls, and from nasal epithelium of 26 healthy current smokers and 21 healthy never smokers. Secondly, we profiled 288 new serum proteomics samples measured at admission from patients hospitalized within the Mount Sinai Health System with positive SARS-CoV-2 infection. We first computed Th1 and Th2 pathway enrichment scores by gene set variation analysis and then compared the differences in Th2 and Th1 pathway scores between patients that died compared to those that survived, by linear regression. The level of Th2/Th1 imbalance, as determined by the enrichment score, was associated with age, sex, and ACE2 expression in sputum, and with active smoking status in nasal epithelium (p < 0.05). Th2/Th1 imbalance at hospital admission in sera of patients was not significantly associated with death from COVID-19 (p = 0.11), unless evaluated in the asthmatic strata (p = 0.01). Using a similar approach we also observed a higher Th17/Th1 cytokine imbalance in all deceased patients compared to those that survived (p < 0.001), as well as in the asthmatic strata only (p < 0.01). Th2/Th1 imbalance is higher in the sera of asthma patients at admission that do not survive COVID-19, suggesting that the Th2/Th1 interplay may affect patient outcomes in SARS-CoV2 infection. In addition, we report that Th17/Th1 imbalance is increased in all patients that die of COVID-19.

Enhancing the anti-leukemia immunity of leukemia-derived exosome-based vaccine by downregulation of PD-L1 expression

Cell-released nanovesicles can induce anti-leukemia immunity. Leukemia cell-derived exosomes (LEXs) are promising anti-tumor vaccine components for cancer immunotherapy. Nonetheless, LEX-based vaccines show modest potency in vivo, likely due to the presence of immunosuppressive PD-L1 proteins in the exosomes. We hypothesized that targeting exosomal PD-L1 could optimize LEX-based vaccines. To test this hypothesis, we compared the capacity of exosomes derived from PD-L1-silenced leukemia cells (LEXPD-L1si) and non-modified exosomes to induce anti-leukemia immunity.Lentivirus-mediated PD-L1 shRNA was used to downregulate PD-L1 expression in parental leukemia cells and LEXs. LEXPD-L1si were characterized by electron microscopy, western blotting, and flow cytometry, and their anti-leukemia immune effects were tested on immune cells and in animal models.In the present study, lentivirus-mediated PD-L1 shRNA successfully downregulated PD-L1 expression in parental leukemia cells and in LEXs. LEXPD-L1si induced better DC maturation and subsequently enhanced T-cell activation, as compared with non-modified LEXs. Consistently, immunization with LEXPD-L1si induced greater T-cell proliferation and Th1 cytokine release. LEXPD-L1si was a more potent inducer of antigen-specific cytotoxic lymphocyte (CTL) response. Finally, we vaccinated DBA/2 mice with exosome formulations to test their ability to induce both protective and therapeutic anti-tumor CTL responses in vivo. Vaccination with LEXPD-L1si strongly inhibited tumor growth and prolonged survival. Downregulation of exosomal PD-L1 expression in LEXs effectively induce more potent anti-leukemia immunity. Therefore our strategy for optimizing LEX-based vaccine has a potential application in leukemia immunotherapy.