Natural Antibodies Alert the Adaptive Immune System of the Presence of Transformed Cells in Early Tumorigenesis.

Recent studies have revealed a critical role for natural Abs (NAbs) in antitumor immune responses. However, the role of NAbs in cancer immunosurveillance remains unexplored, mainly because of the lack of in vivo models that mimic the early recognition and elimination of transforming cells. In this article, we propose a role for NAbs in alerting the immune system against precancerous neoantigen-expressing cells immediately after they escape intrinsic tumor suppression mechanisms. We identify four distinct reproducible, trackable, MHC-matched neoantigen-expressing cell models that do not form tumors as the end point. This amplified readout in the critical window prior to tumor formation allows investigation of new mediators of cancer immunosurveillance. We found that neoantigen-expressing cells adoptively transferred in NAb-deficient mice persisted, whereas they were eliminated in wild-type mice, indicating that the circulating NAb repertoire alerts the immune system to the presence of transformed cells. Moreover, immunity is mounted against immunogenic and nonimmunogenic neoantigens contained in the NAb-tagged cells, regardless of whether the NAb directly recognizes the neoantigens. Beyond these neoantigen-expressing model systems, we observed a significantly greater tumor burden in chemically and virally induced tumor models in NAb-deficient mice compared with wild-type mice. Restoration of the NAb repertoire in NAb-deficient mice elicited the recognition and elimination of neoantigen-expressing cells and cancer. These data show that NAbs are required and sufficient for elimination of transformed cells early in tumorigenesis. These models can now be used to investigate how NAbs stimulate immunity via recognition receptors to eliminate precancerous cells.

Respiratory system: Highly exposed yet under-reported organ in pyrethrin and pyrethroid toxicity.

Pyrethrin and pyrethroid are a relatively new class of pesticides with potent insecticidal properties. Pyrethrins are naturally occurring pesticides obtained from the Chrysanthemum cinerariaefolium flower, while pyrethroids are their synthetic derivatives. They are widely used as the insecticides of choice in agriculture, veterinary medicine, public health programs, and household activities. Pyrethrin, being a broad-spectrum insecticide kills a wide range of pests, while pyrethroids last longer in the environment owing to low susceptibility to sunlight, and greater stability and efficacy than parent molecules. Humans can be exposed through inhalation, ingestion, and dermal routes. Indoor usage of an insecticide poses a serious risk to human health, especially to women, children, and stay-at-home people. Although pyrethrin and pyrethroid are generally considered safe, sustained skin or inhalation exposure or direct contact with open wounds results in higher toxicity to mammals. There is a paucity of data on the impact of pyrethrin and pyrethroid on overall pulmonary health. The respiratory system, from the nose, nasal passages, airways, and bronchi to the pulmonary alveoli, is vulnerable to environmental contaminants such as pesticides because of its anatomical location as well as being a highly blood profused organ. Under and over-functioning of the respiratory system triggers diverse pathologies such as serious infections, allergies, asthma, metastatic malignancies, and auto-immune conditions. While the association between workplace-related pesticide exposures and respiratory diseases and symptoms is well documented, it is important to understand the adverse health impact of pyrethrin and pyrethroid on the general population for awareness and also for better regulation and implementation of the law.

Sublethal chronic effects of oral dietary exposure to deltamethrin in Swiss albino mice.

The hazards of dietary exposure to environmentally relevant levels of deltamethrin are poorly understood though studies enunciate the acute toxicity hazards. In this study, prolonged exposure to low levels of deltamethrin in mice was investigated. The mice were exposed daily via gavage method for 60 days. Four doses (0.1, 0.05, 0.01, and 0.005 mg/kg bwt/d) were selected, which are equal to or less than the maximum residue limits for deltamethrin permitted in animal food/feed. Liver, kidney, lungs, spleen, and testes were collected on day 61 for histology, residue, and biochemical analysis (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALKP), total bilirubin (TBIL), total proteins (TPs), cholesterol (CHOL), urea, and creatinine). No significant changes were observed in body weight gain in all treatment groups ( p > 0.05). The gas chromatography analysis indicated that none of the tissue samples contained deltamethrin residues above the limits of quantification. The significant differences in biochemical profile (AST, ALT, TBIL, and creatinine) reported in animals exposed to 0.1 and 0.05 mg/kg bwt/d deltamethrin ( p < 0.05) suggest respective tissue injury and lipid peroxidation; however, few significant changes in urea and CHOL were also reported in doses 0.01 and 0.005 mg/kg bwt. No significant differences in TP and ALKP were observed ( p > 0.05). The target organs for deltamethrin toxicity showed prominent histopathological changes in concentrations of 0.1 and 0.05 mg/kg bwt. Other two doses showed no or sporadic changes. Our findings suggest that chronic exposure to environmentally relevant levels of deltamethrin can have detrimental effects on vital organs in the circumstances allowing daily exposure, in congruence with available literature.

Bacillus cereus food poisoning: international and Indian perspective.

Food borne illnesses result from eating food or drinking beverages that are contaminated with chemical matter, heavy metals, parasites, fungi, viruses and Bacteria. Bacillus cereus is one of the food-borne disease causing Bacteria. Species of Bacillus and related genera have long been troublesome to food producers on account of their resistant endospores. Their spores may be present on various types of raw and cooked foods, and their ability to survive high cooking temperatures requires that cooked foods be served hot or cooled rapidly to prevent the growth of this bacteria. Bacillus cereus is well known as a cause of food poisoning, and much more is now known about the toxins produced by various strains of this species, so that its significance in such episodes are clearer. However, it is still unclear why such cases are so rarely reported worldwide.

Incidence and enterotoxigenic profile of Bacillus cereus in meat and meat products of Uttarakhand, India.

The present investigation was undertaken to study the incidence and enterotoxigenicity of Bacillus cereus in raw meat and meat products. B. cereus was isolated from 29 (30.9 %) of the 94 samples analyzed. Recorded incidences of B. cereus from raw meat and meat products samples were 27.8 and 35 %, respectively. A high level of organism was found in cooked-meat (35 %) than raw meat samples (27.78 %) from 40 cooked-meat products and 54 raw meat samples analyzed. Screening of isolates by multiplex polymerase chain reaction revealed the overall distribution of various enterotoxin genes hblDAC complex, nheABC complex, cytK and entFM as 55.2, 89.7, 41.4 and 93 %, respectively. The level of contamination with B. cereus was moderately higher in some samples but did not exceed the level which is sufficient to induce food poisoning. A relatively higher incidence of B. cereus in meat products, with the majority of isolates harboring all the enterotoxin genes can pose a potential public health threat.

CCL5-producing migratory dendritic cells guide CCR5+ monocytes into the draining lymph nodes.

Dendritic cells (DCs) and monocytes capture, transport, and present antigen to cognate T cells in the draining lymph nodes (LNs) in a CCR7-dependent manner. Since only migratory DCs express this chemokine receptor, it is unclear how monocytes reach the LN. In steady-state and following inhalation of several PAMPs, scRNA-seq identified LN mononuclear phagocytes as monocytes, resident, or migratory type 1 and type 2 conventional (c)DCs, despite the downregulation of Xcr1, Clec9a, H2-Ab1, Sirpa, and Clec10a transcripts on migratory cDCs. Migratory cDCs, however, upregulated Ccr7, Ccl17, Ccl22, and Ccl5. Migratory monocytes expressed Ccr5, a high-affinity receptor for Ccl5. Using two tracking methods, we observed that both CD88hiCD26lomonocytes and CD88-CD26hi cDCs captured inhaled antigens in the lung and migrated to LNs. Antigen exposure in mixed-chimeric Ccl5-, Ccr2-, Ccr5-, Ccr7-, and Batf3-deficient mice demonstrated that while antigen-bearing DCs use CCR7 to reach the LN, monocytes use CCR5 to follow CCL5-secreting migratory cDCs into the LN, where they regulate DC-mediated immunity.

Redefining innate natural antibodies as important contributors to anti-tumor immunity.

Myeloid, T, and NK cells are key players in the elimination phase of cancer immunoediting, also referred to as cancer immunosurveillance. However, the role of B cells and NAbs, which are present prior to the encounter with cognate antigens, has been overlooked. One reason is due to the popular use of a single B cell-deficient mouse model, muMT mice. Cancer models using muMT mice display a similar tumor burden as their wild-type (WT) counterparts. Empirically, we observe what others have previously reported with muMT mice. However, using two other B cell-deficient mouse models (IgHELMD4 and CD19creDTA), we show a three- to fivefold increase in tumor burden relative to WT mice. In addition, using an unconventional, non-cancer-related, immune neoantigen model where hypoxic conditions and cell clustering are absent, we provide evidence that B cells and their innate, natural antibodies (NAbs) are critical for the detection and elimination of neoantigen-expressing cells. Finally, we find that muMT mice display anti-tumor immunity because of an unexpected compensatory mechanism consisting of significantly enhanced type 1 interferon (IFN)-producing plasmacytoid dendritic cells (pDCs), which recruit a substantial number of NK cells to the tumor microenvironment compared to WT mice. Diminishing this compensatory pDC-IFN-NK cell mechanism revealed that muMT mice develop a three- to fivefold increase in tumor burden compared to WT mice. In summary, our findings suggest that NAbs are part of an early defense against not only microorganisms and dying cells, but precancerous cells as well.

LN Monocytes Limit DC-Poly I:C Induced Cytotoxic T Cell Response via IL-10 and Induction of Suppressor CD4 T Cells.

Every immune response has accelerators and brakes. Depending on the pathogen or injury, monocytes can play either role, promoting or resolving immunity. Poly I:C, a potent TLR3 ligand, licenses cross-presenting dendritic cells (DC1) to accelerate a robust cytotoxic T cells response against a foreign antigen. Poly I:C thus has promise as an adjuvant in cancer immunotherapy and viral subunit vaccines. Like DC1s, monocytes are also abundant in the LNs. They may act as either immune accelerators or brakes, depending on the inflammatory mediator they encounter. However, little is known about their contribution to adaptive immunity in the context of antigen and Poly I:C. Using monocyte-deficient and chimeric mice, we demonstrate that LN monocytes indirectly dampen a Poly I:C induced antigen-specific cytotoxic T cell response, exerting a "braking" function. This effect is mediated by IL-10 production and induction of suppressor CD4+ T cells. In a metastatic melanoma model, we show that a triple-combination prophylactic treatment consisting of anti-IL-10, tumor peptides and Poly I:C works because removing IL-10 counteracts the monocytic brake, resulting in significantly fewer tumors compared to mice treated with tumor peptides and Poly I:C alone. Finally, in human LN tissue, we observed that monocytes (unlike DCs) express high levels of IL-10, suggesting that anti-IL-10 may be an important addition to treatments. Overall, our data demonstrates that LN monocytes regulate the induction of a robust DC1-mediated immune response. Neutralization of either IL-10 or monocytes can augment Poly I:C-based treatments and enhance T cell cytotoxicity.

Human and Mouse Transcriptome Profiling Identifies Cross-Species Homology in Pulmonary and Lymph Node Mononuclear Phagocytes.

The mononuclear phagocyte (MP) system consists of macrophages, monocytes, and dendritic cells (DCs). MP subtypes play distinct functional roles in steady-state and inflammatory conditions. Although murine MPs are well characterized, their pulmonary and lymph node (LN) human homologs remain poorly understood. To address this gap, we have created a gene expression compendium across 24 distinct human and murine lung and LN MPs, along with human blood and murine spleen MPs, to serve as validation datasets. In-depth RNA sequencing identifies corresponding human-mouse MP subtypes and determines marker genes shared and divergent across species. Unexpectedly, only 13%-23% of the top 1,000 marker genes (i.e., genes not shared across species-specific MP subtypes) overlap in corresponding human-mouse MP counterparts. Lastly, CD88 in both species helps distinguish monocytes/macrophages from DCs. Our cross-species expression compendium serves as a resource for future translational studies to investigate beforehand whether pursuing specific MP subtypes or genes will prove fruitful.

Oral exposure of deltamethrin and/or lipopolysaccharide (LPS) induced activation of the pulmonary immune system in Swiss albino mice.

The deltamethrin, a synthetic pyrethroid, is used worldwide and has been linked with several type of acute toxicity. However, effect of low level of deltamethrin alone or in combination with the microbial antigen on pulmonary system is not understood. Lipopolysaccharide (LPS) was used as antigen which is a key inflammatory component of gram-negative bacteria, which induces a distinctive pattern of cytokine release that regulates inflammation. The aim was to determine whether chronic exposure to a low level of deltamethrin alone or in combination with LPS impair the lung response in adult male Swiss albino mice. The mice were orally exposed to different doses of deltamethrin (0.1, 0.05, 0.005, 0.001 mg/kg bwt) and then immunized with LPS at the 60th day. None of the treatment groups contained residues of deltamethrin above the limits of quantification. Deltamethrin combined with LPS challenge caused significant lymphocytosis and neutropenia in group 1 (0.1 mg/kg) mice (P < 0.05). The highest dose of deltamethrin exposure (0.1 mg/kg bwt) alone altered the total cell count significantly in blood and total leukocyte count (TLC) and macrophage count in bronchoalveolar lavage fluid. Microscopic pulmonary damage was evaluated by H&E staining and EM which indicated that two higher doses of deltamethrin, i.e., 0.1 and 0.05 mg/kg bwt, distinctly increased inflammatory cell infiltration and caused alveolar septa thickening and leukocyte infiltration into the alveolar septum (septal cell infiltration) in the lungs. Deltamethrin exposure alone and/or with endotoxin revealed different degrees of immunopositive reaction for Toll-like receptor 4 (TLR4) and pro-inflammatory cytokine-like tumor necrosis factor-alpha (TNFα) in different parts of the lungs. The expression of TLR4 and TNFα in the lung tissue was more pronounced in two higher dose groups. Thus, chronic low-level deltamethrin exposure may impair the main pro-inflammatory response in the lungs which is more pronounced in combination with LPS. Further research is required in direction of the mechanism of action of deltamethrin on the immune cell lineage and their differentiation.

Stroop effects in Alzheimer's disease: selective attention speed of processing, or color-naming? A meta-analysis.

Selective attention, an essential part of daily activity, is often impaired in people with Alzheimer's disease (AD). Usually, it is measured by the color-word Stroop test. However, there is no universal agreement whether performance on the Stroop task changes significantly in AD patients; or if so, whether an increase in Stroop effects reflects a decrease in selective attention, a slowing in generalized speed of processing (SOP), or is the result of degraded color-vision. The current study investigated the impact of AD on Stroop performance and its potential sources in a meta-analysis and mathematical modeling of 18 studies, comparing 637 AD patients with 977 healthy age-matched participants. We found a significant increase in Stroop effects for AD patients, across studies. This AD-related change was associated with a slowing in SOP. However, after correcting for a bias in the distribution of latencies, SOP could only explain a moderate portion of the total variance (25%). Moreover, we found strong evidence for an AD-related increase in the latency difference between naming the font-color and reading color-neutral stimuli (r2 = 0.98). This increase in the dimensional imbalance between color-naming and word-reading was found to explain a significant portion of the AD-related increase in Stroop effects (r2 = 0.87), hinting on a possible sensory source. In conclusion, our analysis highlights the importance of controlling for sensory degradation and SOP when testing cognitive performance and, specifically, selective attention in AD patients. We also suggest possible measures and tools to better test for selective attention in AD.