Escaping from danger is one of the most fundamental survival behaviors for animals. Most freshwater fishes display olfactory alarm reactions in which an injured fish releases putative alarm substances from the skin to notify its shoaling company about the presence of danger. Here, we identified two small compounds in zebrafish skin extract, designated as ostariopterin and daniol sulfate. Ostariopterin is a pterin derivative commonly produced in many freshwater fishes belonging to the Ostariophysi superorder. Daniol sulfate is a novel sulfated bile alcohol specifically present in the Danio species, including zebrafish. Ostariopterin and daniol sulfate activate distinct glomeruli in the olfactory bulb. Zebrafish display robust alarm reactions, composed of darting, freezing, and bottom dwelling, only when they are concomitantly stimulated with ostariopterin and daniol sulfate. These results demonstrate that the fish alarm reaction is driven through a coincidence detection mechanism of the two compounds along the olfactory neural circuitry.

The Danger Model predicts that there are some molecules that no immune system can ever be fully tolerant of, namely proteins that are only transiently expressed during times of stress, infection, or injury. Among these are the danger/alarm signals themselves. Accordingly, a fleeting autoantibody response to danger signals is expected during times when they are released. Depending on context, these autoantibodies may serve beneficial \"housekeeping\" functions by removing surplus danger signals from the circulation or, conversely, create an immunodeficiency. Here, we will focus on the Type 1 Interferons as examples of foreseeable targets for a transient autoantibody response, but the principles outlined should hold for other danger-associated molecules as well.

Galectins are master regulators of maternal immune responses and placentation in pregnancy. Galectin-13 (gal-13) and galectin-14 (gal-14) are expressed solely by the placenta and contribute to maternal-fetal immune tolerance by inducing the apoptosis of activated T lymphocytes and the polarization of neutrophils toward an immune-regulatory phenotype.Furthermore, their decreased placental expression is associated with pregnancy complications, such as preeclampsia and miscarriage. Yet, our knowledge of the immunoregulatory role of placental galectins is incomplete.
This study aimed to investigate the effects of recombinant gal-13 and gal-14 on cell viability, apoptosis, and cytokine production of peripheral blood mononuclear cells (PBMCs) and the signaling pathways involved.
Herein, we show that gal-13 and gal-14 bind to the surface of non-activated PBMCs (monocytes, natural killer cells, B cells, and T cells) and increase their viability while decreasing the rate of their apoptosis without promoting cell proliferation. We also demonstrate that gal-13 and gal-14 induce the production of interleukin (IL)-8, IL-10, and interferon-gamma cytokines in a concentration-dependent manner in PBMCs. The parallel activation of Erk1/2, p38, and NF-ĸB signaling evidenced by kinase phosphorylation in PBMCs suggests the involvement of these pathways in the regulation of the galectin-affected immune cell functions.
These findings provide further evidence on how placenta-specific galectins assist in the establishment and maintenance of a proper immune environment during a healthy pregnancy.

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There is some evidence that radiotherapy (RT) can trigger anti-tumor immune responses. In addition, hyperthermia (HT) is known to be a tumor cell radio-sensitizer. How HT could enhance the anti-tumor immune response produced by RT is still an open question. The aim of this study is the evaluation of potential dynamic effects regarding the adaptive immune response induced by different combinations of RT fractions with HT. The adaptive immune system is considered as a trainable unit (perceptron) which compares danger signals released by necrotic or apoptotic cell death with the presence of tumor- and host tissue cell population-specific molecular patterns (antigens). To mimic the changes produced by HT such as cell radio-sensitization or increase of the blood perfusion after hyperthermia, simplistic biophysical models were included. To study the effectiveness of the different RT+HT treatments, the Tumor Control Probability (TCP) was calculated. In the considered scenarios, the major effect of HT is related to the enhancement of the cell radio-sensitivity while perfusion or heat-based effects on the immune system seem to contribute less. Moreover, no tumor vaccination effect has been observed. In the presented scenarios, HT boosts the RT cell killing but it does not fundamentally change the anti-tumor immune response.

COVID-19 presentations range from mild to moderate through severe disease but also manifest with persistent illness or viral recrudescence. We hypothesized that the spectrum of COVID-19 disease manifestations was a consequence of SARS-CoV-2-mediated delay in the pathogen-associated molecular pattern (PAMP) response, including dampened type I interferon signaling, thereby shifting the balance of the immune response to be dominated by damage-associated molecular pattern (DAMP) signaling. To test the hypothesis, we constructed a parsimonious mechanistic mathematical model. After calibration of the model for initial viral load and then by varying a few key parameters, we show that the core model generates four distinct viral load, immune response and associated disease trajectories termed \"patient archetypes\", whose temporal dynamics are reflected in clinical data from hospitalized COVID-19 patients. The model also accounts for responses to corticosteroid therapy and predicts that vaccine-induced neutralizing antibodies and cellular memory will be protective, including from severe COVID-19 disease. This generalizable modeling framework could be used to analyze protective and pathogenic immune responses to diverse viral infections.

Innate immune cells such as dendritic cells (DCs) sense and engulf nanomaterials potentially leading to an adverse immune response. Indeed, as described for combustion-derived particles, nanomaterials could be sensed as danger signals, enabling DCs to undergo a maturation process, migrate to regional lymph nodes and activate naive T-lymphocytes. Synthetic amorphous silica nanoparticles (SAS-NPs) are widely used as food additives, cosmetics, and construction materials. This work aimed to evaluate in vitro the effects of manufactured SAS-NPs, produced by thermal or wet routes, on human DCs functions and T-cell activation. Human monocyte-derived DCs (moDCs) were exposed for 16 hours to three endotoxin-free test materials: fumed silica NPs from Sigma-Aldrich (#S5505) or the JRC Nanomaterial Repository (NM-202) and colloidal Ludox®TMA NPs. Cell viability, phenotypical changes, cytokines production, internalization, and allogeneic CD4+ T-cells proliferation were evaluated. Our results showed that all SAS-NPs significantly upregulated the surface expression of CD86 and CD83 activation markers. Secretions of pro-inflammatory cytokines (CXCL-8 and CXCL-12) were significantly enhanced in a dose-dependent manner in the moDCs culture supernatants by all SAS-NPs tested. In an allogeneic co-culture, fumed silica-activated moDCs significantly increased T-lymphocyte proliferation at all T-cell:DC ratios compared to unloaded moDCs. Moreover, analysis of co-culture supernatants regarding the production of T-cell-derived cytokines showed a significant increase of IL-9 and IL-17A and F, as well as an upregulation of IL-5, consistent with the pro-inflammatory phenotype of treated-moDCs. Taken together, these results suggest that SAS-NPs could induce functional moDCs maturation and play a role in the immunization process against environmental antigens.

There is a large body of information on testing of chemicals for skin sensitization in the murine local lymph node assay (LLNA), in which potency is quantified by the EC3 value, derived from dose-response data. This information finds use in risk assessment and regulatory classification, and also in assessing the performance of non-animal methods. However, some LLNA results are not straightforward to interpret, and in some cases published EC3 values are questionable. These cases usually arise where the dose-response does not show a monotonic increasing pattern but is bell-shaped, or shows a decrease in response with increasing dose over the whole dose range tested. By analogy with a long-recognised phenomenon in guinea pig sensitization, this is referred to as the overload effect. Here a mechanistic rationale is presented to explain the overload effect, and at the same time to explain the production of danger signals even when the sensitizer is non-irritant. Some illustrative examples are presented where the overload effect can lead to misinterpretation of LLNA results, and chemistry-based read-across is applied to reinterpret the data.

Psoriasis is a complex chronic inflammatory skin disease caused by the dynamic interplay between multiple genetic risk foci, environmental risk factors, and excessive immunological abnormalities. Psoriasis affects approximately 2% of the population worldwide, and dramatic advances have been achieved in the understanding and treatment options for psoriasis. Recent progress in biological therapies has revealed the fundamental roles of tumor necrosis factor-α, interleukin (IL)-23p19, and the IL-17A axis together with skin-resident immune cells and major signal transduction pathways in the pathogenesis of psoriasis. In addition to IL-17-producing T helper17 cells, innate lymphoid cell (ILC)3 induces psoriasis rashes directly without T-cell/antigen interaction in response to the released antimicrobial peptides from activated keratinocytes and inflammatory cytokines. ILC3 typically expresses retinoic acid receptor-related orphan receptor gamma t in the nucleus, matures in the presence of IL-7 and IL-23, and produces IL-17 and IL-22. The number of ILC3s is increased in the blood, psoriasis rash, and even in nonrash areas of psoriatic skin. Psoriasis is significantly associated with cardiovascular disease, metabolic syndrome, and inflammatory disorders, particularly the severe type. The similarity of enterobacteria in the psoriasis gut to that in diabetic patients may be related to its pathogenesis. In the current review, we focus on the pathophysiology of psoriasis in the accelerated immunological inflammatory loop, danger signal from keratinocytes, and cytokines, particularly IL-17 and IL-23p19. In addition, pathophysiological speculation with regard to morphology has been supplemented. Finally, the differences and similarities between psoriasis and atopic dermatitis are discussed.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) of the immune system. They capture foreign antigens and can present them to lymphocytes, that is, T cells and B cells, to activate them. DCs are the most potent of all immune cells at inducing the adaptive immune system. Thus, the presence of DCs at the anatomical site of the immune challenge is imperative for the immune system to mount an effective immune response. From the anatomical site of the immune challenge, DCs cargo antigens to the draining lymph nodes, specialized immune organs where adaptive immunity is generated. DCs are heterogeneous as a type of immune cell, and various subsets of DCs have been reported and their functions described. In this chapter, we discuss various aspects of DC development and function. We further discuss how various tumor microenvironments can affect DC development, function, and migration, thus evading a strong adaptive immune response.