Trained Immunity-Based Vaccines: A Ready-to-Act Strategy to Tackle Viral Outbreaks

Viral outbreaks have become significant threats to global human public health. New emerging viruses, pathogen mutations, and even the progressive loss of efficacy in some existing vaccines are behind this problem, which is amplified by the rapid virus spread given the ease of current mobility. Taking into account that these outbreaks arise in the absence of conventional effective vaccines, alternative approaches based on trained (innate) immunity are being considered. This immunity is dependent on a functional reprogramming of innate immune cells, leading to an enhanced nonspecific response towards different pathogens, including viruses. Trained immunity-based vaccines (TIbVs), defined as vaccine formulations containing trained immunity inducers, could be used during viral outbreaks to confer non-specific protection but also to enhance adaptive specific immune responses. In this chapter, we aim to illustrate how TIbVs could tackle the above-mentioned situations derived from viral outbreaks, reviewing the potential of available TIbVs in such urgent situations with a special mention to COVID-19.

S100A8/A9 Is a Marker for the Release of Neutrophil Extracellular Traps and Induces Neutrophil Activation

Neutrophils are the most abundant innate immune cells in the circulation and they are the first cells recruited to sites of infection or inflammation. Almost half of the intracellular protein content in neutrophils consists of S100A8 and S100A9, though there has been controversy about their actual localization. Once released extracellularly, these proteins are thought to act as damage-associated molecular patterns (DAMPs), though their mechanism of action is not well understood. These S100 proteins mainly form heterodimers (S100A8/A9, also known as calprotectin) and this heterocomplex is recognized as a useful biomarker for several inflammatory diseases. We observed that S100A8/A9 is highly present in the cytoplasmic fraction of neutrophils and is not part of the granule content. Furthermore, we found that S100A8/A9 was not released in parallel with granular content but upon the formation of neutrophil extracellular traps (NETs). Accordingly, neutrophils of patients with chronic granulomatous disease, who are deficient in phorbol 12-myristate 13-acetate (PMA)-induced NETosis, did not release S100A8/A9 upon PMA stimulation. Moreover, we purified S100A8/A9 from the cytoplasmic fraction of neutrophils and found that S100A8/A9 could induce neutrophil activation, including adhesion and CD11b upregulation, indicating that this DAMP might amplify neutrophil activation.

Morphea Profunda with Tertiary Lymphoid Follicles: Description of Two Cases and Review of the Literature

Morphea profunda or subcutaneous (deep) morphea is a variant of localized morphea, characterized by one or more ill-defined, deep sclerotic plaque. Preferential sites are the abdomen, trunk, sacral area, or extremities. The presence of hyperplastic lymphoid follicles in the context of the sclerotic bands of morphea is rarely described. Localized scleroderma is sustained by a profibrotic inflammatory profile. Transforming growth factor-β (TGF-β), an imbalance between functional subclasses of T-lymphocytes (innate immune cells) has a role in activate collagen deposition. In this case report, we present two cases of morphea profunda with lymphoid follicular hyperplasia. A systematic review of the literature on the pathophysiology of localized scleroderma is also presented, with particular reference to the presence of lymphoid structures.

Innate Phagocyte Polarization in the Oral Cavity

The oral cavity is a complex environment constantly exposed to antigens from food and the oral microbiota. Innate immune cells play an essential role in maintaining health and homeostasis in the oral environment. However, these cells also play a significant role in disease progression. This review will focus on two innate phagocytes in the oral cavity: macrophages and neutrophils, and examine their roles during homeostasis and disease development, with a focus on periodontal disease and cancer. Macrophages have a well-known ability to polarize and be activated towards a variety of phenotypes. Several studies have found that macrophages’ polarization changes can play an essential role in maintaining health in the oral cavity and contribute to disease. Recent data also finds that neutrophils display phenotypic heterogeneity in the oral cavity. In both cases, we focus on what is known about how these cellular changes alter these immune cells’ interactions with the oral microbiota, including how such changes can lead to worsening, rather than improving, disease states.

Neuroimmunomodulatory Properties of Flavonoids and Derivates: A Potential Action as Adjuvants for the Treatment of Glioblastoma

Glioblastomas (GBMs) are tumors that have a high ability to migrate, invade and proliferate in the healthy tissue, what greatly impairs their treatment. These characteristics are associated with the complex microenvironment, formed by the perivascular niche, which is also composed of several stromal cells including astrocytes, microglia, fibroblasts, pericytes and endothelial cells, supporting tumor progression. Further microglia and macrophages associated with GBMs infiltrate the tumor. These innate immune cells are meant to participate in tumor surveillance and eradication, but they become compromised by GBM cells and exploited in the process. In this review we discuss the context of the GBM microenvironment together with the actions of flavonoids, which have attracted scientific attention due to their pharmacological properties as possible anti-tumor agents. Flavonoids act on a variety of signaling pathways, counteracting the invasion process. Luteolin and rutin inhibit NFκB activation, reducing IL-6 production. Fisetin promotes tumor apoptosis, while inhibiting ADAM expression, reducing invasion. Naringenin reduces tumor invasion by down-regulating metalloproteinases expression. Apigenin and rutin induce apoptosis in C6 cells increasing TNFα, while decreasing IL-10 production, denoting a shift from the immunosuppressive Th2 to the Th1 profile. Overall, flavonoids should be further exploited for glioma therapy.

CSF1R inhibition by small molecule affects T-helper cell differentiation independently of microglia depletion

Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a specific method for microglia depletion. However, recent work revealed that in addition to microglia, CSF1R inhibition also affects other innate immune cells, such as peripheral monocytes and tissue-resident macrophages of the lung, liver, spleen, and peritoneum. Here, we show that this effect is not restricted to innate immune cells only, but extends to the adaptive immune compartment. CSF1R inhibition alters the transcriptional profile of bone marrow cells that control T helper cell activation. In vivo or ex vivo inhibition of CSF1R profoundly changes the transcriptional profile of CD4+ cells and suppresses Th1 and Th2 differentiation in directionally stimulated and unstimulated cells and independently of microglia depletion. Given that T cells also contribute in CNS pathology, these effects may have practical implications in the interpretation of relevant experimental data.

Cells and Mediators of Inflammation as Effectors of Epithelial Repair in the Inflamed Intestine

Mucosal and histological healing have become the gold standards for assessing the efficacy of therapy in patients living with inflammatory bowel diseases (IBD). Despite these being the accepted goals in therapy, the mechanisms that underlie the healing of the mucosa after an inflammatory insult are not well understood, and many patients fail to meet this therapeutic endpoint. Here we review the emerging evidence that mediators (e.g. prostaglandins, cytokines, proteases, reactive oxygen and nitrogen species) and innate immune cells (e.g. neutrophils and monocytes/macrophages), that are involved in the initiation of the inflammatory response, are also key players in the mechanisms underlying mucosal healing to resolve chronic inflammation in the colon. The dual function mediators comprise an inflammation/repair program that returns damaged tissue to homeostasis. Understanding details of the dual mechanisms of these mediators and cells may provide the basis for the development of drugs that can help to stimulate epithelial repair in patients affected by IBD.