Precision editing of the gut microbiota ameliorates cancer immunotherapy.

In this editorial the authors highlight recent findings which could help design a personalized approach for cancer immunotherapy.

Interrelationship between inflammatory cytokines (IL-1, IL-6, IL-33, IL-37) and acquired immunity.

It is now well-known that interleukins (ILs) play a pivotal role in shaping innate immunity: inflammatory ILs are responsible for all innate aspects of immune response, from the very first vascular reactions to the chronic non-specific response to inflammation; while anti-inflammatory ILs are responsible for keeping adaptive immunity at bay. The interactions between ILs and adaptive immunity have been long considered secondary to the effects on the innate immune system, but in recent years it has appeared more clearly that IL direct interactions with adaptive immunity are extremely important both in physiologic and pathologic immune response. In the present review we analyze the role of inflammatory ILs (IL-1, IL-6, IL-33 and IL-37) on adaptive immunity and briefly discuss the possible therapeutic perspectives of IL-blockade in adaptive immunity disorders.

Interleukin-1 family cytokines and mast cells: activation and inhibition.

Activated mast cells (MCs) secrete a number of compounds including pro-inflammatory and anti-inflammatory cytokines. MCs are a potential source of cytokines and chemokines which participate in allergic reactions and inflammation. MCs can be activated by IgE through its receptor FceRI, but also by Toll-like receptors and/or interleukin (IL)-1. MCs can be a target for both pro-inflammatory and anti-inflammatory cytokines. IL-1 activates MCs to release inflammatory chemical mediators, and cytokines/chemokines, an effect which can be potentially inhibited by IL-37. In addition, IL-36 is also a powerful cytokine with a pro-inflammatory activity. IL-38 binds IL-36R and inhibits the pro-inflammatory activity of IL-36, thus performing a therapeutic action. In this article we review the role of MCs in relation to pro-inflammatory and anti-inflammatory IL-1 family member cytokines and a possible therapeutic effect in inflammatory disorders.

Gut microbiota and immunity in common variable immunodeficiency: crosstalk with pro-inflammatory cytokines.

In recent years, gut microbiota (GM) has emerged as a key factor in shaping the pathogenesis of a vast array of immune-mediated diseases, as well as in the response to immune-based treatments such as anti PD-1 and anti-CTLA4 therapy or influenza vaccination. In addition, GM has a significant role in the immune system development and is fundamental in developing mucosal immunity. Recent data suggest that GM plays an important role in the immune system of immune deficient patients. GM status has a remarkable impact on the immune system and in immune deficient patients; this can lead to important consequences. Prebiotics are indeed a promising candidate in restoring GM homeostasis and improving immunity. Antibiotics are also capable of altering the microbial equilibrium.

Parotid Gland Lesions: Multiparametric Ultrasound and MRI Features.

High-resolution ultrasound (US), as a readily available, cost-effective and harmless imaging technique, is appropriately the initial imaging modality for salivary gland lesions. Benign tumors are reported to present with regular and well-defined margins, a homogeneous hypoechoic structure and demarcated vessel distribution, whereas malignant lesions are irregular, heterogeneous and diffusely perfused. Ultrasound and color Doppler features of benign and malignant salivary gland lesions overlap, and many benign tumors, particularly pleomorphic adenomas, may appear irregularly shaped, with a heterogeneous echo-structure indistinguishable from a malignant lesion. Often skilled US operators are not always able to differentiate benign from malignant lesions. The introduction of US contrast agents has allowed further perspectives in the possible improvement of lesion characterization, and the emergence of US elastography, an innovative tool for assessing lesion stiffness/elasticity characteristics, has been advocated for differentiating salivary gland lesions. When lesions are atypical on US, contrast-enhanced magnetic resonance (MR) imaging is usually the definitive imaging modality. We present a current review of benign and malignant parotid gland tumors with emphasis on the role of multiparametric US and MR imaging.

IMMUNOMODULATORY EFFECTS OF VITAMIN D ON SKIN INFLAMMATION.

Vitamin D has a major role in calcium absorption and maintenance of healthy bones. Vitamin D is also involved in cancer, cardiovascular system, allergic diseases, immune regulation and immune disor¬ders. Irradiation of food as well as animals produces vitamin D and more than 90% of previtamin D3 synthesis in the skin occurs in the epidermis. Vitamin D receptor has been found in many cells including T and B lymphocytes, macrophages, mast cells, NK cells and Tregs, and it selectively binds with high affinity to its ligand. Vitamin D binds its receptor VDR, resulting in transcription of a number of genes playing a role in inhibition of MAPK. Its effect may be also mediated by the direct activation of PKC. Vitamin D has the ability to suppress inflammatory cytokines such as TNF, IL-1, IFN-gamma and IL-2; while it increases the generation of anti-inflammatory cytokines IL-4 and IL-10. In B cells, vitamin D3 have also been shown to suppress IgE antibody class switch partly through the inhibition of NF-kB. Here we discuss the relationship between vitamin D, immunity and skin disorders.

CROSSTALK BETWEEN VITAMIN B AND IMMUNITY.

Vitamin B1 (thiamin) is considered to be the oldest vitamin and in 1936 R.R. Williams and colleagues determined its chemical structure and were able to synthesize this vitamin. Vitamin B1 influences pro-apoptotic proteins, mitochondrial membrane potential, cytochrome C release, protein kinases, p38-MAPK, suppresses oxidative stress-induced NF-kappaB and has anti-inflammatory properties. Deficiency of vitamin B1 may cause beriberi, dysfunction of the nervous system, neuroinflammation, T cell infiltration, chemokine CCL2 activation, over expression of proinflammatory cytokines, such as IL-1, TNF, IL-6, and arachidonic acid products, and induces expression of CD40 by the microglia and CD40L by astrocytes which provoke the death of neurons. Here we report the relationship between vitamin B complex and immunity.

Can vitamin a mediate immunity and inflammation?

Vitamins are natural components of foods and are organic compounds distinct from fat, carbohydrates and proteins. Vitamin A is the generic descriptor for compounds with the qualitative biological activity of retinol. Unlike beta-carotene, vitamin A is not an antioxidant and its benefit is related to possible boosting of immune reactions. The effect of vitamin A on immune function is wide-reaching and its deficiency appears to affect immunity in several ways. Innate and adaptive immune responses are affected in some way by lack of vitamin A. Retinoids seem to act on differentiation of lymphocytes, antibody production, phagocytosis of macrophages, NK, Treg, and T helper cell activity. In addition, in humans, signs of a vitamin A deficiency also include the dysregulation of cytokine/chemokine generation and release. However, excess of vitamin A has been demonstrated to have toxic effects in most species studied. Here we summarize some important effects of vitamin A in immunity and inflammation.

Nerve growth factor interactions with mast cells.

Neuropeptides are involved in neurogenic inflammation where there is vasodilation and plasma protein extravasion in response to this stimulus. Nerve growth factor (NGF), identified by Rita Levi Montalcini, is a neurotrophin family compound which is important for survival of nociceptive neurons during their development. Therefore, NGF is an important neuropeptide which mediates the development and functions of the central and peripheral nervous system. It also exerts its proinflammatory action, not only on mast cells but also in B and T cells, neutrophils and eosinophils. Human mast cells can be activated by neuropeptides to release potent mediators of inflammation, and they are found throughout the body, especially near blood vessels, epithelial tissue and nerves. Mast cells generate and release NGF after degranulation and they are involved in iperalgesia, neuroimmune interactions and tissue inflammation. NGF is also a potent degranulation factor for mast cells in vitro and in vivo, promoting differentiation and maturation of these cells and their precursor, acting as a co-factor with interleukin-3. In conclusion, these studies are focused on cross-talk between neuropeptide NGF and inflammatory mast cells.

Neuropeptide NGF mediates neuro-immune response and inflammation through mast cell activation.

Human mast cells (first described in 1879 by Paul Ehrlich) develop from committed precursors in the bone marrow expressing the differentiation marker CD34+ and distinct from the three other myeloid cells. Mast cells are present in various tissues especially near blood vessels, epithelia and nerves and they are activated by cross-linking of FcεRI, but also by a number of neuropeptides. NGF mediates a number of inflammatory and autoimmune states in conjunction with an increased accumulation of mast cells which appear to be involved in neuroimmune interactions and tissue inflammation. Here we report some relationships between mast cells and nerve growth factor (NGF).

Interrelationship between IL-3 and mast cells.

It is well established that mast cells, which are found in the tissues in the proximity of small blood vessels and post-capillary venules, play a key role in the early phase of IgE-mediated allergic reactions. A greatly expanded understanding of the biology of IL-3 has emerged since the early 1980s. IL-3 is a specific factor that stimulates the growth of hematopoietic stem and progenitor cells of a variety of lineages and can promote the proliferation of certain classes of lymphocytes distinct from those that are dependent on IL-2. IL-3 has been identified among the most important cytokines for regulation of mast cell growth and differentiation, migration and effector function activities of many hematopoietic cells. IL-3 termed multi colony-stimulating-factor (multi-CSF) or mast cell growth factor (MCGF) is a haematopoietic growth factor which stimulates the formation of colonies for erythroid, megakaryocytic, granulocytic and monocytic lineages. It is predominantly produced by activated T cells, natural killer (NK) cells and mast cells and supports the growth-promoting effects of SCF on mast cell precursors. IL-3 causes severe hypersensivity reactions and plays a pivotal role in exacerbating the inflammatory response in vivo. Here we report the interrelationship between IL-3 and mast cells.

IL-36 receptor antagonist with special emphasis on IL-38.

IL-36 is another family member of IL-1 and induces the production of proinflammatory cytokines and activates MAPK and NFkB pathways. IL-36 is a common mediator of innate and adaptive immune response and is inhibited by IL-36 receptor antagonist (RA). IL-36RA acts on IL-36 receptor ligand which exerts proinflammatory effect in vivo and in vitro. IL-38 binds to IL-36 receptor as does IL-36RA and has similar biological effects on immune cells. IL-38 is also a member of IL-1 cytokine and shares some characteristics of IL-1RA, binding the same IL-1 receptor type I. IL-38 plays a role in the pathogenesis of inflammatory diseases, exerting protective effect in some autoimmune diseases. Both IL-38 and IL-36RA have an anti-inflammatory biological effect, however in some cases have contrary effects.

Impact of capsaicin on mast cell inflammation.

Mast cells are inflammatory cells, and they are prominent in inflammatory diseases such as allergy and asthma. Mast cells possess high-affinity receptors for IgE (FcERI) and the cross-linking of these receptors is essential to trigger the secretion of granules containing arachidonic acid metabolism (such as prostaglandin (PG) D2, leukotriene (LT) B4, and LTC4), histamine, cytokines, chemokines, and proteases, including mast cell-specific chymases and tryptases. Activation of mast cells provokes the secretion of cytokines and mediators that are responsible for the pathologic reaction of immediate hypersensitivity. Sensory nerve stimulation by irritants and other inflammatory mediators provokes the release of neuropeptides, causing an increase in vascular permeability, plasma extravasation and edema. Trigeminal nerve stimulation actives dura mast cells and increases vascular permeability, effects inhibited by capsaicin. Capsaicin causes release of sensory neuropeptide, catecholamines and vasodilation. Several studies have reported that capsaicin is effective in relief and prevention of migraine headaches, improves digestion, helps to prevent heart disease, and lowers blood cholesterol and blood pressure levels. The findings reported in these studies may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders.

Vascular endothelial growth factor (VEGF), mast cells and inflammation.

Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis, therefore blocking angiogenesis has led to great promise in the treatment of various cancers and inflammatory diseases. VEGF, expressed in response to soluble mediators such as cytokines and growth factors, is important in the physiological development of blood vessels as well as development of vessels in tumors. In cancer patients VEGF levels are increased, and the expression of VEGF is associated with poor prognosis in diseases. VEGF is a mediator of angiogenesis and inflammation which are closely integrated processes in a number of physiological and pathological conditions including obesity, psoriasis, autoimmune diseases and tumor. Mast cells can be activated by anti-IgE to release potent mediators of inflammation and can also respond to bacterial or viral antigens, cytokines, growth factors and hormones, leading to differential release of distinct mediators without degranulation. Substance P strongly induces VEGF in mast cells, and IL-33 contributes to the stimulation and release of VEGF in human mast cells in a dose-dependent manner and acts synergistically in combination with Substance P. Here we report a strong link between VEGF and mast cells and we depict their role in inflammation and immunity.

Impact of mast cells on the skin.

When through the skin a foreign antigen enters it provokes an immune response and inflammatory reaction. Mast cells are located around small vessels that are involved in vasaldilation. They mature under the influence of local tissue to various cytokines. Human skin mast cells play an essential role in diverse physiological and pathological processes and mediate immediate hypersensitive reaction and allergic diseases. Injection of anti-IgE in the skin or other agents that directly activate mast cells may cause the decrease in vascular tone, leakage of plasma and may lead to a fall in blood pressure with fatal anaphylactic shock. Skin mast cells are also implicated as effector cells in response to multiple parasites such as Leishmania which is primarily characterized by its tissue cutaneous tropism. Activated macrophages by IFNgamma, cytotoxic T cells, activated mast cells and several cytokines are involved in the elimination of the parasites and immunoprotection. IL-33 is one of the latest cytokines involved in IgE-induced anaphylaxis and in the pathogenesis of allergic skin disorders. IL-33 has been shown in epidermis of patients with psoriasis and its skin expression causes atopic dermatitis and it is crucial for the development of this disease. Here we review the impact of mast cells on the skin.

Common variable immunodeficiency - new insight into the pathogenesis and the quest for a workable classification.

In this editorial we argue that more and more complex classifications for patients with common variable immunodeficiency (CVID) fail to identify those patients at high risk of developing infections. We propose that the minimal requirement to identify such patients is the absolute numbers of total and memory B cells and the IgM response to immunization with polysaccharides. If these data should be confirmed, they will provide the basis for a good classification of a heterogeneous group of patients. This simple, workable classification may result in a clinically useful identification of patients prone to more aggressive infections.

Comparison of beneficial actions of non-steroidal anti-inflammatory drugs to flavonoids.

Inflammation is involved in increasing number of diseases necessitating the development of new, effective and safe treatments. Non steroidal anti-inflammatory drugs (NSAIDs) have been helpful in many instances, but they only inhibit cyclooxygenase (COX), but not the generation or actions of cytokines. Instead, some natural flavonoids have multiple anti-inflammatory effects, including COX inhibition, and a much safer profile. Increasing evidence indicates that inflammation plays a critical role in the pathogenesis of many diseases that also involve mast cells. Consequently, the need for new, effective and safe anti-inflammatory drugs is all the more urgent. Corticosteroids are quite potent, but have many adverse effects such as increased risk of infections, osteoporosis, glaucoma and depression. Biological agents such anti-TNF are useful in certain conditions, such as rheumatoid arthritis and psoriasis, but has been associated with increased risk of infection and leukemia.

Mast cell involvement in rheumatoid arthritis.

Autoimmunity is a failure of self-tolerance resulting in immune reactions against autologous antigen. Rheumatoid arthritis is characterized by inflammation of synovium associated with destruction of the join cartilage and bone. A role of mast cell-mediated inflammation and antibodies are involved in this disease. Numerous cytokines such as IL-1, TNF, IL-8, IL-33 and IFN gamma have been implicated in rheumatoid arthritis and in particular in the synovial joint fluid. Since TNF is believed to activates resident synovial cells to produce collagenase that mediate destruction of cartilage, antagonists against the inflammatory cytokine TNF have a beneficial effects in this disease. Here we review the interrelationship between rheumatoid arthritis and mast cell activation.

Role of vitamins D, E and C in immunity and inflammation.

Inflammatory responses are operationally characterized by pain, redness, heat and swelling at the site of infection and trauma. Mast cells reside near small blood vessels and, when activated, release potent mediators involved in allergy and inflammation. Vitamin D modulates contraction, inflammation and remodeling tissue. Vitamin D deficiency has been linked to multiple diseases and several data have demonstrated a strong relationship between serum vitamin D levels and tissue function. Therapy targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions. Mast cells are activated by oxidized lipoproteins, resulting in increased expression of inflammatory cytokines and suggesting that the reduction of oxidation of low density lipoprotein by vitamin E may also reduce mast cell activation. Vitamin C is also an anti-oxidant well-known as an anti-scurvy agent in humans. Vitamin C inhibits peroxidation of membrane phospholipids and acts as a scavenger of free radicals and is also required for the synthesis of several hormones and neurotransmitters. In humans, vitamin C reduces the duration of common cold symptoms, even if its effect is not clear. Supplementation of vitamin C improves the function of the human immune system, such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis and delayed-type hypersensitivity. Vitamin C depletion has been correlated with histaminemia which has been shown to damage endothelial-dependent vasodilation. However, the impact of these vitamins on allergy and inflammation is still not well understood.

Luteolin inhibits mast cell-mediated allergic inflammation.

Mast cells are ubiquitous in the body and multifunctional immune cells; they are known to be primary responders in allergic reactions, orchestrating strong responses to minute amounts of allergens. Mature mast cells perform important beneficial roles in host defense, both in IgE-dependent immune responses to certain parasites and in natural immunity to bacterial infection. In IgE-associated biological responses, the crosslinking of FcεRI-bound IgE with multivalent antigens initiate the activation of mast cells by promoting aggregation of FceRI. This cross-linking receptor-bound IgE by multivalent Ag initiates a cascade of intracellular reactions leading to mediator release such as proinflammatory mediators, chemokines and cytokines. Luteolin belongs to a flavone group of compounds called flavonoids, it has anti-oxidant properties, inhibits some cancer cell proliferation and exerts a regulatory effect on mast cell-mediated inflammatory diseases and allergy. Here we report the impact of luteolin on mast cell activation.