Under physiological conditions, skin mast cells preferentially localize around nerves, blood vessels and hair follicles. This observation, which dates back to Paul Ehrlich, intuitively suggests that these enigmatic, multifacetted protagonists of natural immunity are functionally relevant to many more aspects of tissue physiology than just to the generation of inflammatory and vasodilatory responses to IgE-dependent environmental antigens. And yet, for decades, mainstream-mast cell research has been dominated by a focus on the -undisputedly prominent and important - mast cell functions in type I immune responses and in the pathogenesis and management of allergic diseases. Certainly, it is hard to believe that the very large and rather selectively distributed number of mast cells in normal, uninflamed, non-infected, non-traumatized mammalian skin or mucosal tissue simply hanging around there lazily day and night, just wait for the odd allergen or parasite-associated antigen to come by so the mast cell can finally swing into action. Indeed, the past decade has witnessed a renaissance of mast cell research 'beyond allergy', along with a more systematic exploration of the surprisingly wide range of physiological functions that mast cells may be involved in. The current debate sketches many exciting horizons that have recently come into our vision during this intriguing, ongoing search.

Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood–brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1β), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFβ induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.

Dear EditorThe new coronavirus (severe acute pulmonary syndrome [SARS]-CoV-2) originated in China, where it spread rapidly, 1 and has reached pandemic proportions because of its high rate of infectivity as well as high morbidity and mortality, associated with This coronavirus infects by first binding to the ectoenzyme angiotensinconverting enzyme 2 (ACE 2 ), 3,4 a serine protease acting as the receptor, while another serine protease is necessary for priming the viral "S" protein required for entering the cells. 5 Defense against the virus apparently does not involve inflammatory cytokines, 6 but pulmonary infection and its serious sequelae result from the release of multiple chemokines and cytokines that damage the lungs.A recent report correlated coronaviruses infection with activation of mast cells and subsequent cytokine storms in the lungs. 7 Mast cells are known to be triggered by viruses. 8 Mast cells are unique immune cells that are ubiquitous in the body, especially the lungs, 9 and are critical for allergic and pulmonary diseases, 10 including mastocytosis 11 by secreting histamine, leukotrienes, and proteases. Mast cells are also involved in the development of inflammation 12 via release of multiple pro-inflammatory cytokines and chemokines. 13,14 Mast cells contain the serine protease ACE 2 , which can convert angiotensin I into angiotensin II. 15 In addition to the bronchoconstrictive action of mast cell-derived leukotrienes, mast cells cause further bronchoconstriction via an active renin-angiotensin generating system in the lungs. 16 Moreover, mast cells express a number of serine proteases, 17 especially the mast cell-serine protease tryptase, 18 which are necessary for infection by SARS-CoV-2. A serine protease inhibitor, camostat mesylate, was recently shown to prevent entry of the virus into the lung cells of SARS-CoV-2-infected patients. 19 It would be important to not only inhibit entry of SARS-CoV-2 but also prevent SARS associated with COVID-19.The possible use of nonsteroidal anti-inflammatory agents has come into question for possibly aggravating pulmonary symptoms, 20 while broad-spectrum immune suppressors, such as corticosteroids, 21 would not be advisable given that an intact immune system is necessary to fight the infection and it may even lead to increased plasma viral load. 22 Inhibition of mast cell-associated inflammation could be accomplished with natural molecules, especially the polyphenolic flavonoids. 23 The flavone luteolin (not lutein, which is a carotenoid) has been shown to have broad antiviral properties. [24][25][26] Luteolin specifically binds to the surface spike protein of SARS-Cov-2 and inhibits entry of the virus into host cells. 27 Furthermore, luteolin inhibits serine proteases, 28 including the SARS-CoV 3CL protease 29 required for viral infectivity.Moreover, luteolin inhibits mast cells 30,31 and has anti-inflammatory properties. 32 A novel luteolin analogue, tetramethoxyluteolin, is even more potent 32 and can also inhibit secretion of the pro-inflammatory cy...