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The first case of the new coronavirus, COVID-19, was reported in China on 17 November 2019. By the end of March 2020, the rapid global spread of infection affected over 1 million people. Italy is one of the countries most impacted, with over 100,000 positive cases identified. The first detected cases were reported on 21 February 2020 in two Italian towns: Vo’ Euganeo in the Province of Padua, Veneto region, and Codogno, in the Province of Lodi, Lombardy. In the next weeks the epidemic spread quickly across the country but mainly in the north of Italy. The two regions: Veneto and Lombardy, implemented different strategies to control the viral spread. In Veneto, health personnel tested both symptomatic and asymptomatic subjects, while in Lombardy only symptomatic cases were investigated. We analyzed the evolution of the epidemic in these regions and showed that testing both symptomatic and asymptomatic cases is a more effective strategy to mitigate the epidemic impact. We strongly recommend that decision-makers:

Th17 lymphocytes, beyond their protective role in the clearance of extracellular pathogens, also play a role in the pathogenesis of several autoimmune and inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases, psoriasis and contact dermatitis. Nevertheless, they are very rare at inflammatory sites in comparison with other T cell subsets. Recently, this rarity has been explained by the finding that Th17 cells rapidly shift into the Th1 phenotype in the presence of IL-12 and/or TNF-α as well as by the fact that they possess self-regulatory mechanisms limiting their own expansion. Th17 lymphocytes that have shifted towards a Th1 phenotype seem to be particularly aggressive and more pathogenic than the Th17 unshifted cells. As a consequence, the Th17-derived Th1 cells, named non-classic Th1 cells, can become a possible target for the therapy of some inflammatory disorders. In particular, convincing evidence has recently been accumulated indicating that this subset can play a role in Crohn's disease and juvenile idiopathic arthritis. More importantly, it has been shown that TNF-α inhibitors, which are used for the treatment of such diseases, appear to be able to inhibit the transition of Th17 lymphocytes to the non-classic Th1 phenotype, and thus they possibly help to dampen inflammation and arrest disease progression. Based on this context, the definition of the soluble factors involved in the shifting from Th17 towards non-classic Th1 subset as well as the comprehension of their respective pathogenic role in human inflammatory disorders would be of great help for developing novel therapeutic strategies.

Autoimmune disorders are characterized by tissue damage, caused by self-reactivity of different effectors mechanisms of the immune system, namely antibodies and T cells. Their occurrence may be associated with genetic and/or environmental predisposition and to some extent, have implications for fertility and obstetrics. The relationship between autoimmunity and reproduction is bidirectional. This review only addresses the impact of pregnancy on autoimmune diseases and not the influence of autoimmunity on pregnancy development. Th17/Th1-type cells are aggressive and pathogenic in many autoimmune disorders and inflammatory diseases. The immunology of pregnancy underlies the role of Th2-type cytokines to maintain the tolerance of the mother towards the fetal semi-allograft. Non-specific factors, including hormonal changes, favor a switch to Th2-type cytokine profile. In pregnancy Th2, Th17/Th2 and Treg cells accumulate in the decidua but may also be present in the mother’s circulation and can regulate autoimmune responses influencing the progression of autoimmune diseases.

Previous interethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than are sympatric ethnic groups. This lower susceptibility is not associated to classic malaria-resistance genes, and the analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in Fulani. In the present study we compared the expression profile of a panel of genes involved in immune response in peripheral blood mononuclear cells (PBMC) from Fulani and sympatric Mossi from Burkina Faso. An increased expression of T helper 1 (TH1)-related genes (IL-18, IFNγ, and TBX21) and TH2-related genes (IL-4 and GATA3) and a reduced expression of genes distinctive of T regulatory activity (CTLA4 and FOXP3) were observed in Fulani. Microarray analysis on RNA from CD4⁺CD25⁺ (T regulatory) cells, performed with a panel of cDNA probes specific for 96 genes involved in immune modulation, indicated obvious differences between the two ethnic groups with 23% of genes, including TGFβ, TGFβRs, CTLA4, and FOXP3, less expressed in Fulani compared with Mossi and European donors not exposed to malaria. As further indications of a low T regulatory cell activity, Fulani showed lower serum levels of TGFβ and higher concentrations of the proinflammatory chemokines CXCL10 and CCL22 compared with Mossi; moreover, the proliferative response of Fulani to malaria antigens was not affected by the depletion of CD25⁺ regulatory cells whereas that of Mossi was significantly increased. The results suggest that the higher resistance to malaria of the Fulani could derive from a functional deficit of T regulatory cells.

Atherosclerotic lesions are infiltrated by macrophages and T lymphocytes, potentially reactive to pathogens. We studied in vivo activated T lymphocytes that infiltrate atherosclerotic plaques of Helicobacter pylori-infected patients with or without anti-Chlamydia pneumoniae antibodies. In all atherosclerotic lesions, T helper type 1 (Th1) cells were predominant. C. pneumoniae-specific T cells were detected only in the plaques of anti-C. pneumoniae seropositive patients, whereas H. pylori-specific T cells were found in the gastric mucosa but not in the plaques of the same patients. Plaque-derived Th1 cells expressed cytotoxicity, proapoptotic activity, and help for monocyte tissue factor production. Although multifactorial, atherosclerosis can be regarded as a Th1-driven immunopathological condition.

SummaryA large body of evidence indicates the existence of functionally polarized CD4+ T-cell responses based on their profile of cytokine secretion. Type 1 T helper (Th1) cells produce interferon-gamma, interleukin (IL)-2, and tumor necrosis factor (TNF)-β, which activate macrophages and are responsible for cell-mediated immunity and phagocyte-dependent protective responses. By contrast, type 2 Th (Th2) cells produce IL-4, IL-5, IL-10, and IL-13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions, thus providing phagocyte-independent protective responses. Th1 cells mainly develop following infections by intracellular bacteria and some viruses, whereas Th2 cells predominate in response to infestations by gastrointestinal nematodes. Polarized Th1 and Th2 cells not only exhibit different functional properties, but also show the preferential expression of some activation markers and distinct transcription factors. Several mechanisms may influence the Th cell differentiation, which include the cytokine profile of “natural immunity” evoked by different offending agents, the nature of the peptide ligand, as well as the activity of some costimulatory molecules and microenvironmentally secreted hormones, in the context of the individual genetic background. In addition to playing different roles in protection, polarized Th1-type and Th2-type responses are also responsible for different types of immunopathological reactions. Th1 cells are involved in the pathogenesis of organ-specific autoimmune disorders, Crohn's disease, Helicobacter pylori-induced peptic ulcer, acute kidney allograft rejection, and unexplained recurrent abortions. In contrast, allergen-specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals. Moreover, Th2 responses against still unknown antigens predominate in Omenn's syndrome, idiopathic pulmonary fibrosis, and progressive systemic sclerosis. Finally, the prevalence of Th2 responses may play some role in a more rapid evolution of human immunodeficiency virus infection to the full-blown disease. The Th1/Th2 paradigm also provides the rationale for the development of new types of vaccines against infectious agents and of novel strategies for the therapy of allergic and autoimmune disorders.

BACKGROUNDCoronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Antiviral immune response is crucial to achieve pathogen clearance; however, in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options.METHODSWe performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes.RESULTSPatients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in patients with COVID-19, particularly in those who required intensive care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme A-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells.CONCLUSIONThe association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms.FUNDINGThis study was supported by funds from the Department of Experimental and Clinical Medicine of University of Florence (the ex-60% fund and the \"Excellence Departments 2018-2022 Project\") derived from Ministero dell'Istruzione, dell'Università e della Ricerca (Italy).

Type 17 T helper (T H 17 ) cells were first discovered in mice as a distinct population of T helper cells that produce interleukin-17. Since then, the origin of human T H 17 cells, the factors inducing their differentiation and the possible role these cells have in the pathogenesis of human rheumatologic disorders have been matter of intense debate. Type 17 T helper (T H 17) cells are a population of CD4 + effector T cells that are distinct from T H 1 and T H 2 cells owing to their ability to produce interleukin (IL)-17. Although T H 1 and T H 2 cells are similar in mice and humans, T H 17 cells differ in several ways. The differentiation of mouse T H 17 cells requires transforming growth factor β and IL-6, whereas human naive T cells can develop into T H 17 cells in the presence of IL-1β and IL-23 alone, transforming growth factor β having an indirect role in their development via the selective inhibition of T H 1 cell expansion. In both mice and humans, a late developmental plasticity of T H 17 cells towards the T H 1 lineage has been shown. Mainly based on mouse gene knockout studies, T H 17 lymphocytes have been found to have a pathogenic role in several autoimmune disorders; however, whether human autoimmune disorders, including rheumatoid arthritis (RA) and psoriasis, are prevalently T H 1-mediated or T H 17-mediated, is still unclear. Research suggests that both T H 1 and T H 17 cells are involved in RA pathogenesis, raising the possibility that interventions that target both the IL-23–IL-17 (T H 17) and the IL-12–interferon γ (T H 1) axes might be successful future therapeutic approaches for RA. Key Points It is our opinion that the origin and development of type 17 T helper (T H 17) cells in humans is different than in mice Human T H 17 cells can be induced to produce interferon-γ in the presence of interleukin (IL)-12, thus becoming T H 17/T H 1 cells T H 17 cells are associated with several immune-mediated diseases, particularly psoriasis and rheumatoid arthritis, owing to the pleiotropic effects exerted by IL-17 and related-cytokines on osteoblasts, B cells and monocytes The pathogenesis of rheumatoid arthritis is more complex than previously thought; both T H 17 and T H 1 cells are probably involved in the maintenance of inflammation that leads to joint destruction Immune-mediated diseases could perhaps be treated more effectively by therapeutic interventions that target both the IL-23–IL-17 (T H 17) and IL12–interferon-γ (T H 1) axes, rather than just a single pathway

Immunological tolerance is a complex series of mechanisms that impair the immune system to mount responses against self antigens. Central tolerance occurs when immature lymphocytes encounter self antigens in the primary lymphoid organs, and consequently they die or become unreactive. Peripheral tolerance occurs when mature lymphocytes, escaped from negative selection during ontogeny, encounter self antigens in secondary lymphoid organs and undergo anergy, deletion or suppression. A heterogeneous family of T regulatory cells has recently been identified, which have been found to play an important role in suppressing immune responses against self. Failure or breakdown of immunological tolerance results in autoimmunity and autoimmune diseases. Such events are related to both genetic and environmental factors, the latter being mainly represented by infections. Infectious agents can indeed promote autoimmune responses either by inducing tissue inflammation and therefore an unintended bystander activation of autoreactive T cells, or by promoting T cell responses to microbial epitopes that cross react against self peptides.

Background: The aim of this study was to investigate whether human mast cells express functional active CCR3 receptors, which are activated by CC chemokines. These ligands include the CCR3-selective chemokines eotaxin and eotaxin-2 and the more promiscuous CC chemokines, MCP-4, MCP-3, MCP-2 and RANTES. Methods: Immunohistochemical analysis was performed on skin, gut and lung specimens. Double immunostaining was performed with anti-CCR3 and antitryptase, and anti-CCR3 and antichymase antibody (Ab) by using the avidin-biotin-peroxidase system with two different substrates. Mast cells were isolated and purified from human lung parenchyma (HLMC) by countercurrent elutriation followed by discontinuous Percoll density gradient. Flow-cytometric analysis of HLMC surface CCR3 expression was performed with the monoclonal Ab anti-CCR3 (7B11). Functional activation of HLMC was verified by the ability of cells to release histamine and/or migrate in response to eotaxin. Results: High percentages (>70%) of tryptase-positive cells showing CCR3 expression were found in the skin and in the intestinal submucosa, whereas much lower percentages (≤20%) were found in the intestinal mucosa and in the lung interstitium. Eotaxin (1–100 nM) neither induced histamine release from HLMC nor enhanced anti-IgE-induced histamine release. In contrast, eotaxin (10–100 nM) and RANTES (10–100 nM) induced HLMC chemotaxis in vitro. Preincubation of HLMC with antibody anti-CCR3 (5 µg/ml) before loading into the chemotaxis chamber abrogated chemotaxis elicited by eotaxin. Double immunostaining with anti-CCR3 and anti-chymase antibody showed that the vast majority of CCR3-expressing mast cells in the various human tissues examined were tryptase-chymase double-positive. Conclusions: These results indicate that CCR3 is expressed on human mast cells and that these cells are attracted by CCR3-binding chemokines.