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      Type 3 hypersensitivity in COVID-19 vasculitis

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          Abstract

          Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden around the world. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response ( humoral immunity) to type 3 hypersensitivity ( immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.

          Highlights

          • COVID-19 is an ongoing public health emergency around the world.

          • New knowledge about its immunopathogenic mechanisms is required.

          • Type 3 hypersensitivity reaction in COVID-19 vasculitis is here disclosed.

          • Inflamed vascular smooth muscle cells concur to the cytokine storm via IL-6.

          • Histology, histochemistry and immunofluorescence have been successfully applied.

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          Most cited references7

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          Thromboembolic risk and anticoagulant therapy in COVID‐19 patients: emerging evidence and call for action

          Summary Emerging evidence shows that severe coronavirus disease 2019 (COVID‐19) can be complicated with coagulopathy, namely disseminated intravascular coagulation, which has a rather prothrombotic character with high risk of venous thromboembolism. The incidence of venous thromboembolism among COVID‐19 patients in intensive care units appears to be somewhat higher compared to that reported in other studies including such patients with other disease conditions. D‐dimer might help in early recognition of these high‐risk patients and also predict outcome. Preliminary data show that in patients with severe COVID‐19, anticoagulant therapy appears to be associated with lower mortality in the subpopulation meeting sepsis‐induced coagulopathy criteria or with markedly elevated d‐dimer. Recent recommendations suggest that all hospitalized COVID‐19 patients should receive thromboprophylaxis, or full therapeutic‐intensity anticoagulation if such an indication is present.
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            Type 1/Type 2 immunity in infectious diseases.

            T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-gamma, and lymphotoxin-alpha and stimulate type 1 immunity, which is characterized by intense phagocytic activity. Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody titers. Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation. Severe systemic stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a type 2 response to an infection normally controlled by type 1 immunity. In such cases, administration of antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful immune responses to clear the infection.
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              Signals of T h 2 immune response from COVID-19 patients requiring intensive care

              Dear Editor, Naїve T-helper cells (Th0) can respond to novel pathogens that the immune system has never encountered before, as is the specific case of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the positive-sense single-stranded RNA virus responsible for the ongoing pandemic named coronavirus disease 2019 (COVID-19). Depending on the infectious agent, Th0 polarize the immune response into T-helper type 1 (Th1), the default response in immunocompetent subjects to intracellular or phagocytosable pathogens (e.g. viruses, bacteria, protozoa, fungi) and mediated by macrophages and T-cytotoxic (Tc) cells (cell-mediated immunity), or into T-helper type 2 (Th2), classically directed against extracellular non-phagocytosable pathogens, for instance helminths, and whose main effectors are eosinophils, basophils and mastocytes, as well as B cells (humoral immunity) [1]. Eosinophils play a direct role in fighting RNA viruses, as demonstrated by the presence of RNases inside their granules [1]; however, they have been negatively associated with the pathophysiology of the respiratory virus infections, since they trigger bronchoconstriction and dyspnea, besides virus-induced exacerbations of allergic airways diseases, by releasing a large amount of cationic proteins and cytokines, among which interleukin-6 (IL-6), a key mediator also for the development of the “cytokine storm” in COVID-19 fatal cases [2, 3]. At some extent, the smooth muscle cells in the tunica media of blood vessels can produce IL-6, too [4]. It belongs to Th2 cytokines class together with IL-4, IL-5, IL-9, IL-10, IL-13 and IL-25; contrariwise, IL-2, IL-12, interferon-γ and tumor necrosis factor-α are the main Th1 cytokines, able to stimulate the inducible form of the nitric oxide (NO) synthase to produce NO free radicals endowed with virucidal activity [1]. To minimize the contagion risk in healthcare personnel, we have prepared and examined a limited number of 15 peripheral blood smears from a wider series of hospitalized COVID-19 patients, just admitted to intensive care and monitored through blood tests; in all the cases, we have found cytological signals of Th2 immune response, represented by eosinophilia plus basophilia, degranulated eosinophils, Türk cells or plasma cells, together with rouleaux and Tc lymphopenia (Fig. 1). On the basis of our findings, for reasons still unclear, maybe related to the viral load, Th1 and Tc breakdown, antigenic cross-reactivity or the type of antigen-presenting cell stimulating Th0, the immune system mounts a Th2 response against SARS-CoV-2 in patients requiring intensive care, rather than a Th1 response, which would keep the infection under control by means of macrophages and Tc cells. This event is more likely in patients affected by cancer, immunodeficiency, autoimmune disorders, congestive heart failure, chronic obstructive pulmonary disease and hepatic cirrhosis, or in those who have suffered major surgery and traumatic injury, or who are on glucocorticoid therapy and total parenteral nutrition, all known conditions suppressive to Th1 immunity [1]. The mounting of a Th2 immune response allows to explain well the concurrent gastrointestinal symptoms present up to 30% of COVID-19 patients and significantly associated with dyspnea [5]; in fact, hyperperistalsis and gastric fluid acidification are also two notorious default mechanisms of defense to expel parasites governed by Th2 cytokines [1]. Fig. 1 Cytological signals of Th2 immune response on peripheral blood smears from COVID-19 patients requiring intensive care: a on the right side of the panel, three eosinophils in a row accompanied by a basophile in the upper left corner (× 40 objective); b an eosinophil in the degranulation phase (× 100 objective); c a bilobed degranulated eosinophil in the center of the panel (× 100 objective); d an immature plasma cell (Türk cell) in the midst of prominent rouleaux (× 100 objective) (May-Grünwald stain)
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                Author and article information

                Contributors
                Journal
                Clin Immunol
                Clin. Immunol
                Clinical Immunology (Orlando, Fla.)
                Elsevier Inc.
                1521-6616
                1521-7035
                29 May 2020
                29 May 2020
                : 108487
                Affiliations
                [a ]Institute of Pathology, University of Modena and Reggio Emilia, Modena, Italy
                [b ]Hemolymphopathology Team, University Hospital of Modena, Modena, Italy
                [c ]Immunohistochemistry Lab, University Hospital of Modena, Modena, Italy
                [d ]Nephrology Lab, University of Modena and Reggio Emilia, Modena, Italy
                [e ]Department of Surgery, University of Modena and Reggio Emilia, Modena, Italy
                Author notes
                [* ]Corresponding author at: Hemolymphopathology Team Coordinator and Immunohistochemistry Lab Executive, Polyclinic Hospital, Largo del Pozzo 71, 41124 Modena, Italy. roncati.luca@ 123456aou.mo.it
                Article
                S1521-6616(20)30452-6 108487
                10.1016/j.clim.2020.108487
                7256503
                32479986
                1c7f4abc-c06c-44b9-82a2-303bf82e5d28
                © 2020 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 23 May 2020
                : 26 May 2020
                : 27 May 2020
                Categories
                Article

                Immunology
                coronavirus disease 2019 (covid-19),severe acute respiratory syndrome coronavirus 2 (sars-cov-2),type iii hypersensitivity,immune complex disease,vasculitis,interleukin-6 (il-6)

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