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      Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases

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      Clinical Immunology (Orlando, Fla.)
      Published by Elsevier Inc.

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          Abstract

          Since the outbreak of COVID-19 caused by SARS-CoV-2, we tested 5 different blood specimens that were confirmed positive for SARS-CoV-2 IgG and IgM antibodies [1]. The measurements were for anti-nuclear antibody (ANA), anti-extractable nuclear antigen (ENA), anti-double-stranded DNA (dsDNA), actin antibody, mitochondrial antibody, rheumatoid factor (RF), and C1q immune complexes. We were surprised to find out that 3 of the 5 specimens had significant elevations in ANA, ENA, actin and mitochondrial antibodies, but not against dsDNA or RF. This prompted us to investigate patterns of cross-reactivity between SARS-CoV-2 and autoimmune target proteins. Vaccine-induced autoimmunity from autoimmune cross-reactivity is associated with narcolepsy, Guillain-Barré syndrome, multiple sclerosis, demyelinating neuropathies, systemic lupus erythematosus, and postural orthostatic tachycardia syndrome in susceptible subgroups as reported by Segal and Shoenfeld [2]. Due to the significant red flags for the potential cross-reactive interactions with the current COVID-19 pandemic, we studied the relationships between spike and nuclear proteins of SARS-CoV-2 and autoimmune target proteins. Commercially available mouse monoclonal antibody made against recombinant SARS coronavirus spike protein and rabbit monoclonal antibody made against SARS coronavirus nucleoprotein were applied at optimal dilution to the SARS-CoV-2 proteins and to 50 different tissue antigens using enzyme-linked immunosorbent assay (ELISA). Recombinant SARS-CoV-2 spike protein S1 and recombinant SARS-CoV-2 nucleocapsid protein were purchased from RayBiotech. ELISA wells were coated with nuclear antigens, dsDNA, F-actin, and mitochondria (M2) antigen purchased from different companies. An additional 45 tissue antigens used in this study have been previously described [9]. Each SARS-CoV-2 antibody was applied to quadruplicate wells. After the completion of all ELISA steps, the developed color was measured at 405 nm. Looking at the reaction between SARS-CoV-2 spike protein antibody and tissue proteins (Fig. 1A), we found that the strongest reactions were with transglutaminase 3 (tTG3), transglutaminase 2 (tTG2), ENA, myelin basic protein (MBP), mitochondria, nuclear antigen (NA), α-myosin, thyroid peroxidase (TPO), collagen, claudin 5 + 6, and S100B. The reaction of this antibody was not as strong with several other antigens (Fig. 1A). Fig. 1 (A) Reaction of anti-SARS-CoV-2 spike protein monoclonal antibody with human tissue antigens. (B) Reaction of anti-SARS-CoV-2 nucleoprotein monoclonal antibody with human tissue antigens. Fig. 1 The nucleoprotein antibody showed some overlap in immune cross-reactivity with anti-spike protein antibody. As shown in Fig. 1B, nucleoprotein antibody reacted strongly with mitochondria, tTG6, NA, TPO, ENA, TG, actin, and MBP. Similar to spike protein, the nucleoprotein antibody reaction was not as strong with several other antigens as shown in Fig. 1A and B. As the number of SARS-CoV-2 infections increase from day to day, scientists are learning that the damage caused by this virus can extend well beyond the lungs, where infection can lead to pneumonia and the often fatal condition called acute respiratory distress syndrome [3]. The virus can in fact affect the body from head to toe, including the nervous [4], cardiovascular [5], immune [6], and digestive systems [7]. Is it possible that some of the extensive organ, tissue, and cellular damage done by SARS-CoV-2 is due to viral antigenic mimicry with human tissue? If the answer is yes, then we may face an increase in the rates of autoimmune disease in the future, because any factor that causes chronic inflammation in the body can potentially induce autoimmune disease. Because SARS-CoV-2 attacks the respiratory system first, in a very interesting letter [8] Kanduc and Shoenfeld suggested that because the SARS-CoV-2 spike glycoprotein and lung surfactant proteins shared 13 out of 24 pentapeptides, the immune response following infection with SARS-CoV-2 may lead to cross-reactions with pulmonary surfactant proteins, followed by SARS-CoV-2-associated lung disease [8]. Based on their findings, they warned against the use of the entire SARS-CoV-2 antigens in the vaccines and cautioned that perhaps the use of only unique peptides would be the most effective way to fight the SARS-CoV-2 infection. Very similar suggestions were made by Razim et al., in designing a vaccine against Clostridium difficile [9]. Two sequences, peptide 9 and peptide 10, of C. difficile were recognized not only by the sera of patients with C. difficile infections but also by the sera of patients with autoimmune disease. Razim et al. concluded that before considering a protein as a vaccine antigen, special care should be taken in analyzing the sequence of tissue cross-reactive epitopes in order to avoid possible future side effects [9]. We agree with Razim et al., and we feel that our own findings that 21 out of 50 tissue antigens had moderate to strong reactions with the SARS-CoV-2 antibodies are a sufficiently strong indication of cross-reaction between SARS-CoV-2 proteins and a variety of tissue antigens beyond just pulmonary tissue, which could lead to autoimmunity against connective tissue and the cardiovascular, gastrointestinal, and nervous systems. We live in critical times when the world may be veering towards the very real possibility of requiring immunity certification “passports” earned by prior infection with SARS-CoV-2 or vaccination before being allowed to travel, or perhaps even to work [10]. At the moment, scientists are frantically trying to develop either a definitive cure, neutralizing antibodies, or a vaccine to protect us from contracting the disease in the first place, and they want it right now. We must consider that finding a vaccine for a disease may normally take years. There are reasons for all the cautions involved in developing a vaccine, not the least of which are unwanted side-effects. In light of the information discussed above about the cross-reactivity of the SARS-CoV-2 proteins with human tissues and the possibility of either inducing autoimmunity, exacerbating already unhealthy conditions, or otherwise resulting in unforeseen consequences, it would only be prudent to do more extensive research regarding the autoimmune-inducing capacity of the SARS-CoV-2 antigens. The promotion and implementation of such an aggressive “immune passport” program worldwide in the absence of thorough and meticulous safety studies may exact a monumental cost on humanity in the form of another epidemic, this time a rising tide of increased autoimmune diseases and the years of suffering that come with them. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest None.

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          A pneumonia outbreak associated with a new coronavirus of probable bat origin

          Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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            Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection

            Objective To study the GI symptoms in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. Design We analysed epidemiological, demographic, clinical and laboratory data of 95 cases with SARS-CoV-2 caused coronavirus disease 2019. Real-time reverse transcriptase PCR was used to detect the presence of SARS-CoV-2 in faeces and GI tissues. Results Among the 95 patients, 58 cases exhibited GI symptoms of which 11 (11.6%) occurred on admission and 47 (49.5%) developed during hospitalisation. Diarrhoea (24.2%), anorexia (17.9%) and nausea (17.9%) were the main symptoms with five (5.3%), five (5.3%) and three (3.2%) cases occurred on the illness onset, respectively. A substantial proportion of patients developed diarrhoea during hospitalisation, potentially aggravated by various drugs including antibiotics. Faecal samples of 65 hospitalised patients were tested for the presence of SARS-CoV-2, including 42 with and 23 without GI symptoms, of which 22 (52.4%) and 9 (39.1%) were positive, respectively. Six patients with GI symptoms were subjected to endoscopy, revealing oesophageal bleeding with erosions and ulcers in one severe patient. SARS-CoV-2 RNA was detected in oesophagus, stomach, duodenum and rectum specimens for both two severe patients. In contrast, only duodenum was positive in one of the four non-severe patients. Conclusions GI tract may be a potential transmission route and target organ of SARS-CoV-2.
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              COVID-19 infection: the perspectives on immune responses

              More than 100 years since the outbreak of the 1918 influenza pandemic, we now seem to face another pandemic. The outbreak of the new coronavirus (SARS-CoV-2) infection is spreading to every continent, forcing us to live with this virus for perhaps a long time. Scientists and clinicians have learned much of coronavirus disease 2019, COVID-19, and its pathogenesis [1]: not all people exposed to SARS-CoV-2 are infected and not all infected patients develop severe respiratory illness. Accordingly, SARS-CoV-2 infection can be roughly divided into three stages: stage I, an asymptomatic incubation period with or without detectable virus; stage II, non-severe symptomatic period with the presence of virus; stage III, severe respiratory symptomatic stage with high viral load [2]. From the point of view of prevention, individuals at stage I, the stealth carriers, are the least manageable because, at least on some occasions, they spread the virus unknowingly: indeed, the first asymptomatic transmission has been reported in Germany [3]. The role of asymptomatic SARS-CoV-2 infected individuals in disseminating the infection remains to be defined. Among over 1000 patients analyzed in Wuhan, except occasionally in children and adolescence, it infects all the other age groups evenly. About 15% of the confirmed cases progress to the severe phase, although there is a higher chance for patients over 65 to progress into the severe phase [1]. One of the biggest unanswered questions is why some develop severe disease, whilst others do not. Clearly, the conventional wisdom based on overall immunity of the infected patients cannot explain this broad spectrum in disease presentation. Two-phase immune responses induced by COVID-19 infection Clinically, the immune responses induced by SARS-CoV-2 infection are two phased. During the incubation and non-severe stages, a specific adaptive immune response is required to eliminate the virus and to preclude disease progression to severe stages. Therefore, strategies to boost immune responses (anti-sera or pegylated IFNα) at this stage are certainly important. For the development of an endogenous protective immune response at the incubation and non-severe stages, the host should be in good general health and an appropriate genetic background (e.g. HLA) that elicits specific antiviral immunity. Genetic differences are well-known to contribute to individual variations in the immune response to pathogens. However, when a protective immune response is impaired, virus will propagate and massive destruction of the affected tissues will occur, especially in organs that have high ACE2 expression, such as intestine and kidney. The damaged cells induce innate inflammation in the lungs that is largely mediated by pro-inflammatory macrophages and granulocytes. Lung inflammation is the main cause of life-threatening respiratory disorders at the severe stage [4]. Therefore, good general health may not be advantageous for patients who have advanced to the severe stage: once severe lung damage occurs, efforts should be made to suppress inflammation and to manage the symptoms. Alarmingly, after discharge from hospital, some patients remain/return viral positive and others even relapse. This indicates that a virus-eliminating immune response to SARS-CoV-2 may be difficult to induce at least in some patients and vaccines may not work in these individuals. Those recovered from the non-severe stage should be monitored for the virus together with T/B cell responses. These scenarios should be considered when determining the strategies of vaccine development. In addition, there are many types or subtypes of coronavirus. Thus, if vaccines directly targeting SARS-CoV-2 prove to be difficult to develop, the Edward Jenner approach should be considered. Cytokine storm and lung damage The cytokine release syndrome (CRS) seems to affect patients with severe conditions. Since lymphocytopenia is often seen in severe COVID-19 patients, the CRS caused by SARS-CoV-2 virus has to be mediated by leukocytes other than T cells, as in patients receiving CAR-T therapy; a high WBC-count is common, suggesting it, in association with lymphocytopenia, as a differential diagnostic criterion for COVID-19. In any case, blocking IL-6 may be effective. Blocking IL-1 and TNF may also benefit patients. Although various clinical sites in China have announced the use of mesenchymal stromal/stem cells (MSCs) in severe cases with COVID-19 infection, solid results have yet to be seen. One caveat is that MSCs need to be activated by IFNγ to exert their anti-inflammatory effects, which may be absent in severely affected patients as T cells are not well activated by SARS-CoV-2 infection. To enhance effectiveness, one could consider employing the “licensing-approach”: pretreat MSCs with IFNγ with/without TNF or IL-1 [5]. Such cytokine-licensed MSCs could be more effective in the suppression of hyperactive immune response and promotion of tissue repair, as licensed-MSCs are effective in LPS-induced acute lung damage [6]. Lung damage is a major hurdle to recovery in those severe patients. Through producing various growth factors, MSCs may help repair of the damaged lung tissue. It is important to mention that various studies have shown that in animal models with bleomycin-induced lung injury, vitamin B3 (niacin or nicotinamide) is highly effective in preventing lung tissue damage [7]. It might be a wise approach to supply this food supplement to the COVID-19 patients. HLA haplotypes and SARS-CoV-2 infection The major-histocompatibility-complex antigen loci (HLA) are the prototypical candidates for genetic susceptibility to infectious diseases [8, 9]. Haplotype HLA-loci variability results from selective pressure during co-evolution with pathogens. Immunologists have found that T-cell antigen receptors, on CD4+ or CD8+ T cells recognize the conformational structure of the antigen-binding-grove together with the associated antigen peptides. Therefore, different HLA haplotypes are associated with distinct disease susceptibilities. The repertoire of the HLA molecules composing a haplotype determines the survival during evolution. Accordingly, it seems advantageous to have HLA molecules with increased binding specificities to the SARS-CoV-2 virus peptides on the cell surface of antigen-presenting cells. Indeed, the susceptibility to various infectious diseases such as tuberculosis, leprosy, HIV, hepatitis B, and influenza is associated with specific HLA haplotypes. Particular murine MHC class II haplotypes are associated with the susceptibility to influenza. In man, HLA class I is also associated with H1N1 infections: HLA-A*11, HLA-B*35, and HLA-DRB1*10 confers susceptibility to influenza A(H1N1)pdm09 infection [10]. Therefore, it is imperative to study whether specific HLA loci are associated with the development of anti-SARS-CoV-2 immunity and, if so, to identify the alleles, either class I or II, that demonstrate induction of protective immunity. Once the dominant alleles are identified, simple detection kits can be developed. Such information is critical for (1) strategic clinical management; (2) evaluation of the efficacy of vaccination in different individuals in the general population; (3) assignment of clinical professional and managerial teams amid interactions with COVID-19 patients. Hyaluronan: a potential cause of fatalities The innate immune response to tissue damage caused by the virus could lead to acute respiratory distress syndrome (ARDS), in which respiratory failure is characterized by the rapid onset of widespread inflammation in the lungs and subsequent fatality [4]. The symptoms of ARDS patients include short/rapid breathing, and cyanosis. Severe patients admitted to intensive care units often require mechanical ventilators and those unable to breath have to be connected to extracorporeal membrane oxygenation (ECMO) to support life [11]. CT images revealed that there are characteristic white patches called “ground glass”, containing fluid in the lungs [2]. Recent autopsies have confirmed that the lungs are filled with clear liquid jelly, much resembling the lungs of wet drowning [4]. Although the nature of the clear jelly has yet to be determined, hyaluronan (HA) is associated with ARDS [12]; moreover, during SARS infection, the production and regulation of hyaluronan is defective. The levels of inflammatory cytokines (IL-1, TNF) are high in the lungs of COVID-19 patients and these cytokines are strong inducers of HA-synthase-2 (HAS2) in CD31+ endothelium, EpCAM+ lung alveolar epithelial cells, and fibroblasts [13]. Importantly, HA has the ability to absorb water up to 1000 times its molecular weight. Therefore, reducing the presence or inhibiting the production of HA holds a great promise in helping COVID-19 patients breathe. Doctors can simply provide patients medical grade hyaluronidase to reduce the accumulation of HA and thus to clear the jelly in the lung. In animal models, influenza-induced breathing difficulties can be relieved by intranasal administration of hyaluronidase. Doctors can also use a clinically approved bile therapy drug, Hymecromone (4-Methylumbelliferone, 4-MU), an inhibitor of HAS2 [14]. LPS-induced lung inflammation can be relieved by 4-MU. 4-MU or its chemical derivatives exist widely in various herbs used in traditional Chinese medicine, which may explain the observed effectiveness of combined herbal medicine in some patients. Overall, this synopsis is based on some clinical common sense. We propose some simple, but largely ignored, approaches to the treatment of COVID-19 patients (Fig. 1). We believe that the two-phase division is very important: the first immune defense-based protective phase and the second inflammation-driven damaging phase. Doctors should try to boost immune responses during the first, while suppressing it in the second phase. Since Vitamin B3 is highly lung protective, it should be used as soon as coughing begins. When breathing difficulty becomes apparent, hyaluronidase can be used intratracheally and at the same time 4-MU can be given to inhibit HAS2. Of course, HLA typing will provide susceptibility information for strategizing prevention, treatment, vaccination, and clinical approaches. We hope that some of the above ideas can be employed to help combat this deadly contagious disease of increasing incidence around the world. Fig. 1 Schematic representation of the progression of COVID-19 infection and potential adjuvant interventions. After an incubation period, the invading COVID-19 virus causes non-severe symptoms and elicits protective immune responses. The successful elimination of the infection relies on the health status and the HLA haplotype of the infected individual. In this period, strategies to boost immune response can be applied. If the general health status and the HLA haplotype of the infected individual do not eliminate the virus, the patient then enters the severe stage, when strong damaging inflammatory response occurs, especially in the lungs. At this stage, inhibition of hyaluronan synthase and elimination of hyaluronan can be prescribed. Cytokine activated mesenchymal stem cells can be used to block inflammation and promote tissue reparation. Vitamin B3 can be given to patients starting to have lung CT image abnormalities.
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                Author and article information

                Contributors
                Journal
                Clin Immunol
                Clin. Immunol
                Clinical Immunology (Orlando, Fla.)
                Published by Elsevier Inc.
                1521-6616
                1521-7035
                24 May 2020
                24 May 2020
                : 108480
                Affiliations
                [a ]Immunosciences Lab, Inc, 822 S. Robertson Blvd, Ste. 312, Los Angeles, CA 90035, USA
                [b ]Department of Preventive Medicine, Loma Linda University, Loma Linda, CA 92350, USA
                [c ]Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA
                Author notes
                [* ]Corresponding author at: Immunosciences Lab, Inc, 822 S. Robertson Blvd, Ste. 312, Los Angeles, CA 90035, USA. drari@ 123456msn.com
                Article
                S1521-6616(20)30425-3 108480
                10.1016/j.clim.2020.108480
                7246018
                32461193
                485970fe-ee82-484b-b863-27f983a19591
                © 2020 Published by Elsevier Inc.

                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
                : 21 May 2020
                : 21 May 2020
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                Immunology
                Immunology

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