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Id Subject Object Predicate Lexical cue
T1 0-65 Sentence denotes Covid-19, induced activation of hemostasis, and immune reactions:
T2 66-167 Sentence denotes Can an auto-immune reaction contribute to the delayed severe complications observed in some patients?
T3 169-177 Sentence denotes Abstract
T4 178-329 Sentence denotes Covid-19 is characterized by weak symptoms in most affected patients whilst severe clinical complications, with frequent fatal issues, occur in others.
T5 330-388 Sentence denotes Disease severity is associated with age and comorbidities.
T6 389-512 Sentence denotes Understanding of viral infectious mechanisms, and antibody immune response, can help to better control disease progression.
T7 513-732 Sentence denotes SARS-CoV-2 has a major impact on the Renin Angiotensin Aldosterone System (RAAS), through its binding to the membrane cellular glycoprotein, Angiotensin Converting Enzyme-2 (ACE-2), then infecting cells for replication.
T8 733-914 Sentence denotes This report hypothesizes the possible implication of an autoimmune response, induced by generation of allo- or autoantibodies to ACE-2, or to its complexes with viral spike protein.
T9 915-1005 Sentence denotes This could contribute to some delayed severe complications occurring in affected patients.
T10 1006-1068 Sentence denotes We also propose a strategy for investigating this eventuality.
T11 1070-1085 Sentence denotes 1 Introduction
T12 1086-1244 Sentence denotes Fast and extended knowledge is becoming available on the new viral disease that emerged in December 2019, causing enormous challenges at international levels.
T13 1245-1638 Sentence denotes The pathology of this obscure virus, named Severe Acute Respiratory Syndrome - Coronavirus-2 (SARS-CoV-2), is characterized by many patients remaining asymptomatic or with only benign symptoms, but this disease becomes life-threatening in some patients and requires hospitalization in intensive care units or resuscitation [1,2], and is often with a fatal outcome, yet to be fully established.
T14 1639-1857 Sentence denotes Activation of the hemostasis system has been observed in many patients with severe complications, with occurrence of disseminated intravascular coagulopathy (DIC) or pulmonary embolism (PE), and multiorgan failure [3].
T15 1858-1961 Sentence denotes DDimer is frequently elevated, and the disease prognosis worsens with its increasing concentration [2].
T16 1962-2003 Sentence denotes Sepsis can also be present in some cases.
T17 2004-2122 Sentence denotes Anticoagulant therapy, especially with LMWH, can improve the disease evolution and reduce the lethality incidence [4].
T18 2123-2421 Sentence denotes In addition, many patients with severe complications face a sudden worsening, starting 7 to > 14 days after the preliminary symptoms, although the immune response is effective with the presence of IgG and/or IgMs and is expected to fight the disease by controlling its pathological evolution [5,6].
T19 2422-2552 Sentence denotes This worsening is associated with an exacerbated immunological activity, a strong inflammatory response, and a cytokine storm [7].
T20 2553-2662 Sentence denotes New therapeutic approaches rely on controlling the pro-inflammatory cytokines, mainly IL-6, IL-10, and TNF-α.
T21 2663-2873 Sentence denotes Lastly, there is a strong association of disease severity with age and presence of comorbidities, mainly hypertension, diabetes, obesity, chronic obstructive pulmonary disease and cardiovascular diseases (CVD).
T22 2874-2968 Sentence denotes However, complications can also occur in younger persons without any known risk factors [1,2].
T23 2970-2992 Sentence denotes 2 Disease development
T24 2993-3251 Sentence denotes Understanding how SARS-Cov-2 infects patients, how disease develops, and why some patients have this delayed exacerbated immune response, is of major importance for better disease management and control, and for implementing promising therapeutic strategies.
T25 3252-3445 Sentence denotes Association with age and existing pathologies is now well-documented, but the causes explaining the disease course in patients with severe or lethal complications are not completely understood.
T26 3446-3627 Sentence denotes Viral load (increased tendency with age), infection development in affected patients, age, presence of comorbidities, and extent of tissue injuries contribute to this evolution [8].
T27 3628-3739 Sentence denotes However, the paradoxal delayed cytokine storm associated with the amplified immune reaction deserves attention.
T28 3740-3867 Sentence denotes Analyzing the disease development and infection mechanisms can help to elaborate an hypothesis to understand this complication.
T29 3868-4079 Sentence denotes SARS-CoV-2 enters human cells through Angiotensin Converting Enzyme-2 (ACE-2), a membrane surface protein [9], which is a major regulator of blood pressure and of the Renin Angiotensin Aldosterone System (RAAS).
T30 4080-4259 Sentence denotes This enzyme has an opposite effect to that of Angiotensin I Converting Enzyme (ACE), which generates Angiotensin II (AII: a nonapeptide) by cleaving angiotensin I (a decapeptide).
T31 4260-4509 Sentence denotes Angiotensin II has many pleiotropic effects by acting on its receptors, leading to aldosterone production and, finally, inducing vasoconstriction, increased blood pressure and volume (through Na + and water reabsorption), fibrosis and tissue injury.
T32 4510-4671 Sentence denotes ACE-2 opposes and regulates these effects, by cleaving AII to Angiotensin 1–7 [A (1–7)], which acts through its binding to Mas Receptor [[10], [11], [12], [13]].
T33 4672-4819 Sentence denotes This induces vasodilatation, reduces blood pressure, regulates blood volume, and protects from tissue damages and fibrosis in liver and lungs [13].
T34 4820-4890 Sentence denotes RAAS function and implication in SARS-CoV-2 are summarized in Fig. 1 .
T35 4891-5050 Sentence denotes ACE-2 is highly distributed in lungs (epithelial alveolar cells), but also in some other tissues such as the small intestine, pancreas, heart, liver and brain.
T36 5051-5176 Sentence denotes Both ACE and ACE-2 soluble forms can be present in blood circulation at low concentrations (< 10 ng/mL for ACE-2 in normals).
T37 5177-5378 Sentence denotes The ACE/ACE-2 ratio is then of essence for maintaining the right balance of the RAAS, and it is impaired in patients with hypertension, obesity, cardiovascular diseases (CVD), and diabetes for example.
T38 5379-5506 Sentence denotes Interestingly, the presence of these pathologies highly increases the risk for severe complications in Covid-19 patients [1,2].
T39 5507-5582 Sentence denotes Noteworthy, a dysfunction of RAAS can favor development of type 2 diabetes.
T40 5583-5676 Sentence denotes Through its binding to ACE-2, SARS-CoV-2 interferes in the RAAS, and can impact its function.
T41 5677-5804 Sentence denotes In addition to destruction of infected cells, this binding probably impacts RAAS balance and contributes to the disease course.
T42 5805-5960 Sentence denotes Fig. 1 ACE-2 regulates blood pressure and volume, inflammation, diuresis, N+/K + balance, and protects organs (mainly lung, heart and liver) from fibrosis.
T43 5961-6212 Sentence denotes It is a key cell transmembrane glycoprotein which prevents hypertension and protects from tissue injury by opposing the activation of the Renin Angiotensin Aldosterone System (RAAS), and the deleterious effects of Angiotensin II (AII) and Aldosterone.
T44 6213-6407 Sentence denotes Through its binding to ACE2, SARS-CoV-2 infects cells, such as lung alveolar epithelial cells (where ACE-2 is highly expressed), and interferes in the RAAS, by impacting ACE-2 beneficial action.
T45 6408-6524 Sentence denotes We hypothesize that binding of SARS-CoV-2 S Protein to ACE-2 could induce generation of allo- or/and autoantibodies.
T46 6526-6561 Sentence denotes 3 Role of ACE-2 in viral infection
T47 6562-6696 Sentence denotes The S Protein of SRAS Cov-2 (S Protein) presents a sequence, named Receptor Binding Domain (RBD), which has a high affinity for ACE-2.
T48 6697-6875 Sentence denotes SARS-CoV-2 is first primed by another membrane protein, TMPRSS2 (a membrane serine protease encoded by the TMPRSS2 gene), which cleaves S Protein and favors its binding to ACE-2.
T49 6876-7078 Sentence denotes This S Protein is then separated in 2 subunits, S1 bound to ACE-2, and S2, which helps the viral envelope to merge with the infected cell membrane, permitting the viral RNA entrance and replication [9].
T50 7079-7182 Sentence denotes The binding of viral S Protein to ACE-2 is a critical phenomenon for infection and disease progression.
T51 7183-7375 Sentence denotes Interestingly, ACE-2, which is a transmembrane cell surface expressed enzyme, can form a dimer with a high affinity for S1 trimers, which increases binding of viruses and their cell entry [9].
T52 7376-7437 Sentence denotes In addition, ACE-2 is present in a soluble form in the blood.
T53 7438-7596 Sentence denotes In infected patients, it could circulate bound to SARS-CoV-2 or to the S1 subunit of viral S Protein, and virus has been detected in blood from some patients.
T54 7597-7914 Sentence denotes As ACE-2 plays a major role in patients with hypertension, CVD, obesity, or type 2 diabetes, by opposing the harmful effects of the RAAS, mainly through the ACE-AI [[1], [2], [3], [4], [5], [6], [7]] axis and Mas Receptor, the ACE/ACE-2 ratio could be a good indicator of disease progression [[10], [11], [12], [13]].
T55 7915-8014 Sentence denotes Lastly, there are polymorphisms of ACE and ACE-2 which increase the risk to develop these diseases.
T56 8015-8282 Sentence denotes From these considerations, the role of ACE-2 (and impairment of its function when complexed with S1) can be important for Covid-19 clinical complications, especially those associated with comorbidities, and not only because it is the entrance receptor for SARS-CoV-2.
T57 8284-8311 Sentence denotes 4 Activation of hemostasis
T58 8312-8458 Sentence denotes Activation of hemostasis is a major event occurring in Covid-19 patients with severe complications and a need for intensive care or resuscitation.
T59 8459-8581 Sentence denotes From the Yang report, DIC develops in most patients with a fatal outcome, whilst it remains rare in those who survive [1].
T60 8582-8724 Sentence denotes The extensive tissue damage, especially in the lung, and the multiorgan failure can be causes for this extensive blood coagulation activation.
T61 8725-8868 Sentence denotes Use of an anticoagulant therapy, as, for example with low molecular weight heparin, improves the patients’ outcome and reduces lethality [3,4].
T62 8869-9108 Sentence denotes Many coagulation assays are impacted with prolonged prothrombine time (PT) or activated partial thromboplastin time (APTT), reduced antithrombin (AT), elevated DDimer, thrombocytopenia, associated with leucopenia, and low lymphocytes [14].
T63 9109-9318 Sentence denotes Mechanisms that cause this direct blood activation can be multiple, and involve the damaged tissues’ debris or released procoagulants, or exposure of activating surfaces to blood circulation in damaged organs.
T64 9319-9485 Sentence denotes The amplified immune response itself, with inflammation and cytokines release and the cross talks with other response modifiers, can contribute to hypercoagulability.
T65 9486-9613 Sentence denotes The entry mode for SARS-CoV-2 in infected cells leads one to suspect the involvement of all side effects of a RAAS dysfunction.
T66 9615-9633 Sentence denotes 5 Immune response
T67 9634-9811 Sentence denotes For virus cell entry, a strong complex is first formed between the viral S protein, primed and cleaved by TMPRSS2, and ACE-2, at the cell surface which exposes this protein [9].
T68 9812-9983 Sentence denotes In addition, ACE-2 is also present in the blood at low concentration where it could be complexed with S1 or with the virus itself (detected in the blood of some patients).
T69 9984-10158 Sentence denotes IgM and IgG antibodies to the various viral proteins, including S Protein RBD and nucleoprotein can be detected in patients several days after the onset of symptoms [5,6,15].
T70 10159-10309 Sentence denotes With the present data available, this serological positivity sometimes develops concomitantly with a virus load detectable by PCR, or some days later.
T71 10310-10532 Sentence denotes One to 2 weeks after the onset of symptoms, patients have IgMs and/or IgGs, with little delay between generation of IgGs and IgMs. IgMs tend to decrease after 2 weeks, whilst IgGs continue increasing or stabilize [5,6,15].
T72 10533-10629 Sentence denotes The presence of these antibodies is expected to control, reverse and stop infection progression.
T73 10630-10720 Sentence denotes Surprisingly, patients with the highest antibody concentration were the most critical [5].
T74 10722-10783 Sentence denotes 6 Hypothesis on the induction of an auto-immune complication
T75 10784-11117 Sentence denotes The formation of a strong complex between ACE-2, a self-component, and viral S1 (or S Protein), constitutes the basic context for developing allo-antibodies and generating a delayed autoimmune response, with antibodies first targeted to viral antigens, but which can extend to the associated self-component through epitope spreading.
T76 11118-11230 Sentence denotes Then, antibodies to ACE-2 could develop, or eventually to another cell protein close to or complexed with ACE-2.
T77 11231-11544 Sentence denotes We then hypothesize that an allo-immune response can follow the initial immune reaction to the viral infection, and that epitope spreading can induce antibodies to ACE-2, or to proteins with which it is complexed, thus targeting the immune system to cells exposing ACE-2 (abundant in lungs and some other organs).
T78 11545-11658 Sentence denotes This delayed autoimmune response can contribute to the cytokine storm and generate tissue injury and destruction.
T79 11659-11921 Sentence denotes This can activate hemostasis, beyond acute hypercoagulability, stimulate tissue injury, and totally impair the body’s regulation of hypertension and physiological defense mechanisms such as existing pathways of haemostasis/ thrombosis and inflammatory processes.
T80 11922-12134 Sentence denotes We do not know, at this stage, if interaction between ACE-2 and S Protein, or its S1 subunit or with another viral or cell protein, can induce structural modifications of ACE-2 and expose cryptic or neo-epitopes.
T81 12135-12249 Sentence denotes This possibility needs to be considered as it could yet stimulate the immune reaction and generate autoantibodies.
T82 12251-12300 Sentence denotes 7 Strategy for investigating allo/autoantibodies
T83 12301-12527 Sentence denotes We are convinced that this hypothesis could be easily explored by testing allo-antibodies to ACE-2, or to its complexes with SARS-CoV-2 S Protein or its cleaved subunits, S1, and eventually associated with S2 or nucleoprotein.
T84 12528-12729 Sentence denotes ACE-2 is now available in the recombinant form, even if still very expensive, and recombinant SARS-CoV-2 proteins or peptide sequences, including S Protein and S1, are available from various suppliers.
T85 12730-13024 Sentence denotes A capture ELISA, designed by coating recombinant ACE-2, or its complexes with S-Protein or its S1 subunit, or eventually the viral nucleoprotein, onto the plate could be designed for capturing possible antibodies present in Covid-19 patients, especially those with delayed severe complications.
T86 13025-13119 Sentence denotes Binding of antibody to these components, in the presence or absence of ACE-2 must be compared.
T87 13120-13296 Sentence denotes This approach can allow the measurement amount of the kinetic course of these antibodies during the pathological evolution, and eventually in patients following their recovery.
T88 13297-13439 Sentence denotes If present, these antibodies are expected to be alloantibodies, as induced by the association of a viral protein with a body’s self-component.
T89 13440-13591 Sentence denotes However, if immuno stimulation is first induced by neo-epitopes exposed on ACE-2 when complexed with S Protein or S1, the response could be autoimmune.
T90 13592-13651 Sentence denotes Laboratory investigations can clarify these considerations.
T91 13653-13667 Sentence denotes 8 Conclusions
T92 13668-13887 Sentence denotes This concise manuscript is intended to spotlight some of the factors involved in the COVID-19 process focusing on our current efforts to shine some light by proving laboratory evidence to support our working hypothesis.
T93 13888-14068 Sentence denotes People respond differently to COVID-19 some without major clinical problems, others, especially older population or with comorbidities, develop severe or fatal complications [1,2].
T94 14069-14352 Sentence denotes This virus does not recognize age or rank and where the individual variability appears to matter is how people respond to viral infectivity: the good responders overcome the virus by developing high affinity antibodies, whereas the poor responders are doomed to severe health Issues.
T95 14353-14558 Sentence denotes It is nevertheless more than intriguing to note that the highest antibody concentrations are noted in the most severe patients, and this does not always correspond to the viral load detected by PCR [5,15].
T96 14559-14834 Sentence denotes We emphasize that, in addition to the viral deleterious effects of infection in lungs and organs, and stimulation of the immune system, a possible rebound trigger could be induced by an autoimmune response, especially when complications are delayed from the initial symptoms.
T97 14835-15070 Sentence denotes The mechanisms of viral infection and entry into cells through the ACE-2 receptor create a unique context for development of allo- or autoantibodies, which can induce their harmful effect on the body’s cells and tissues exposing ACE-2.
T98 15071-15179 Sentence denotes This mode of action is similar to that of 2002 SARS-CoV [16], but SARS-CoV-2 has a higher affinity for ACE2.
T99 15180-15329 Sentence denotes Therefore COVID-19-induced activation of hemostasis and immune reactions remains, for a while, in the spotlight to be fully proven without any doubt.
T100 15330-15534 Sentence denotes Autoimmune complications, although rare, have been observed in many infectious diseases, as for example anti-coagulation Protein S in varicella, anti-prothrombine, anti-Platelet Factor 4, anti-FXIII, etc.
T101 15535-15671 Sentence denotes Autoantibodies are investigated only because of the associated clinical syndromes induced (as Lupus Anticoagulant, thrombosis, bruises).
T102 15672-15840 Sentence denotes Understanding the various routes of pathology development can help to design the most efficient diagnostic tools and therapeutic approaches as recently reviewed [9,12].
T103 15841-15930 Sentence denotes Recombinant ACE2 is being developed for treating the acute respiratory distress syndrome.
T104 15931-16069 Sentence denotes Other strategies in the spirit of unities in these massive risky periods, in the real crisis time, requiring prompt action, are warranted.
T105 16070-16227 Sentence denotes Specific recommendations for a standardized preparation, and an optimal use of convalescent plasma at a global level are greatly needed in COVID 19 patients.
T106 16228-16315 Sentence denotes This will be helpful in designing future clinical trials in this area of investigation.