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Autoimmune complications of COVID-19 and potential consequences for long-lasting disease syndromes

Published:December 16, 2022DOI:https://doi.org/10.1016/j.transci.2022.103625

      Abstract

      The latest WHO report determined the increasing diversity within the CoV-2 omicron and its descendent lineages. Some heavily mutated offshoots of BA.5 and BA.2, such as BA.4.6, BF.7, BQ.1.1, and BA.2.75, are responsible for about 20% of infections and are spreading rapidly in multiple countries. It is a sign that Omicron subvariants are now developing a capacity to be more immune escaping and may contribute to a new wave of COVID-19. Covid-19 infections often induce many alterations in human physiological defense and the natural control systems, with exacerbated activation of the inflammatory and homeostatic response, as for any infectious diseases. Severe activation of the early phase of hemostatic components, often occurs, leading to thrombotic complications and often contributing to a lethal outcome selectively in certain populations. Development of autoimmune complications increases the disease burden and lowers its prognosis. While the true mechanism still remains unclear, it is believed to mainly be related to the host autoimmune responses as demonstrated, only in some patients suffering from the presence of autoantibodies that worsens the disease evolution. In fact in some studies the development of autoantibodies to angiotensin converting enzyme 2 (ACE2) was identified, and in other studies autoantibodies, thought to be targeting interferon or binding to annexin A1, or autoantibodies to phospholipids were seen. Moreover, the occurrence of autoimmune heparin induced thrombocytopenia has also been described in infected patients treated with heparin for controlling thrombogenicity. This commentary focuses on the presence of various autoantibodies reported so far in Covid-19 diseases, exploring their association with the disease course and the durability of some related symptoms. Attempts are also made to further analyze the potential mechanism of actions and link the presence of antibodies with pathological complications.

      Keywords

      1. Introduction

      These past years, the world is facing the Covid-19 pandemic and its many side effects on lock-down, economy impact, morbidity and mortality, especially in at risk people, with many associated or synergistic clinical complications, with lung and tissue damage, exacerbated inflammation, immuno-thrombosis leading to multiorgan failure and fatal outcome in some infected patients [
      • Borges do Nascimento I.J.
      • Cacic N.
      • Abdulazeem H.M.
      • von Groote T.C.
      • Jayarajah U.
      • Weerasekara I.
      • et al.
      Novel coronavirus infection (COVID-19) in humans: a scoping review and meta-analysis.
      ,
      • Gupta A.
      • Madhavan M.V.
      • Sehgal K.
      • Nair N.
      • Mahajan S.
      • Sehrawat T.S.
      • et al.
      Extrapulmonary manifestations of COVID-19.
      ]. In addition, in a significant group of SARS-Cov-2 infected patients, long-lasting symptoms of fatigue and other health burdens are reported, following the acute phase disease, and recovery from its major health concerns [
      • Castanares-Zapatero D.
      • Chalon P.
      • Kohn L.
      • Dauvrin M.
      • Detollenaere J.
      • Maertens de Noordhout C.
      • Primus-de Jong C.
      • Cleemput I.
      • Van den Heede K.
      Pathophysiology and mechanism of long COVID: a comprehensive review.
      ,
      • Naeije R.
      • Caravita S.
      Phenotyping long COVID.
      ,
      • Petersen M.S.
      • Kristiansen M.F.
      • Hanusson K.D.
      • Danielsen M.E.
      • Á Steig B.
      • Gaini S.
      • et al.
      Long COVID in the Faroe Islands: a longitudinal study among nonhospitalized patients.
      ]. These persistent pathological consequences are independent of disease severity, and patients’ age, gender and health status [
      • Petersen M.S.
      • Kristiansen M.F.
      • Hanusson K.D.
      • Danielsen M.E.
      • Á Steig B.
      • Gaini S.
      • et al.
      Long COVID in the Faroe Islands: a longitudinal study among nonhospitalized patients.
      ,
      • Augustin M.
      • Schommers P.
      • Stecher M.
      • Dewald F.
      • Gieselmann L.
      • Gruell H.
      • et al.
      Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study.
      ]. Little is still known about factors which can favor or induce this long Covid-19 syndrome, although some characteristics have been elucidated recently, and involve the remanence of a strong inflammatory context [
      • Maamar M.
      • Artime A.
      • Pariente E.
      • Fierro P.
      • Ruiz Y.
      • Gutiérrez S.
      • et al.
      Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study.
      ]. We, and others, early suspected the possible involvement of autoimmune complications during the disease course [
      • Amiral J.
      • Vissac A.M.
      • Seghatchian J.
      Covid-19, induced activation of hemostasis, and immune reactions: Can an auto-immune reaction contribute to the delayed severe complications observed in some patients?.
      ,
      • Townsend A.
      Autoimmunity to ACE2 as a possible cause of tissue inflammation in Covid-19.
      ,
      • Rodriguez-Perez A.I.
      • Labandeira C.M.
      • Pedrosa M.A.
      • Valenzuela R.
      • Suarez-Quintanilla J.A.
      • Cortes-Ayaso M.
      • et al.
      Autoantibodies against ACE2 and angiotensin type-1 receptors increase severity of COVID-19.
      ,
      • McMillan P.
      • Dexhiemer T.
      • Neubig R.R.
      • Uhal B.D.
      COVID-19-A theory of autoimmunity against ACE-2 explained.
      ].
      Yet, generation of autoantibodies during infectious diseases has been reported in some cases, associated with many different causative pathogens, but mainly with cytomegalovirus, Epstein Barr virus and Human Immunodeficiency virus [
      • Smatti M.K.
      • Cyprian F.S.
      • Nasrallah G.K.
      • Al Thani A.A.
      • Almishal R.O.
      • Yassine H.M.
      Viruses and autoimmunity: a review on the potential interaction and molecular mechanisms.
      ,
      • Halenius A.
      • Hengel H.
      Human cytomegalovirus and autoimmune disease.
      ,
      • Houen G.
      • Trier N.H.
      Epstein-barr virus and systemic autoimmune diseases.
      ,
      • Zandman-Goddard G.
      • Shoenfeld Y.
      HIV and autoimmunity.
      ]. These induced autoantibodies are identified when they produce severe complications, which depend on the autoantigen target, their concentration, and their impact on physiological processes [
      • Ercolini A.M.
      • Miller S.D.
      The role of infections in autoimmune disease.
      ,
      • Abdel-Wahab N.
      • Lopez-Olivo M.A.
      • Pinto-Patarroyo G.P.
      • Suarez-Almazor M.E.
      Systematic review of case reports of antiphospholipid syndrome following infection.
      ]. However, their prevalence is probably underestimated, as these autoantibodies are only investigated when severe and unusual complications occur in patients, often associated with unexpected laboratory results [
      • Getts D.R.
      • Chastain E.M.
      • Terry R.L.
      • Miller S.D.
      Virus infection, antiviral immunity, and autoimmunity.
      ]. This, is for example, the case of autoantibodies to coagulation Protein S, which have been identified in rare patients who developed thrombotic events during or just after varicella [
      • Levin M.
      • Eley B.S.
      • Louis J.
      • Cohen H.
      • Young L.
      • Heyderman R.S.
      Postinfectious purpura fulminans caused by an autoantibody directed against protein S.
      ,
      • Peyvandi F.
      • Faioni E.
      • Alessandro Moroni G.
      • Rosti A.
      • Leo L.
      • Moia M.
      Autoimmune protein S deficiency and deep vein thrombosis after chickenpox.
      ,
      • Manco-Johnson M.J.
      • Nuss R.
      • Key N.
      • Moertel C.
      • Jacobson L.
      • Meech S.
      • et al.
      Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis.
      ,
      • Regnault V.
      • Boehlen F.
      • Ozsahin H.
      • Wahl D.
      • de Groot P.G.
      • Lecompte T.
      • de Moerloose P.
      Anti-protein S antibodies following a varicella infection: detection, characterization and influence on thrombin generation.
      ,
      • Samyn B.
      • Grunebaum L.
      • Amiral J.
      • Ammouche C.
      • Lounis K.
      • Eicher E.
      • et al.
      Thrombophlébite cérébrale post-varicelle avec anticorps anti-protéine S: à propos d'un cas pédiatrique [Post-varicella cerebral thrombophlebitis with anti-protein S: report of a pediatric case].
      ], but many other situations could be cited, and will be briefly discussed in the following paragraph.
      The components not the body which are candidates to become autoantigens are blood or cell surface proteins which bind strongly to pathogens or to their metabolites, and are then involved in complexes targeted by the body’s immune response [
      • Amiral J.
      Immunomodulation, autoimmunity and haemostatic dysfunctions.
      ]. Other reports have suggested that the immune system can contribute to regulate excess of inflammation by generating autoantibodies reactive with some inflammatory cytokines, as shown for Interleukine-8 (IL8) or other cytokines by Bendzen et al. [
      • Bendtzen K.
      • Hansen M.B.
      • Ross C.
      • Svenson M.
      High-avidity autoantibodies to cytokines.
      ,
      • Watanabe M.
      • Uchida K.
      • Nakagaki K.
      • Kanazawa H.
      • Trapnell B.C.
      • Hoshino Y.
      • et al.
      Anti-cytokine autoantibodies are ubiquitous in healthy individuals.
      ,
      • Puel A.
      • Casanova J.L.
      Autoantibodies against cytokines: back to human genetics.
      ,
      • Nielsen C.H.
      • Bendtzen K.
      Immunoregulation by naturally occurring and disease-associated autoantibodies: binding to cytokines and their role in regulation of T-cell responses.
      ]. These latter can be present in healthy individuals. In Covid-19, SARS-Cov-2 binds strongly to the Angiotensin-Converting-Enzyme 2 (ACE2) through the Receptor Binding domain (RBD) from its spike protein [
      • Gordon D.E.
      • Jang G.M.
      • Bouhaddou M.
      • Xu J.
      • Obernier K.
      • White K.M.
      • et al.
      A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
      ], and in severe cases a cytokine storm occurs and strongly worsens the disease course and its prognosis [
      • Sarzi-Puttini P.
      • Giorgi V.
      • Sirotti S.
      • Marotto D.
      • Ardizzone S.
      • Rizzardini G.
      • et al.
      COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?.
      ,
      • Nazerian Y.
      • Ghasemi M.
      • Yassaghi Y.
      • Nazerian A.
      • Hashemi S.M.
      Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: Molecular pathways and potential therapeutic options.
      ]. Autoimmune complications can contribute to worsen disease and to induce lasting symptoms with persistent inflammation [
      • Lyons-Weiler J.
      Pathogenic priming likely contributes to serious and critical illness and mortality in COVID-19 via autoimmunity.
      ,
      • Rodríguez Y.
      • Novelli L.
      • Rojas M.
      • De Santis M.
      • Acosta-Ampudia Y.
      • et al.
      Autoinflammatory and autoimmune conditions at the crossroad of COVID-19.
      ]. When present, autoantibodies remain for weeks or months, and then they progressively decrease with time, when the autoantigen stimulus disappears. However, in a small subset of patients, these complications can switch to chronic autoimmune diseases [
      • de Groot P.G.
      • Horbach D.A.
      • Simmelink M.J.
      • van Oort E.
      • Derksen R.H.
      Anti-prothrombin antibodies and their relation with thrombosis and lupus anticoagulant.
      ,
      • Amiral J.
      • Peyrafitte M.
      • Dunois C.
      • Vissac A.M.
      • Seghatchian J.
      Anti-phospholipid syndrome: current opinion on mechanisms involved, laboratory characterization and diagnostic aspects.
      ]. This systematic review is focused on various autoimmune complications, which have been observed in Covid-19, their contribution to disease evolution, laboratory tools for their identification and quantitation, and their possible implication in long-lasting disease [
      • Halpert G.
      • Shoenfeld Y.
      SARS-CoV-2, the autoimmune virus.
      ,
      • Zhou Y.
      • Han T.
      • Chen J.
      • Hou C.
      • Hua L.
      • He S.
      • et al.
      Clinical and autoimmune characteristics of severe and critical cases of COVID-19.
      ,
      • Zuo Y.
      • Estes S.K.
      • Ali R.A.
      • Gandhi A.A.
      • Yalavarthi S.
      • Shi H.
      • et al.
      Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.
      ,
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • Xia P.
      • Cao W.
      • Jiang W.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with covid-19.
      ,
      • Elrashdy F.
      • Tambuwala M.M.
      • Hassan S.S.
      • Adadi P.
      • Seyran M.
      • Abd El-Aziz
      • et al.
      Autoimmunity roots of the thrombotic events after COVID-19 vaccination.
      ].

      2. Association of autoantibodies with infectious diseases

      Development of autoantibodies in many infectious diseases has been widely reported, with a high variety of pathogens, but these complications remain rare, at least for those characterized, and they are reported to affect a subgroup of infected individuals [
      • Delogu L.G.
      • Deidda S.
      • Delitala G.
      • Manetti R.
      Infectious diseases and autoimmunity.
      ,
      • Bigley T.M.
      • Cooper M.A.
      Monogenic autoimmunity and infectious diseases: the double-edged sword of immune dysregulation.
      ]. Actually, only some patients with symptomatic antibodies are currently diagnosed, when the target antigen is identified and clinical complications associated to the presence of these antibodies. This could, however, remain highly underdiagnosed as autoantibodies can remain asymptomatic, when their concentration is not high enough for being pathogenic, or because their binding to the target antigen is irrelevant. Interestingly, the Lupus Anticoagulant occurs, most often as transitory, as is much infectious pathology, suggesting a more extended implication of autoimmune processes [
      • Uthman I.W.
      • Gharavi A.E.
      Viral infections and antiphospholipid antibodies.
      ,
      • Ercolini A.M.
      • Miller S.D.
      The role of infections in autoimmune disease.
      ]. Even if some autoantibodies develop more specifically in certain diseases, the causes which explain why only few individuals are affected remains highly problematic. This could result: i) from a specific presentation of the autoantigen exposing cryptic epitopes or a modified structure, ii) when this autoantigen forms complexes with a viral non-self-component, or its metabolites, iii) from some mimicry of viral proteins with self-components or, iv) from the involvement of self-components in pathogenic complexes, which then induces the spreading of the immune response (epitope spreading) [
      • Tuohy V.K.
      • Kinkel R.P.
      Epitope spreading: a mechanism for progression of autoimmune disease.
      ,
      • Powell A.M.
      • Black M.M.
      Epitope spreading: protection from pathogens, but propagation of autoimmunity?.
      ,
      • Rojas M.
      • Restrepo-Jiménez P.
      • Monsalve D.M.
      • Pacheco Y.
      • Acosta-Ampudia Y.
      • Ramírez-Santana C.
      • et al.
      Molecular mimicry and autoimmunity.
      ]. The autoimmune complications described in infected patients can affect many different targets, especially those present in the blood. Epstein Barr or Cytomegalovirus infections can generate autoantibodies to platelets, which can provoke thrombocytopenia [
      • Barzilai O.
      • Sherer Y.
      • Ram M.
      • Izhaky D.
      • Anaya J.M.
      • Shoenfeld Y.
      Epstein-Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? A preliminary report.
      ,
      • de Melo Silva J.
      • Pinheiro-Silva R.
      • Dhyani A.
      • Pontes G.S.
      Cytomegalovirus and epstein-barr infections: prevalence and impact on patients with hematological diseases.
      ]. Adenovirus infections can induce autoantibodies to prothrombin, which are detected because they produce a strong Lupus Anticoagulant (LA) like activity, with an apparent decrease of Factors X, VIII, IX, X, XI and XII clotting activities, while antigenic concentrations remain normal [
      • Vivaldi P.
      • Rossetti G.
      • Galli M.
      • Finazzi G.
      Severe bleeding due to acquired hypoprothrombinemia-lupus anticoagulant syndrome.
      ,
      • Amiral J.
      • Aronis S.
      • Adamtziki E.
      • Garoufi A.
      • Karpathios T.
      Association of lupus anticoagulant with transient antibodies to prothrombin in a patient with hypoprothrombinemia.
      ,
      • Carvalho C.
      • Viveiro C.
      • Maia P.
      • Rezende T.
      Acquired antiprothrombin antibodies: an unusual cause of bleeding.
      ]. Another striking case concerns autoantibodies to Protein S, which can develop in some patients with varicella, and are identified because thrombosis occurs and is associated with a decreased Protein S anticoagulant activity, occurring in patients not known before the infectious disease to carry any such deficiency [
      • Levin M.
      • Eley B.S.
      • Louis J.
      • Cohen H.
      • Young L.
      • Heyderman R.S.
      Postinfectious purpura fulminans caused by an autoantibody directed against protein S.
      ,
      • Peyvandi F.
      • Faioni E.
      • Alessandro Moroni G.
      • Rosti A.
      • Leo L.
      • Moia M.
      Autoimmune protein S deficiency and deep vein thrombosis after chickenpox.
      ,
      • Manco-Johnson M.J.
      • Nuss R.
      • Key N.
      • Moertel C.
      • Jacobson L.
      • Meech S.
      • et al.
      Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis.
      ]. Table 1 shows some of these antibodies reported in various clinical conditions, and their pathological effects. In all these contexts, autoimmune disease occurs within the infectious disease course, which demonstrates the causative origin the complication, and autoantibodies tend to decrease and vanish months after their induction. This complication can then be classed as allo-immune. In some rare cases autoantibodies can become chronic, and last for a very long time with the symptomatic complications remaining [
      • Pender M.P.
      Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases.
      ,
      • Driul L.
      • Bertozzi S.
      • Londero A.P.
      • Fruscalzo A.
      • Rusalen A.
      • Marchesoni D.
      • et al.
      Risk factors for chronic pelvic pain in a cohort of primipara and secondipara at one year after delivery: association of chronic pelvic pain with autoimmune pathologies.
      ]. Treatments used for treating autoimmune diseases target the symptoms to reduce their harmful effect, or they reduce the immune response as with corticoid therapy. In many cases of suspected autoimmune complications, only the Lupus Anticoagulant is detected during or after an infectious disease, and the target phospholipid cofactor protein is not always identified, although β2-Glyco-Protein 1 (β2GP1) or prothrombin are frequently involved [
      • Favaloro E.J.
      Variability and diagnostic utility of antiphospholipid antibodies including lupus anticoagulants.
      ,
      • Olayemi E.
      • Halim N.K.
      Antiphospholipid antibodies in medical practice: a review.
      ]. Many other phospholipid binding proteins can also generate LA activities, like those targeted to Annexin V (A5) [
      • Horimoto A.M.C.
      • de Jesus L.G.
      • de Souza A.S.
      • Rodrigues S.H.
      • Kayser C.
      Anti-annexin V autoantibodies and vascular abnormalities in systemic sclerosis: a longitudinal study.
      ], Protein S or Factor XIII.
      Table 1Possible occurrence of some acquired autoantibodies in various clinical conditions et their pathological consequences (non-exhaustive); LA: lupus anticoagulant; DIC: disseminated intravascular coagulation; PF4: platelet factor 4; FV: factor V; FVIII: factor VIII.
      Clearly, the associations between some viral infectious diseases, such as Covid-19, and autoimmunity, are bidirectional, as if the pathogen itself or its metabolites, especially when complexed with self-proteins or the body’s cells, generate autoantibodies through molecular mimicry or epitope spreading [
      • Tuohy V.K.
      • Kinkel R.P.
      Epitope spreading: a mechanism for progression of autoimmune disease.
      ,
      • Powell A.M.
      • Black M.M.
      Epitope spreading: protection from pathogens, but propagation of autoimmunity?.
      ,
      • Rojas M.
      • Restrepo-Jiménez P.
      • Monsalve D.M.
      • Pacheco Y.
      • Acosta-Ampudia Y.
      • Ramírez-Santana C.
      • et al.
      Molecular mimicry and autoimmunity.
      ]. Conversely, patients with autoimmune diseases show a higher propensity for viral infections, resulting from the chronic inflammation and weakening of the body’s defenses.

      3. Other potential causes of autoantibodies generation

      Any cause which leads to the introduction of a foreign component to the body has a potential capacity to induce autoantibodies, especially when it binds to cell receptors or to functional proteins, particularly those present in the blood circulation. The basic mechanism relies on the exposure of self-proteins in an unfolded way or an unusual presentation, unmasking cryptic epitopes, or on the extension of the immune response, first targeted to non-self-components, complexed with self-components, through epitope spreading. These conditions can also occur with some drug treatments, after insect, parasite or snake bites, or can be associated with malignancies and degenerative diseases which alter the cell origin presentation and can expose receptors or proteins in an unusual manner. The beneficial immune response to malignant cells can be deviated to healthy original cells, and this leads to development of an autoimmune response.
      To illustrate this feature, we can cite: i) the generation of autoantibodies following tick bites [
      • Rodríguez Y.
      • Rojas M.
      • Gershwin M.E.
      • Anaya J.M.
      Tick-borne diseases and autoimmunity: a comprehensive review.
      ], ii) those to Factor V, induced for example, by second line antibiotics to treat iatrogenic infections [
      • Ajzner E.
      • Balogh I.
      • Haramura G.
      • Boda Z.
      • Kalmár K.
      • Pfliegler G.
      • et al.
      Anti-factor V auto-antibody in the plasma and platelets of a patient with repeated gastrointestinal bleeding.
      ,
      • Hoffmann C.
      • Amiral J.
      • Rezig S.
      • Kerspern H.
      • Jantzem H.
      • Robin S.
      • et al.
      A very potent factor V inhibitor interferes with the levels of all coagulation factors and causes a fatal hemorrhagic syndrome.
      ], iii) those induced by heparin therapy and platelet factor 4 (PF4) dependent, which can cause thrombocytopenia and thrombosis, iv) antibodies generated by treatments with a variety of other drugs [
      • Arepally G.M.
      • Cines D.B.
      Pathogenesis of heparin-induced thrombocytopenia.
      ,
      • Amiral J.
      • Marfaing-Koka A.
      • Poncz M.
      • Meyer D.
      The biological basis of immune heparin-induced thrombocytopenia.
      ,
      • Visentin G.P.
      • Newman P.J.
      • Aster R.H.
      Characteristics of quinine- and quinidine-induced antibodies specific for platelet glycoproteins IIb and IIIa.
      ,
      • Dlott J.S.
      • Roubey R.A.
      Drug-induced lupus anticoagulants and antiphospholipid antibodies.
      ], v) anti-PF4 autoantibodies developed in vaccine induced thrombotic thrombocytopenia, occurring in very rare patients vaccinated with adenovirus-vector vaccines against SARS-Cov-2 [
      • Greinacher A.
      • Schönborn L.
      • Siegerist F.
      • Steil L.
      • Palankar R.
      • Handtke S.
      • et al.
      Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT).
      ,
      • Reilly-Stitt C.
      • Jennings I.
      • Kitchen S.
      • Makris M.
      • Meijer P.
      • de Maat M.
      • et al.
      Anti-PF4 testing for vaccine-induced immune thrombocytopenia and thrombosis (VITT): Results from a NEQAS, ECAT and SSC collaborative exercise in 385 centers worldwide.
      ], vi) and autoimmune complications in cancer patients [
      • Tabrez S.
      • Jabir N.R.
      • Khan M.I.
      • Khan M.S.
      • Shakil S.
      • Siddiqui A.N.
      • Zaidi S.K.
      • Ahmed B.A.
      • Kamal M.A.
      Association of autoimmunity and cancer: an emphasis on proteolytic enzymes.
      ,
      • Masetti R.
      • Tiri A.
      • Tignanelli A.
      • Turrini E.
      • Argentiero A.
      • Pession A.
      • Esposito S.
      Autoimmunity and cancer.
      ]. This list is obviously not exhaustive. In most cases, when the cause inducing autoimmunity is withdrawn, autoantibodies progressively decrease and disappear within few months, but the immune memory can remain activatable in case of a new exposure to the autoantigen, and generation of autoantibodies can therefore occur much faster [
      • Duhlin A.
      • Chen Y.
      • Wermeling F.
      • Sedimbi S.K.
      • Lindh E.
      • Shinde R.
      • Halaby M.J.
      • Kaiser Y.
      • Winqvist O.
      • McGaha T.L.
      • Karlsson M.C.
      Selective Memory to Apoptotic Cell-Derived Self-Antigens with Implications for Systemic Lupus Erythematosus Development.
      ]. The autoimmune complication is usually transitory, and patients fully return to a healthy state within few months. However, in some cases, autoimmune disorders can be persistent, with autoantibodies becoming chronic [
      • Picchianti-Diamanti A.
      • Rosado M.M.
      • D'Amelio R.
      Infectious agents and inflammation: the role of microbiota in autoimmune arthritis.
      ].

      4. Pathogenicity of autoantibodies

      Autoimmune complications are usually detected when clinical symptoms develop, and they are the result of the generation of autoantibodies targeted to body components. The target antigen is not always identified. Often, the reported autoantibody target concerns a side effect (like lupus anticoagulant) and not the exquisite autoantibody targeted structures, or the entire targeted cell or organ (anti-platelet, anti-endothelial cells, anti-kidney, etc.). A better understanding of the mechanisms involved requires the accurate identification of the autoantigen, and of the targeted epitopes, which have been described in many cases, but in many others still need to be identified [
      • Noordermeer T.
      • Molhoek J.E.
      • Schutgens R.E.G.
      • Sebastian S.A.E.
      • Drost-Verhoef S.
      • van Wesel A.C.W.
      • et al.
      Anti-β2-glycoprotein I and anti-prothrombin antibodies cause lupus anticoagulant through different mechanisms of action.
      ,
      • Huynh A.
      • Kelton J.G.
      • Arnold D.M.
      • Daka M.
      • Nazy I.
      Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia.
      ].
      Not all antibodies are pathogenic. They can be irrelevant, or remain asymptomatic. Harmful effects develop when antibodies react with proteins, impacting their function, or when they are targeted to cells or organ/tissues, where they activate the immune response and the complement pathways [
      • Bakchoul T.
      • Sachs U.J.
      Platelet destruction in immune thrombocytopenia.
      ,
      • Cines D.B.
      • Wilson S.B.
      • Tomaski A.
      • Schreiber A.D.
      Platelet antibodies of the IgM class in immune thrombocytopenic purpura.
      ,
      • Cockwell P.
      • Tse W.Y.
      • Savage C.O.
      Activation of endothelial cells in thrombosis and vasculitis.
      ]. An autoimmune response more often develops to low or very low concentration proteins, although it can also be observed to proteins or biological structures present at high concentrations. Deleterious effects occur when antibodies block a key physiological function, like that of cytokines, growth factors, or other mediators, or when they activate, or destroy a cell line, like platelets or endothelial cells, or an organ. The pathogenicity of autoantibodies depends on the targeted autoantigen and specific epitopes, their concentration, and their affinity, which define their interference in physiological functions, or the destruction extent of the targeted cell line or organ. The higher is the autoantibody concentration and avidity, the stronger are the deleterious pathological effects, through the activation or destruction of the targeted cells or organs. The presence of risk factors can highly enhance the harmful effects of autoantibodies, especially when they favor thrombotic events: a preexisting imbalance of hemostasis leads to the development of thromboism in the presence of low autoimmune stimuli, which do not induce pathological impact in healthy individuals. This is, for example,the case of the association of LA with factor V Leiden or deficiencies of antithrombotic proteins, like Antithrombin, Protein C or Protein S, or a hypofibrinolytic state [
      • Moulis G.
      • Audemard-Verger A.
      • Arnaud L.
      • Luxembourger C.
      • Montastruc F.
      • Gaman A.M.
      • et al.
      Risk of thrombosis in patients with primary immune thrombocytopenia and antiphospholipid antibodies: A systematic review and meta-analysis.
      ,
      • Fijnheer R.
      • Horbach D.A.
      • Donders R.C.
      • Vilé H.
      • von Oort E.
      • et al.
      Factor V Leiden, antiphospholipid antibodies and thrombosis in systemic lupus erythematosus.
      ].

      5. Pathological complications of autoantibodies

      Pathological conditions resulting from autoantibodies are very heterogenous, and are associated with their autoantigen target, its physiological function and location, its binding onto cell surfaces, and its concentration. Deleterious effects are enhanced when targeted components, carrying a key biological activity, are present at low concentration, and bind onto cell surface receptors. The immune response is then targeted to these cells, which expose receptors or components able to interact with the autoantigen. Therefore, when autoantibodies bind directly or indirectly onto blood cells, they frequently can produce cell destruction, or activation, and they can generate thrombotic episodes. Activation of endothelial cells or platelets by autoantibodies, or their interference in antithrombotic processes is an important cause of thrombosis. When autoantibodies are targeted at hemostasis proteins in the blood, their effect depends on their interaction with physiological functions. Autoantibodies can reduce the activity of targeted antigens and induce bleeding when coagulation factors are concerned, like Factor V or Factor VIII, or thrombosis if they bind antithrombotic proteins, like Protein S. Another potential effect of autoantibodies concerns their binding to non-active epitopes on proteins, which reduces their half-life in the blood by accelerating their clearance.
      Autoantibody-protein complexes can also interfere in physiological functions by binding to active biological surfaces inducing a steric hindrance which interferes with normal activities. Examples are those of autoantibodies to coagulation Protein S, Prothrombin, β2-GlycoProtein 1, Annexin V, all producing Lupus Anticoagulant activities [
      • Roubey R.A.
      Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other "antiphospholipid" autoantibodies.
      ,
      • Knight J.S.
      • Kanthi Y.
      Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome.
      ], or to Thrombomodulin [
      • Guermazi S.
      • Mellouli F.
      • Trabelsi S.
      • Bejaoui M.
      • Dellagi K.
      Anti-thrombomodulin antibodies and venous thrombosis.
      ]. In other cases, antibodies can produce bleeding, especially when targeted to some platelet surface glycoproteins, inducing thrombocytopenia, or to clotting factors like Factor V, Factor VIII, Factor IX, von Willebrand Factor or Factor XIII [
      • van Genderen P.J.
      • Michiels J.J.
      Acquired von Willebrand disease.
      ,
      • Chong B.H.
      • Ho S.J.
      Autoimmune thrombocytopenia.
      ,
      • Kruse-Jarres R.
      • Kempton C.L.
      • Baudo F.
      • Collins P.W.
      • Knoebl P.
      • Leissinger C.A.
      • et al.
      Acquired hemophilia A: updated review of evidence and treatment guidance.
      ,
      • Ichinose A.
      Japanese collaborative research group on AH13. Autoimmune acquired factor XIII deficiency due to anti-factor XIII/13 antibodies: a summary of 93 patients.
      ].
      When present, autoantibodies are extremely difficult to control. The first key action is to remove the cause producing autoimmunization, when possible. In heparin induced thrombocytopenia, stopping heparin has the double advantage of suppressing the immune stimulation and removing the target antigen which requires heparin Platelet Factor 4 [
      • Amiral J.
      • Marfaing-Koka A.
      • Poncz M.
      • Meyer D.
      The biological basis of immune heparin-induced thrombocytopenia.
      ]. But in the vast majority of autoimmune complications, suppressing the target autoantigen is not possible, and, when stimulated, autoantibody production lasts for a long time, even though it tends to decrease with time. However, the half-life of antibodies, when B-cells are stimulated, is of several weeks or months, and their harmful consequences require appropriate management. Current treatments are symptomatic, to control and limit the major deleterious effects of autoantibodies, or they aim to reduce the autoantibody concentration, through the use of corticotherapy [
      • Al-Adhoubi N.K.
      • Bystrom J.
      Systemic lupus erythematosus and diffuse alveolar hemorrhage, etiology and novel treatment strategies.
      ].
      Conversely, autoantibodies can also contribute to control the pathogenic process resulting from an excess of inflammation. The specific autoimmune response to some cytokines or mediators has been proposed as a way to regulate their generation excess as it was demonstrated for autoantibodies to Interleukin (IL-6), but also to other cytokines [
      • Gordon D.E.
      • Jang G.M.
      • Bouhaddou M.
      • Xu J.
      • Obernier K.
      • White K.M.
      • et al.
      A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
      ,
      • Sarzi-Puttini P.
      • Giorgi V.
      • Sirotti S.
      • Marotto D.
      • Ardizzone S.
      • Rizzardini G.
      • et al.
      COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?.
      ,
      • Nazerian Y.
      • Ghasemi M.
      • Yassaghi Y.
      • Nazerian A.
      • Hashemi S.M.
      Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: Molecular pathways and potential therapeutic options.
      ,
      • Peichl P.
      • Pursch E.
      • Bröll H.
      • Lindley I.J.
      Anti-IL-8 autoantibodies and complexes in rheumatoid arthritis: polyclonal activation in chronic synovial tissue inflammation.
      ]. This could be the case for autoantibodies to Interleukin 8 (IL-8), which remain irrelevant or asymptomatic as long as their concentration stays low, and their binding onto blood cells is not enhanced. We found that some patients with heparin Induced thrombocytopenia (HIT), and without anti Heparin-PF4 antibodies were reactive to IL-8 or its complexes with heparin. In that case, thrombocytopenia occurred rapidly following heparin therapy, which enhance bridging of IL-8 to blood cells. As IL-8 can bind heparin, itself reacting particularly with platelets and endothelial cells, especially activated platelets, this triggers anti-IL-8 autoantibodies onto these cells, where an anti-IL-8 immune response focuses. This phenomenon then generates a HIT-like syndrome, producing thrombocytopenia and sometimes disseminated thrombosis [
      • Amiral J.
      • Marfaing-Koka A.
      • Wolf M.
      • Alessi M.C.
      • Tardy B.
      • Boyer-Neumann C.
      • et al.
      Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia.
      ,
      • de Maistre E.
      • Regnault V.
      • Lecompte T.
      • Scheid P.
      • Martinet Y.
      • Bellou A.
      • Amiral J.
      • Vissac A.M.
      Antibodies to interleukin-8 and paraneoplastic catastrophic recurrent thromboses.
      ]. A similar complication can develop in the presence of preexisting anti-PF4 autoantibodies if patients receive heparin [
      • Desprez D.
      • Desprez P.
      • Tardy B.
      • Amiral J.
      • Droulle C.
      • Ducassou S.
      • et al.
      Anti-PF4 antibodies and thrombophlebitis in a child with cerebral venous thrombosis.
      ,
      • Warkentin T.E.
      • Greinacher A.
      Spontaneous HIT syndrome: Knee replacement, infection, and parallels with vaccine-induced immune thrombotic thrombocytopenia.
      ]. A rapid HIT onset can develop and it reverses with heparin withdrawal [
      • Desprez D.
      • Desprez P.
      • Tardy B.
      • Amiral J.
      • Droulle C.
      • Ducassou S.
      • et al.
      Anti-PF4 antibodies and thrombophlebitis in a child with cerebral venous thrombosis.
      ]. In VITT, autoantibodies to some PF4 epitopes, especially those defining the PF4 heparin binding domain, are generated and provoke a severe thrombocytopenia, with thrombosis occurring at unusual cites, like the splanchnic vein, although heparin is absent [
      • Greinacher A.
      • Schönborn L.
      • Siegerist F.
      • Steil L.
      • Palankar R.
      • Handtke S.
      • et al.
      Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT).
      ,
      • Reilly-Stitt C.
      • Jennings I.
      • Kitchen S.
      • Makris M.
      • Meijer P.
      • de Maat M.
      • et al.
      Anti-PF4 testing for vaccine-induced immune thrombocytopenia and thrombosis (VITT): Results from a NEQAS, ECAT and SSC collaborative exercise in 385 centers worldwide.
      ,
      • Huynh A.
      • Kelton J.G.
      • Arnold D.M.
      • Daka M.
      • Nazy I.
      Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia.
      ]. This complication is often life-threatening, and anti-PF4 autoantibodies’ concentration is roughly associated with disease severity and evolution. The association of autoantibody concentration and avidity with severity of autoimmune burden is a confirmed key feature and constitutes a major risk factor for their pathogenicity of clinically relevance.

      6. Autoantibodies detected in patients with Covid-19

      In Covid-19, as in many infectious diseases, autoimmune complications have been suspected early, and especially associated with long-lasting syndromes [
      • Galeotti C.
      • Bayry J.
      Autoimmune and inflammatory diseases following COVID-19.
      ,
      • Dotan A.
      • Muller S.
      • Kanduc D.
      • David P.
      • Halpert G.
      • Shoenfeld Y.
      The SARS-CoV-2 as an instrumental trigger of autoimmunity.
      ,
      • Acosta-Ampudia Y.
      • Monsalve D.M.
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Ramírez-Santana C.
      • et al.
      Persistent autoimmune activation and proinflammatory state in post-coronavirus disease 2019 syndrome.
      ]. There is now evidence that the SARS-Cov-2 infection like cytomegalovirus, is among the infectious diseases, which are capable of triggering many different autoantibodies like Epstein Barr virus, or HIV infections. As in many infectious states, the emerging part of the “autoimmune iceberg” is detected through the identification of LA activity, IgG or IgM anti-cardiolipin/anti-phospholipid antibodies, or thrombocytopenia [
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • Xia P.
      • Cao W.
      • Jiang W.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with covid-19.
      ,
      • Bhattacharjee S.
      • Banerjee M.
      Immune thrombocytopenia secondary to COVID-19: a systematic review.
      ,
      • Lingamaneni P.
      • Gonakoti S.
      • Moturi K.
      • Vohra I.
      • Zia M.
      Heparin-induced thrombocytopenia in COVID-19.
      ]. These observations are mainly the “side effect” of autoantibodies, which are targeted to phospholipid binding proteins, directly, like β2-Glyco-Protein 1, or indirectly, through divalent cations, like prothrombin, Protein S, Protein C or Annexin 5. Many other autoantibodies, forming complexes with self-proteins, are able to bind to phospholipid surfaces present on all cells, which are exposed with a high density of anionic phospholipids when activated, like platelets. This interaction competes with the targeted initiation of coagulation pathways and generates an apparent anticoagulant response (through steric hindrance for the binding of functional phospholipid binding proteins), although those autoantibodies are associated with thrombotic complications. In addition, the exacerbated inflammatory response in many Covid-19 patients generates NETosis, containing electronegative DNA complexed with histones and other blood proteins or immune complexes, contributing to increase the thrombotic risk [
      • Bertin D.
      • Brodovitch A.
      • Lopez A.
      • Arcani R.
      • Thomas G.M.
      • Beziane A.
      • et al.
      Anti-cardiolipin IgG autoantibodies associate with circulating extracellular DNA in severe COVID-19.
      ,
      • Zhu Y.
      • Chen X.
      • Liu X.
      NETosis and neutrophil extracellular traps in COVID-19: immunothrombosis and beyond.
      ,
      • Gillot C.
      • Favresse J.
      • Mullier F.
      • Lecompte T.
      • Dogné J.M.
      • Douxfils J.
      NETosis and the immune system in COVID-19: mechanisms and potential treatments.
      ]. NETosis can contribute to stimulate an autoimmune response, which worsens the disease evolution. The presence of anti-PF4 autoantibodies, not associated with HIT, has been reported recently in very severe clinical Covid-19 cases [
      • Liu Q.
      • Miao H.
      • Li S.
      • Zhang P.
      • Gerber G.F.
      • Follmann D.
      • et al.
      Anti-PF4 antibodies associated with disease severity in COVID-19.
      ]. More generally, as heparin is frequently used to treat the thrombotic complications in Covid-19 patients, HIT can develop and requires the replacement of heparin by another anticoagulant [
      • Lingamaneni P.
      • Gonakoti S.
      • Moturi K.
      • Vohra I.
      • Zia M.
      Heparin-induced thrombocytopenia in COVID-19.
      ,
      • Julian K.
      • Bucher D.
      • Jain R.
      Autoimmune heparin-induced thrombocytopenia: a rare manifestation of COVID-19.
      ].
      Development of autoimmune complications in Covid-19 is suspected: i) from the characteristic clinical presentation in some patients; ii) from the presence of long-lasting effects with a persistent hyper-inflammatory state, and iii) from laboratory testing for some associated activities, like that of LA or thrombocytopenia [
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • Xia P.
      • Cao W.
      • Jiang W.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with covid-19.
      ,
      • Bhattacharjee S.
      • Banerjee M.
      Immune thrombocytopenia secondary to COVID-19: a systematic review.
      ]. A more accurate analysis needs to focus on which mechanisms can induce the development of these autoantibodies, which are reported to be very heterogenous, and how the autoantigen responsible for that autoimmune response is generated. Pathogens need an entry door to infect their targeted cells. That is provided usually by a cell surface receptor which interacts with a pathogen structure. That mechanism is of special relevance for viruses, which need the infected cell machinery to reproduce themselves and to expand through the body. Binding of viruses to specific cell surface receptors can then interfere in physiological functions, depending on the biological role of the concerned receptors. If these cell surface binding proteins are highly specific for a cell line or an organ, infection will be limited to these targets. However, if receptors are more ubiquitous, and are present on many cell lines or organs, the infection is then more extended and concerns different sites. This is the case for SARS-Cov-2, whose entry door is the Angiotensin Converting Enzyme 2 (ACE2) receptor, present at a high density on epithelial lung and pharyngeal cells, but also on many other cell lines and organs, like endothelial cells, kidneys, liver, heart, brain, spleen, pancreas, and nerves. Disease evolution depends then on the “race” between virus reproduction, its expansion and diffusion throughout the body, the development of the first innate immune response, with inflammation, neutrophils and macrophages activation, production of cytokines, and later, the adaptive immune cellular and humoral responses. This fight is complicated by other contributors, resulting from the side effects generated, like the cytokine storm, with thrombo-inflammation, highly stimulated by NETs. Although beneficial to slow down the progress of viral infection, NETs can become harmful and highly thrombogenic when present at too a high concentration, and are generate high kinetics [
      • Zhu Y.
      • Chen X.
      • Liu X.
      NETosis and neutrophil extracellular traps in COVID-19: immunothrombosis and beyond.
      ,
      • Gillot C.
      • Favresse J.
      • Mullier F.
      • Lecompte T.
      • Dogné J.M.
      • Douxfils J.
      NETosis and the immune system in COVID-19: mechanisms and potential treatments.
      ]. Yet, another player can join the battle when autoantibodies are induced. The adaptive immune response goal is to generate specific antibodies to bind and remove viruses. These antibodies are targeted to viral proteins. However, some viral proteins have mimicry with human structures, and therefore cross-react with them, behaving like autoantibodies. In addition, the viral proteins or peptides targeted by the immune defense against the viral infection can be in intimate complexes with body’s structures, usually proteins. In a first step, the immune response is specific to viral structures. But sometimes this response can be misdirected and antibodies are targeted to the whole complex, also becoming reactive with the body’s self-protein. Autoantibodies are then generated.

      7. Autoantibody characteristics in covid-19 patients

      We early speculated that specific and high affinity reaction of the SARS-Cov-2 viral spike protein with ACE2 is a key situation for generating autoantibodies to ACE2 [
      • Amiral J.
      • Vissac A.M.
      • Seghatchian J.
      Covid-19, induced activation of hemostasis, and immune reactions: Can an auto-immune reaction contribute to the delayed severe complications observed in some patients?.
      ]. This idea was shared by others, and some speculative papers proposed the potential development of these autoantibodies in Covid-19 patients [
      • Townsend A.
      Autoimmunity to ACE2 as a possible cause of tissue inflammation in Covid-19.
      ,
      • Rodriguez-Perez A.I.
      • Labandeira C.M.
      • Pedrosa M.A.
      • Valenzuela R.
      • Suarez-Quintanilla J.A.
      • Cortes-Ayaso M.
      • et al.
      Autoantibodies against ACE2 and angiotensin type-1 receptors increase severity of COVID-19.
      ,
      • McMillan P.
      • Dexhiemer T.
      • Neubig R.R.
      • Uhal B.D.
      COVID-19-A theory of autoimmunity against ACE-2 explained.
      ]. In a subsequent study on hospitalized Covid-19 patients, with various grades of severity,including fatal cases, we identified the presence of autoantibodies to ACE2, of IgG, IgM or IgA isotypes, or a combination of them, in about 10% of patients, and many of these autoantibodies were detected at a very high concentration [
      • Amiral J.
      • Busch M.H.
      Timmermans SAMEG, Reutelingsperger CP, van Paassen P. Development of IgG, IgM, and IgA Autoantibodies Against Angiotensin Converting Enzyme 2 in Patients with COVID-19.
      ]. Other studies confirmed the development of these autoantibodies in Covid-19 patients [
      • Casciola-Rosen L.
      • Thiemann D.R.
      • Andrade F.
      • Trejo-Zambrano M.I.
      • Leonard E.K.
      • Spangler J.B.
      • et al.
      IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function.
      ,
      • Arthur J.M.
      • Forrest J.C.
      • Boehme K.W.
      • Kennedy J.L.
      • Owens S.
      • Herzog C.
      • Liu J.
      • Harville T.O.
      Development of ACE2 autoantibodies after SARS-CoV-2 infection.
      ]. At present, there is not yet evidence on the contribution of these autoantibodies to disease complications or worsening, but investigations are ongoing. The relevance of anti-ACE2 autoantibodies could be of importance according to the key regulatory role of ACE2 for controlling hypertension, sodium cell balance, and diuresis among other functions to regulate the Renin-Angiotensin-Aldosterone System (RAAS) [
      • Verano-Braga T.
      • Martins A.L.V.
      • Motta-Santos D.
      • Campagnole-Santos M.J.
      • Santos R.A.S.
      ACE2 in the renin-angiotensin system.
      ]. As neutrophils play a key role for innate immunity, NETosis and thrombo-inflammation, we also looked for the presence of autoantibodies to Annexin A1, which is a major neutrophil released protein with anti-inflammatory activity [
      • Bruschi M.
      • Petretto A.
      • Vaglio A.
      • Santucci L.
      • Candiano G.
      • Ghiggeri G.M.
      Annexin A1 and autoimmunity: from basic science to clinical applications.
      ,
      • Suwanchote S.
      • Rachayon M.
      • Rodsaward P.
      • Wongpiyabovorn J.
      • Deekajorndech T.
      • Wright H.L.
      • et al.
      Anti-neutrophil cytoplasmic antibodies and their clinical significance.
      ,
      • Han P.F.
      • Che X.D.
      • Li H.Z.
      • Gao Y.Y.
      • Wei X.C.
      • Li P.C.
      Annexin A1 involved in the regulation of inflammation and cell signaling pathways.
      ]. Surprisingly, autoantibodies to Annexin A1 were detected at a high to very high concentration, with mainly IgG isotypes, but sometimes IgM, IgA or a combination, in a significant group of patients (about 20%), with some association with disease severity. In addition, we had the opportunity to test a Hemophilia A patient suffering from long-lasting Covid-19 symptoms for more than 1 year (plasma kindly provided by Dr D Desprez, from the University-Hospital of Strasbourg, France), and we found a high concentration of autoantibodies to Annexin A1, which remained at a very high concentration throughout the follow-up, although at this stage there is no evidence on the association of those autoantibodies with the persistence of symptoms.
      Other studies have reported different targets for autoantibodies present in Covid-19 patients. In particular, preexisting or newly generated autoantibodies to interferons have been reported and they could be associated to disease severity and prognosis [
      • Koning R.
      • Bastard P.
      • Casanova J.L.
      • Brouwer M.C.
      • van de Beek D.
      with the Amsterdam U.M.C. COVID-19 Biobank Investigators. Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients.
      ,
      • Bastard P.
      • Orlova E.
      • Sozaeva L.
      • Lévy R.
      • James A.
      • Schmitt M.M.
      • et al.
      Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.
      ]. These autoantibodies could be generated as a regulatory mechanism for controlling the excess of interferon release, but as for cytokines, in the presence of some extreme pathological conditions, they can deviate the immune response by interfering in their function. Among the autoantibodies described in patients with Covid-19 are those provoking Guillain-Barré syndrome, thrombocytopenia, and anti-nuclear antibodies [
      • Bhattacharjee S.
      • Banerjee M.
      Immune thrombocytopenia secondary to COVID-19: a systematic review.
      ,
      • Caress J.B.
      • Castoro R.J.
      • Simmons Z.
      • Scelsa S.N.
      • Lewis R.A.
      • Ahlawat A.
      • Narayanaswami P.
      COVID-19-associated Guillain-Barré syndrome: The early pandemic experience.
      ,
      • Son K.
      • Jamil R.
      • Chowdhury A.
      • Mukherjee M.
      • Venegas C.
      • Miyasaki K.
      • et al.
      Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptoms.
      ]. Of special relevance is the Kawasaki disease, observed in a few children infected with SARS-Cov-2, which is an autoimmune vasculitis probably induced by autoantibodies to endothelial cells [
      • Sakurai Y.
      Autoimmune aspects of kawasaki disease.
      ,
      • Berthelot J.M.
      • Drouet L.
      • Lioté F.
      Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?.
      ]. Autoantibodies to ACE2, a receptor also present on endothelial cells, were already reported in 2010, in patients with Connective Tissue Disease [
      • Takahashi Y.
      • Haga S.
      • Ishizaka Y.
      • Mimori A.
      Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseases.
      ].

      8. Laboratory assays for diagnosis of autoantibodies

      Laboratory methods are essential for characterizing autoimmune complications associated with or induced by Covid-19, and following their evolution. Testing helps to identify the autoantibody target, and when possible the autoantigen, and to estimate the antibody concentration and avidity, two key parameters associated with autoantibodies’ pathogenicity. The techniques used are either global, or they involve a specific antigen for capturing autoantibodies and isotyping them. Global methods characterize autoantibodies to the targeted cell or organ autoantibodies, or evaluate their interference of some biological functions, like anticoagulant activity. For example, antibodies to endothelial cells, to platelets, to neutrophils, to phospholipids have been reported. When the accurate target autoantigen is identified, more specific assays are designed by using the purified protein for capturing the autoantibodies, isotyping and quantitating them. That specific approach was used for identifying autoantibodies to ACE2, to Annexin A1 or to interferons [
      • Amiral J.
      • Busch M.H.
      Timmermans SAMEG, Reutelingsperger CP, van Paassen P. Development of IgG, IgM, and IgA Autoantibodies Against Angiotensin Converting Enzyme 2 in Patients with COVID-19.
      ,
      • Bruschi M.
      • Petretto A.
      • Vaglio A.
      • Santucci L.
      • Candiano G.
      • Ghiggeri G.M.
      Annexin A1 and autoimmunity: from basic science to clinical applications.
      ,
      • Han P.F.
      • Che X.D.
      • Li H.Z.
      • Gao Y.Y.
      • Wei X.C.
      • Li P.C.
      Annexin A1 involved in the regulation of inflammation and cell signaling pathways.
      ]. The laboratory methods developed for measuring autoantibodies involved in Covid-19 will be described later, in a separate report.

      9. Persistence of autoantibodies

      Transitory autoantibodies reach a concentration peak, before progressively declining. When present, their biological effects persist for some time, and are detectable for several weeks or a few months, but their immunological detection can last for a longer time, up to 6 months or more. If autoantibodies become chronic, they can then stay at a high concentration, and remain active. What induces the switch to long-lasting autoantibodies and the evolution to a chronic autoimmune disease remains poorly understood. Genetic factors and individual predispositions could be involved, and some immunological system dysfunctions could lead to a misdirected response. With the availability of accurate tools, the increasing identification of the specific autoantibody targeted epitopes on autoantigens, and the understanding of circumstances favoring the development of autoimmune complications; a better knowledge of this field is being generated.(Table 2).
      Table 2Autoantibodies reported in Covid-19 patients and possible clinical consequences; ACE2: angiotensin converting enzyme 2; PF4: platelet factor 4; RAAS: renin angiotensin aldosterone system;.

      10. Discussion and conclusions

      The Covid-19 disease produced by the SARS-Cov-2 viral infection is characterized by the strong innate and adaptive responses associated with an exacerbated inflammatory reaction, and a cytokine storm [
      • Borges do Nascimento I.J.
      • Cacic N.
      • Abdulazeem H.M.
      • von Groote T.C.
      • Jayarajah U.
      • Weerasekara I.
      • et al.
      Novel coronavirus infection (COVID-19) in humans: a scoping review and meta-analysis.
      ,
      • Gupta A.
      • Madhavan M.V.
      • Sehgal K.
      • Nair N.
      • Mahajan S.
      • Sehrawat T.S.
      • et al.
      Extrapulmonary manifestations of COVID-19.
      ]. This excess of immunological activity contributes to disease severity, morbidity and mortality. Neutrophils activity and NETosis play an important role, and, if they participate in the body’s defense against viral infection and expansion, they also contribute to develop the thrombo-inflammatory syndrome, with a high incidence of thromboembolic complications [
      • Zhu Y.
      • Chen X.
      • Liu X.
      NETosis and neutrophil extracellular traps in COVID-19: immunothrombosis and beyond.
      ,
      • Gillot C.
      • Favresse J.
      • Mullier F.
      • Lecompte T.
      • Dogné J.M.
      • Douxfils J.
      NETosis and the immune system in COVID-19: mechanisms and potential treatments.
      ]. Patients might develop enormous hemostatic abnormalities and biomarkers of hypercoagulability with a high thrombotic tendency. In affected patients, there is an increase of von Willebrand Factor ( vWF), fibrinogen and Factor VIII, a tendency to antithrombin decrease, a high increase of plasminogen activator inhibitor 1 activity and protein concentration, and a low fibrinolysis potential. DDimer is very elevated, and is used as an essential indicator of disease severity. Severe cases have benefitted from anticoagulant therapies using heparin, especially unfractionated, and anti-inflammatory treatments, like dexamethasone [
      • Hosseinzadeh M.H.
      • Shamshirian A.
      • Ebrahimzadeh M.A.
      Dexamethasone vs COVID-19: an experimental study in line with the preliminary findings of a large trial.
      ]. This has contributed to significantly decrease the disease associated mortality rate.
      Autoimmune complications can be an additional contributor to disease burden. They are involved in the disease course of various pathogen infections, especially with Cytomegalovirus, Epstein Barr or Human Immunodeficiency Virus. For the SARS-Cov-2 infection, involvement of autoimmune processes appears to be relevant, with a high variety of autoantibody targets, many being pan-specific, and anti-endothelial observed in various diseases, like anti-phospholipids, antibodies, or thrombocytopenia. Others could be more specific and linked to the viral strategy to infect human cells, through its specific binding to ACE2 [
      • Amiral J.
      • Busch M.H.
      Timmermans SAMEG, Reutelingsperger CP, van Paassen P. Development of IgG, IgM, and IgA Autoantibodies Against Angiotensin Converting Enzyme 2 in Patients with COVID-19.
      ,
      • Casciola-Rosen L.
      • Thiemann D.R.
      • Andrade F.
      • Trejo-Zambrano M.I.
      • Leonard E.K.
      • Spangler J.B.
      • et al.
      IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function.
      ,
      • Arthur J.M.
      • Forrest J.C.
      • Boehme K.W.
      • Kennedy J.L.
      • Owens S.
      • Herzog C.
      • Liu J.
      • Harville T.O.
      Development of ACE2 autoantibodies after SARS-CoV-2 infection.
      ]. The mechanisms underlying the induction of these various autoantibodies in certain patients could involve the many possibilities including antigen mimicry, and epitope spreading, like in most acquired autoimmune complications, as recently reviewed for VITT [
      • Amiral J.
      • Legros E.
      • Vivant M.
      • Rossi D.
      • Renaud G.
      Vaccine induced thrombotic thrombocytopenia: development and reactivity of anti-platelet factor 4 antibodies and immune pathogenic mechanisms.
      ].
      Apart from the identification of some autoimmune reactivities in patients suffering from Covid-19, and their possible association with disease severity and evolution, clinical studies on large cohorts are still missing. One could expect that availability of laboratory tools can contribute to perform transversal and longitudinal clinical studies to understand and document the contribution of autoantibodies to the disease prognosis.
      The ongoing new omicron subvariants in combination with two other respiratory infections having similar symptoms, namely influenza (flu), and respiratory syncytial virus (RSV), all appearing with the coming colder season [as a Triple- endemic] are among some of the unmet high priority issues to be resolved. Needless to highlight that we must keep our immunity as high as possible and avoid reinfections as well as reduce the risk of long COVID that can occur these in cold days ahead even in the young.

      References

        • Borges do Nascimento I.J.
        • Cacic N.
        • Abdulazeem H.M.
        • von Groote T.C.
        • Jayarajah U.
        • Weerasekara I.
        • et al.
        Novel coronavirus infection (COVID-19) in humans: a scoping review and meta-analysis.
        J Clin Med. 2020; 9: 941
        • Gupta A.
        • Madhavan M.V.
        • Sehgal K.
        • Nair N.
        • Mahajan S.
        • Sehrawat T.S.
        • et al.
        Extrapulmonary manifestations of COVID-19.
        Nat Med. 2020; 26: 1017-1032
        • Castanares-Zapatero D.
        • Chalon P.
        • Kohn L.
        • Dauvrin M.
        • Detollenaere J.
        • Maertens de Noordhout C.
        • Primus-de Jong C.
        • Cleemput I.
        • Van den Heede K.
        Pathophysiology and mechanism of long COVID: a comprehensive review.
        Ann Med. 2022; 54: 1473-1487
        • Naeije R.
        • Caravita S.
        Phenotyping long COVID.
        Eur Respir J. 2021; 582101763
        • Petersen M.S.
        • Kristiansen M.F.
        • Hanusson K.D.
        • Danielsen M.E.
        • Á Steig B.
        • Gaini S.
        • et al.
        Long COVID in the Faroe Islands: a longitudinal study among nonhospitalized patients.
        Clin Infect Dis. 2021; 73: e4058-e4063
        • Augustin M.
        • Schommers P.
        • Stecher M.
        • Dewald F.
        • Gieselmann L.
        • Gruell H.
        • et al.
        Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study.
        Lancet Reg Health Eur. 2021; 6100122
        • Maamar M.
        • Artime A.
        • Pariente E.
        • Fierro P.
        • Ruiz Y.
        • Gutiérrez S.
        • et al.
        Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study.
        Curr Med Res Opin. 2022; 38: 901-909
        • Amiral J.
        • Vissac A.M.
        • Seghatchian J.
        Covid-19, induced activation of hemostasis, and immune reactions: Can an auto-immune reaction contribute to the delayed severe complications observed in some patients?.
        Transfus Apher Sci. 2020; 59: 3
        • Townsend A.
        Autoimmunity to ACE2 as a possible cause of tissue inflammation in Covid-19.
        Med Hypotheses. 2020; 144110043
        • Rodriguez-Perez A.I.
        • Labandeira C.M.
        • Pedrosa M.A.
        • Valenzuela R.
        • Suarez-Quintanilla J.A.
        • Cortes-Ayaso M.
        • et al.
        Autoantibodies against ACE2 and angiotensin type-1 receptors increase severity of COVID-19.
        J Autoimmun. 2021; 122102683
        • McMillan P.
        • Dexhiemer T.
        • Neubig R.R.
        • Uhal B.D.
        COVID-19-A theory of autoimmunity against ACE-2 explained.
        Front Immunol. 2021; 12582166
        • Smatti M.K.
        • Cyprian F.S.
        • Nasrallah G.K.
        • Al Thani A.A.
        • Almishal R.O.
        • Yassine H.M.
        Viruses and autoimmunity: a review on the potential interaction and molecular mechanisms.
        Viruses. 2019; 11: 762
        • Halenius A.
        • Hengel H.
        Human cytomegalovirus and autoimmune disease.
        Biomed Res Int. 2014; 2014472978
        • Houen G.
        • Trier N.H.
        Epstein-barr virus and systemic autoimmune diseases.
        Front Immunol. 2021; 11587380
        • Zandman-Goddard G.
        • Shoenfeld Y.
        HIV and autoimmunity.
        Autoimmun Rev. 2002; 1: 329-337
        • Ercolini A.M.
        • Miller S.D.
        The role of infections in autoimmune disease.
        Clin Exp Immunol. 2009; 155: 1-15
        • Abdel-Wahab N.
        • Lopez-Olivo M.A.
        • Pinto-Patarroyo G.P.
        • Suarez-Almazor M.E.
        Systematic review of case reports of antiphospholipid syndrome following infection.
        Lupus. 2016; 25: 1520-1531
        • Getts D.R.
        • Chastain E.M.
        • Terry R.L.
        • Miller S.D.
        Virus infection, antiviral immunity, and autoimmunity.
        Immunol Rev. 2013; 255: 197-209
        • Levin M.
        • Eley B.S.
        • Louis J.
        • Cohen H.
        • Young L.
        • Heyderman R.S.
        Postinfectious purpura fulminans caused by an autoantibody directed against protein S.
        J Pedia. 1995; 127: 355-363
        • Peyvandi F.
        • Faioni E.
        • Alessandro Moroni G.
        • Rosti A.
        • Leo L.
        • Moia M.
        Autoimmune protein S deficiency and deep vein thrombosis after chickenpox.
        Thromb Haemost. 1996; 75: 212-213
        • Manco-Johnson M.J.
        • Nuss R.
        • Key N.
        • Moertel C.
        • Jacobson L.
        • Meech S.
        • et al.
        Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis.
        J Pedia. 1996; 128: 319-323
        • Regnault V.
        • Boehlen F.
        • Ozsahin H.
        • Wahl D.
        • de Groot P.G.
        • Lecompte T.
        • de Moerloose P.
        Anti-protein S antibodies following a varicella infection: detection, characterization and influence on thrombin generation.
        J Thromb Haemost. 2005; 3: 1243-1249
        • Samyn B.
        • Grunebaum L.
        • Amiral J.
        • Ammouche C.
        • Lounis K.
        • Eicher E.
        • et al.
        Thrombophlébite cérébrale post-varicelle avec anticorps anti-protéine S: à propos d'un cas pédiatrique [Post-varicella cerebral thrombophlebitis with anti-protein S: report of a pediatric case].
        Ann Biol Clin (Paris). 2012; 70: 99-103
        • Amiral J.
        Immunomodulation, autoimmunity and haemostatic dysfunctions.
        Transfus Sci. 1997; 18: 361-365
        • Bendtzen K.
        • Hansen M.B.
        • Ross C.
        • Svenson M.
        High-avidity autoantibodies to cytokines.
        Immunol Today. 1998; 19: 209-211
        • Watanabe M.
        • Uchida K.
        • Nakagaki K.
        • Kanazawa H.
        • Trapnell B.C.
        • Hoshino Y.
        • et al.
        Anti-cytokine autoantibodies are ubiquitous in healthy individuals.
        FEBS Lett. 2007; 581: 2017-2021
        • Puel A.
        • Casanova J.L.
        Autoantibodies against cytokines: back to human genetics.
        Blood. 2013; 121: 1246-1247
        • Nielsen C.H.
        • Bendtzen K.
        Immunoregulation by naturally occurring and disease-associated autoantibodies: binding to cytokines and their role in regulation of T-cell responses.
        Adv Exp Med Biol. 2012; 750: 116-132
        • Gordon D.E.
        • Jang G.M.
        • Bouhaddou M.
        • Xu J.
        • Obernier K.
        • White K.M.
        • et al.
        A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
        Nature. 2020; 583: 459-468
        • Sarzi-Puttini P.
        • Giorgi V.
        • Sirotti S.
        • Marotto D.
        • Ardizzone S.
        • Rizzardini G.
        • et al.
        COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?.
        Clin Exp Rheuma. 2020; 38: 337-342
        • Nazerian Y.
        • Ghasemi M.
        • Yassaghi Y.
        • Nazerian A.
        • Hashemi S.M.
        Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: Molecular pathways and potential therapeutic options.
        Int Immunopharmacol. 2022; 113109428
        • Lyons-Weiler J.
        Pathogenic priming likely contributes to serious and critical illness and mortality in COVID-19 via autoimmunity.
        J Transl Autoimmun. 2020; 9
        • Rodríguez Y.
        • Novelli L.
        • Rojas M.
        • De Santis M.
        • Acosta-Ampudia Y.
        • et al.
        Autoinflammatory and autoimmune conditions at the crossroad of COVID-19.
        J Autoimmun. 2020; 114
        • de Groot P.G.
        • Horbach D.A.
        • Simmelink M.J.
        • van Oort E.
        • Derksen R.H.
        Anti-prothrombin antibodies and their relation with thrombosis and lupus anticoagulant.
        Lupus. 1998; 7 (S32-6)
        • Amiral J.
        • Peyrafitte M.
        • Dunois C.
        • Vissac A.M.
        • Seghatchian J.
        Anti-phospholipid syndrome: current opinion on mechanisms involved, laboratory characterization and diagnostic aspects.
        Transfus Apher Sci. 2017; 56: 612-625
        • Halpert G.
        • Shoenfeld Y.
        SARS-CoV-2, the autoimmune virus.
        Autoimmun Rev. 2020; 19: 12
        • Zhou Y.
        • Han T.
        • Chen J.
        • Hou C.
        • Hua L.
        • He S.
        • et al.
        Clinical and autoimmune characteristics of severe and critical cases of COVID-19.
        Clin Transl Sci. 2020; 13: 6
        • Zuo Y.
        • Estes S.K.
        • Ali R.A.
        • Gandhi A.A.
        • Yalavarthi S.
        • Shi H.
        • et al.
        Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.
        Sci Transl Med. 2020; 12: 570
        • Zhang Y.
        • Xiao M.
        • Zhang S.
        • Xia P.
        • Cao W.
        • Jiang W.
        • et al.
        Coagulopathy and antiphospholipid antibodies in patients with covid-19.
        N Engl J Med. 2020; 382: 17
        • Elrashdy F.
        • Tambuwala M.M.
        • Hassan S.S.
        • Adadi P.
        • Seyran M.
        • Abd El-Aziz
        • et al.
        Autoimmunity roots of the thrombotic events after COVID-19 vaccination.
        Autoimmun Rev. 2021; 20102941
        • Delogu L.G.
        • Deidda S.
        • Delitala G.
        • Manetti R.
        Infectious diseases and autoimmunity.
        J Infect Dev Ctries. 2011; 5 (679-8)
        • Bigley T.M.
        • Cooper M.A.
        Monogenic autoimmunity and infectious diseases: the double-edged sword of immune dysregulation.
        Curr Opin Immunol. 2021; 72 (230-23)
        • Uthman I.W.
        • Gharavi A.E.
        Viral infections and antiphospholipid antibodies.
        Semin Arthritis Rheum. 2002; 31: 256-263
        • Ercolini A.M.
        • Miller S.D.
        The role of infections in autoimmune disease.
        Clin Exp Immunol. 2009; 155: 1-15
        • Tuohy V.K.
        • Kinkel R.P.
        Epitope spreading: a mechanism for progression of autoimmune disease.
        Arch Immunol Ther Exp (Warsz). 2000; 48: 347-351
        • Powell A.M.
        • Black M.M.
        Epitope spreading: protection from pathogens, but propagation of autoimmunity?.
        Clin Exp Dermatol. 2001; 26: 427-433
        • Rojas M.
        • Restrepo-Jiménez P.
        • Monsalve D.M.
        • Pacheco Y.
        • Acosta-Ampudia Y.
        • Ramírez-Santana C.
        • et al.
        Molecular mimicry and autoimmunity.
        J Autoimmun. 2018; 95: 100-123
        • Barzilai O.
        • Sherer Y.
        • Ram M.
        • Izhaky D.
        • Anaya J.M.
        • Shoenfeld Y.
        Epstein-Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? A preliminary report.
        Ann N Y Acad Sci. 2007; 1108: 567-577
        • de Melo Silva J.
        • Pinheiro-Silva R.
        • Dhyani A.
        • Pontes G.S.
        Cytomegalovirus and epstein-barr infections: prevalence and impact on patients with hematological diseases.
        Biomed Res Int. 2020 24; 20201627824
        • Vivaldi P.
        • Rossetti G.
        • Galli M.
        • Finazzi G.
        Severe bleeding due to acquired hypoprothrombinemia-lupus anticoagulant syndrome.
        Case Rep Rev Lit Haematol. 1997; 82: 345-347
        • Amiral J.
        • Aronis S.
        • Adamtziki E.
        • Garoufi A.
        • Karpathios T.
        Association of lupus anticoagulant with transient antibodies to prothrombin in a patient with hypoprothrombinemia.
        Thromb Res. 1997; 86: 73-78
        • Carvalho C.
        • Viveiro C.
        • Maia P.
        • Rezende T.
        Acquired antiprothrombin antibodies: an unusual cause of bleeding.
        BMJ Case Rep. 2013; : 2013
        • Pender M.P.
        Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases.
        Trends Immunol. 2003; 24: 584-588
        • Driul L.
        • Bertozzi S.
        • Londero A.P.
        • Fruscalzo A.
        • Rusalen A.
        • Marchesoni D.
        • et al.
        Risk factors for chronic pelvic pain in a cohort of primipara and secondipara at one year after delivery: association of chronic pelvic pain with autoimmune pathologies.
        Minerva Ginecol. 2011; 63: 181-187
        • Favaloro E.J.
        Variability and diagnostic utility of antiphospholipid antibodies including lupus anticoagulants.
        Int J Lab Hematol. 2013; 35: 269-274
        • Olayemi E.
        • Halim N.K.
        Antiphospholipid antibodies in medical practice: a review.
        Niger J Med. 2006; 15: 7-15
        • Horimoto A.M.C.
        • de Jesus L.G.
        • de Souza A.S.
        • Rodrigues S.H.
        • Kayser C.
        Anti-annexin V autoantibodies and vascular abnormalities in systemic sclerosis: a longitudinal study.
        Adv Rheuma. 2020; 60: 38
        • Rodríguez Y.
        • Rojas M.
        • Gershwin M.E.
        • Anaya J.M.
        Tick-borne diseases and autoimmunity: a comprehensive review.
        J Autoimmun. 2018; 88: 21-42
        • Ajzner E.
        • Balogh I.
        • Haramura G.
        • Boda Z.
        • Kalmár K.
        • Pfliegler G.
        • et al.
        Anti-factor V auto-antibody in the plasma and platelets of a patient with repeated gastrointestinal bleeding.
        J Thromb Haemost. 2003; 1: 943-949
        • Hoffmann C.
        • Amiral J.
        • Rezig S.
        • Kerspern H.
        • Jantzem H.
        • Robin S.
        • et al.
        A very potent factor V inhibitor interferes with the levels of all coagulation factors and causes a fatal hemorrhagic syndrome.
        Eur J Haematol. 2019; 103: 137-139
        • Arepally G.M.
        • Cines D.B.
        Pathogenesis of heparin-induced thrombocytopenia.
        Transl Res. 2020; 225: 131-140
        • Amiral J.
        • Marfaing-Koka A.
        • Poncz M.
        • Meyer D.
        The biological basis of immune heparin-induced thrombocytopenia.
        Platelets. 1998; 9: 77-91
        • Visentin G.P.
        • Newman P.J.
        • Aster R.H.
        Characteristics of quinine- and quinidine-induced antibodies specific for platelet glycoproteins IIb and IIIa.
        Blood. 1991 15; 77 (2668-7)
        • Dlott J.S.
        • Roubey R.A.
        Drug-induced lupus anticoagulants and antiphospholipid antibodies.
        Curr Rheuma Rep. 2012; 14: 71-78
        • Greinacher A.
        • Schönborn L.
        • Siegerist F.
        • Steil L.
        • Palankar R.
        • Handtke S.
        • et al.
        Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT).
        Semin Hematol. 2022; 59: 97-107
        • Reilly-Stitt C.
        • Jennings I.
        • Kitchen S.
        • Makris M.
        • Meijer P.
        • de Maat M.
        • et al.
        Anti-PF4 testing for vaccine-induced immune thrombocytopenia and thrombosis (VITT): Results from a NEQAS, ECAT and SSC collaborative exercise in 385 centers worldwide.
        J Thromb Haemost. 2022; 20: 1875-1879
        • Tabrez S.
        • Jabir N.R.
        • Khan M.I.
        • Khan M.S.
        • Shakil S.
        • Siddiqui A.N.
        • Zaidi S.K.
        • Ahmed B.A.
        • Kamal M.A.
        Association of autoimmunity and cancer: an emphasis on proteolytic enzymes.
        Semin Cancer Biol. 2020; 64: 19-28
        • Masetti R.
        • Tiri A.
        • Tignanelli A.
        • Turrini E.
        • Argentiero A.
        • Pession A.
        • Esposito S.
        Autoimmunity and cancer.
        Autoimmun Rev. 2021; 20102882
        • Duhlin A.
        • Chen Y.
        • Wermeling F.
        • Sedimbi S.K.
        • Lindh E.
        • Shinde R.
        • Halaby M.J.
        • Kaiser Y.
        • Winqvist O.
        • McGaha T.L.
        • Karlsson M.C.
        Selective Memory to Apoptotic Cell-Derived Self-Antigens with Implications for Systemic Lupus Erythematosus Development.
        J Immunol. 2016; 197: 2618-2626
        • Picchianti-Diamanti A.
        • Rosado M.M.
        • D'Amelio R.
        Infectious agents and inflammation: the role of microbiota in autoimmune arthritis.
        Front Microbiol. 2018; 8: 269
        • Noordermeer T.
        • Molhoek J.E.
        • Schutgens R.E.G.
        • Sebastian S.A.E.
        • Drost-Verhoef S.
        • van Wesel A.C.W.
        • et al.
        Anti-β2-glycoprotein I and anti-prothrombin antibodies cause lupus anticoagulant through different mechanisms of action.
        J Thromb Haemost. 2021; 19: 1018-1028
        • Huynh A.
        • Kelton J.G.
        • Arnold D.M.
        • Daka M.
        • Nazy I.
        Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia.
        Nature. 2021; 596 (565-56)
        • Bakchoul T.
        • Sachs U.J.
        Platelet destruction in immune thrombocytopenia.
        Underst Mech Hamost. 2016; 36: 187-194
        • Cines D.B.
        • Wilson S.B.
        • Tomaski A.
        • Schreiber A.D.
        Platelet antibodies of the IgM class in immune thrombocytopenic purpura.
        J Clin Invest. 1985; 75: 1183-1190
        • Cockwell P.
        • Tse W.Y.
        • Savage C.O.
        Activation of endothelial cells in thrombosis and vasculitis.
        Scand J Rheuma. 1997; 26: 145-150
        • Moulis G.
        • Audemard-Verger A.
        • Arnaud L.
        • Luxembourger C.
        • Montastruc F.
        • Gaman A.M.
        • et al.
        Risk of thrombosis in patients with primary immune thrombocytopenia and antiphospholipid antibodies: A systematic review and meta-analysis.
        Autoimmun Rev. 2016; 15: 203-209
        • Fijnheer R.
        • Horbach D.A.
        • Donders R.C.
        • Vilé H.
        • von Oort E.
        • et al.
        Factor V Leiden, antiphospholipid antibodies and thrombosis in systemic lupus erythematosus.
        Thromb Haemost. 1996; 76 (514-)
        • Roubey R.A.
        Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other "antiphospholipid" autoantibodies.
        Blood. 1994; 84: 2854-2867
        • Knight J.S.
        • Kanthi Y.
        Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome.
        Semin Immunopathol. 2022; 44: 347-362
        • Guermazi S.
        • Mellouli F.
        • Trabelsi S.
        • Bejaoui M.
        • Dellagi K.
        Anti-thrombomodulin antibodies and venous thrombosis.
        Blood Coagul Fibrinolysis. 2004; 15: 553-558
        • van Genderen P.J.
        • Michiels J.J.
        Acquired von Willebrand disease.
        Baillieres Clin Haematol. 1998; 11: 319-330
        • Chong B.H.
        • Ho S.J.
        Autoimmune thrombocytopenia.
        J Thromb Haemost. 2005; 3: 1763-1772
        • Kruse-Jarres R.
        • Kempton C.L.
        • Baudo F.
        • Collins P.W.
        • Knoebl P.
        • Leissinger C.A.
        • et al.
        Acquired hemophilia A: updated review of evidence and treatment guidance.
        Am J Hematol. 2017; 92: 695-705
        • Ichinose A.
        Japanese collaborative research group on AH13. Autoimmune acquired factor XIII deficiency due to anti-factor XIII/13 antibodies: a summary of 93 patients.
        Blood Rev. 2017; 31: 37-45
        • Al-Adhoubi N.K.
        • Bystrom J.
        Systemic lupus erythematosus and diffuse alveolar hemorrhage, etiology and novel treatment strategies.
        Lupus. 2020; 29: 355-363
        • Peichl P.
        • Pursch E.
        • Bröll H.
        • Lindley I.J.
        Anti-IL-8 autoantibodies and complexes in rheumatoid arthritis: polyclonal activation in chronic synovial tissue inflammation.
        Rheuma Int. 1999; 18: 141-145
        • Amiral J.
        • Marfaing-Koka A.
        • Wolf M.
        • Alessi M.C.
        • Tardy B.
        • Boyer-Neumann C.
        • et al.
        Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia.
        Blood. 1996; 88: 410-416
        • de Maistre E.
        • Regnault V.
        • Lecompte T.
        • Scheid P.
        • Martinet Y.
        • Bellou A.
        • Amiral J.
        • Vissac A.M.
        Antibodies to interleukin-8 and paraneoplastic catastrophic recurrent thromboses.
        Am J Med. 2001; 111: 580-581
        • Desprez D.
        • Desprez P.
        • Tardy B.
        • Amiral J.
        • Droulle C.
        • Ducassou S.
        • et al.
        Anti-PF4 antibodies and thrombophlebitis in a child with cerebral venous thrombosis.
        Ann Biol Clin (Paris). 2010 -; 68: 725-728
        • Warkentin T.E.
        • Greinacher A.
        Spontaneous HIT syndrome: Knee replacement, infection, and parallels with vaccine-induced immune thrombotic thrombocytopenia.
        Thromb Res. 2021; 204: 40-51
        • Galeotti C.
        • Bayry J.
        Autoimmune and inflammatory diseases following COVID-19.
        Nat Rev Rheuma. 2020; 16: 413-414
        • Dotan A.
        • Muller S.
        • Kanduc D.
        • David P.
        • Halpert G.
        • Shoenfeld Y.
        The SARS-CoV-2 as an instrumental trigger of autoimmunity.
        Autoimmun Rev. 2021; 20102792
        • Acosta-Ampudia Y.
        • Monsalve D.M.
        • Rojas M.
        • Rodríguez Y.
        • Zapata E.
        • Ramírez-Santana C.
        • et al.
        Persistent autoimmune activation and proinflammatory state in post-coronavirus disease 2019 syndrome.
        J Infect Dis. 2022; 225: 2155-2162
        • Bhattacharjee S.
        • Banerjee M.
        Immune thrombocytopenia secondary to COVID-19: a systematic review.
        SN Compr Clin Med. 2020; 2: 2048-2058
        • Lingamaneni P.
        • Gonakoti S.
        • Moturi K.
        • Vohra I.
        • Zia M.
        Heparin-induced thrombocytopenia in COVID-19.
        J Invest Med High Impact Case Rep. 2020; 8
        • Bertin D.
        • Brodovitch A.
        • Lopez A.
        • Arcani R.
        • Thomas G.M.
        • Beziane A.
        • et al.
        Anti-cardiolipin IgG autoantibodies associate with circulating extracellular DNA in severe COVID-19.
        Sci Rep. 2022; 12: 12523
        • Zhu Y.
        • Chen X.
        • Liu X.
        NETosis and neutrophil extracellular traps in COVID-19: immunothrombosis and beyond.
        Front Immunol. 2022; 13838011
        • Gillot C.
        • Favresse J.
        • Mullier F.
        • Lecompte T.
        • Dogné J.M.
        • Douxfils J.
        NETosis and the immune system in COVID-19: mechanisms and potential treatments.
        Front Pharm. 2021; 12708302
        • Liu Q.
        • Miao H.
        • Li S.
        • Zhang P.
        • Gerber G.F.
        • Follmann D.
        • et al.
        Anti-PF4 antibodies associated with disease severity in COVID-19.
        Proc Natl Acad Sci USA. 2022; 119e2213361119
        • Lingamaneni P.
        • Gonakoti S.
        • Moturi K.
        • Vohra I.
        • Zia M.
        Heparin-induced thrombocytopenia in COVID-19.
        J Invest Med High Impact Case Rep. 2020; 8 (232470962094409)
        • Julian K.
        • Bucher D.
        • Jain R.
        Autoimmune heparin-induced thrombocytopenia: a rare manifestation of COVID-19.
        BMJ Case Rep. 2021; 14e243315
        • Amiral J.
        • Busch M.H.
        Timmermans SAMEG, Reutelingsperger CP, van Paassen P. Development of IgG, IgM, and IgA Autoantibodies Against Angiotensin Converting Enzyme 2 in Patients with COVID-19.
        J Appl Lab Med. 2022; 7: 382-386
        • Casciola-Rosen L.
        • Thiemann D.R.
        • Andrade F.
        • Trejo-Zambrano M.I.
        • Leonard E.K.
        • Spangler J.B.
        • et al.
        IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function.
        JCI Insight. 2022; 7e158362
        • Arthur J.M.
        • Forrest J.C.
        • Boehme K.W.
        • Kennedy J.L.
        • Owens S.
        • Herzog C.
        • Liu J.
        • Harville T.O.
        Development of ACE2 autoantibodies after SARS-CoV-2 infection.
        PLoS One. 2021; 16e0257016
        • Verano-Braga T.
        • Martins A.L.V.
        • Motta-Santos D.
        • Campagnole-Santos M.J.
        • Santos R.A.S.
        ACE2 in the renin-angiotensin system.
        Clin Sci (Lond). 2020 11; 134: 3063-3078
        • Bruschi M.
        • Petretto A.
        • Vaglio A.
        • Santucci L.
        • Candiano G.
        • Ghiggeri G.M.
        Annexin A1 and autoimmunity: from basic science to clinical applications.
        Int J Mol Sci. 2018; 19: 1348
        • Suwanchote S.
        • Rachayon M.
        • Rodsaward P.
        • Wongpiyabovorn J.
        • Deekajorndech T.
        • Wright H.L.
        • et al.
        Anti-neutrophil cytoplasmic antibodies and their clinical significance.
        Clin Rheuma. 2018; 37: 875-884
        • Han P.F.
        • Che X.D.
        • Li H.Z.
        • Gao Y.Y.
        • Wei X.C.
        • Li P.C.
        Annexin A1 involved in the regulation of inflammation and cell signaling pathways.
        Chin J Trauma. 2020; 23: 96-101
        • Koning R.
        • Bastard P.
        • Casanova J.L.
        • Brouwer M.C.
        • van de Beek D.
        with the Amsterdam U.M.C. COVID-19 Biobank Investigators. Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients.
        Intensive Care Med. 2021; 47: 704-706
        • Bastard P.
        • Orlova E.
        • Sozaeva L.
        • Lévy R.
        • James A.
        • Schmitt M.M.
        • et al.
        Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.
        J Exp Med. 2021; 218e20210554
        • Caress J.B.
        • Castoro R.J.
        • Simmons Z.
        • Scelsa S.N.
        • Lewis R.A.
        • Ahlawat A.
        • Narayanaswami P.
        COVID-19-associated Guillain-Barré syndrome: The early pandemic experience.
        Muscle Nerve. 2020; 62: 485-491
        • Son K.
        • Jamil R.
        • Chowdhury A.
        • Mukherjee M.
        • Venegas C.
        • Miyasaki K.
        • et al.
        Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptoms.
        Eur Respir J. 2022; 2200970
        • Sakurai Y.
        Autoimmune aspects of kawasaki disease.
        J Invest Allergol Clin Immunol. 2019; 29: 251-261
        • Berthelot J.M.
        • Drouet L.
        • Lioté F.
        Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?.
        Emerg Microbes Infect. 2020; 9: 1514-1522
        • Takahashi Y.
        • Haga S.
        • Ishizaka Y.
        • Mimori A.
        Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseases.
        Arthritis Res Ther. 2010; 12: R85
        • Hosseinzadeh M.H.
        • Shamshirian A.
        • Ebrahimzadeh M.A.
        Dexamethasone vs COVID-19: an experimental study in line with the preliminary findings of a large trial.
        Int J Clin Pr. 2021; 75e13943
        • Amiral J.
        • Legros E.
        • Vivant M.
        • Rossi D.
        • Renaud G.
        Vaccine induced thrombotic thrombocytopenia: development and reactivity of anti-platelet factor 4 antibodies and immune pathogenic mechanisms.
        Explor Immunol. 2022; 2: 604-621