key: cord-0712659-qexarxjl
authors: Dotan, Arad; Muller, Sylviane; Kanduc, Darja; David, Paula; Halpert, Gilad; Shoenfeld, Yehuda
title: The SARS-CoV-2 as an instrumental trigger of autoimmunity
date: 2021-02-19
journal: Autoimmun Rev
DOI: 10.1016/j.autrev.2021.102792
sha: 61758f2a24c893a648b76037ef2f5246bea4f447
doc_id: 712659
cord_uid: qexarxjl

Autoimmunity may be generated by a variety of factors by creating a hyper-stimulated state of the immune system. It had been established long ago that viruses are a substantial component of environmental factors that contribute to the production of autoimmune antibodies, as well as autoimmune diseases. Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) are viruses that withhold these autoimmune abilities. In a similar manner, SARS-CoV-2 may be counted to similar manifestations, as numerous records demonstrating the likelihood of COVID-19 patients to develop multiple types of autoantibodies and autoimmune diseases. In this review, we focused on the association between COVID-19 and the immune system concerning the tendency of patients to develop over 15 separate types of autoantibodies and above 10 distinct autoimmune diseases. An additional autoimmunity manifestation may be one of the common initial symptoms in COVID-19 patients, anosmia, the complete loss of the ability to sense smell, and other olfactory alterations. We summarize current knowledge on principal mechanisms that may contribute to the development of autoimmunity in the disease: the ability of SARS-CoV-2 to hyper-stimulate the immune system, induce excessive neutrophil extracellular traps formation with neutrophil-associated cytokine responses and the molecular resemblance between self-components of the host and the virus. Additionally, we will examine COVID-19 potential risk on the new-onsets of autoimmune diseases, such as antiphospholipid syndrome, Guillain-Barré syndrome, Kawasaki disease and numerous others. It is of great importance to recognize those autoimmune manifestations of COVID-19 in order to properly cope with their outcomes in the ongoing pandemic and the long-term post-pandemic period. Lastly, an effective vaccine against SARS-CoV-2 may be the best solution in dealing with the ongoing pandemic. We will discuss the new messenger RNA vaccination strategy with an emphasis on autoimmunity implications.

The onset of autoimmune diseases (AIDs) may be generated by a variety of factors through the creating a hyper-stimulated state of the immune system. It is accustomed to classifying factors that affect the immune system into three primary groups: genetical, environmental and hormonal (1) (2) (3) (4) . Viruses are a substantial component of the environmental factors that affect the immune system. Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV) and human T lymphotropic virus 1 (HTLV-1) are examples of viruses with an established association to multiple AIDs (5) (6) (7) (8) (9) . The autoimmune influence of these viruses is not atypical, there are many other viruses that are also associated with AIDs (10) . The combination of a genetically predisposed individual with a hyperstimulated state of the immune system may trigger an AID, and eventually lymphoma might develop as a consequence (4, 11) (Fig. 1A) .

December 2019 in Wuhan, China, is induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 had spread to numerous countries with roughly 107 million confirmed cases including 2.3 million deaths up to February 2021. SARS-CoV-2 is using angiotensin-converting enzyme-2 (ACE-2) and the transmembrane serine protease-2 (TMPRSS2) as receptors, which are expressed on type 2 pneumocytes and many other cell types, in order to fuse the envelope with the cell membrane and penetrates the cells (12, 13) . Thus ACE-2 and TMPRSS-2 are crucial viral fusion proteins of the SARS-CoV-2. ACE-2 is also widely expressed on endothelial cells and acts as a major constituent in the maintenance of vascular homeostasis (14) .

Furthermore, SARS-CoV-2 downregulates ACE-2 in targeted cells, which leads to the excess generation of angiotensin II, an active metabolite that promotes inflammation, vasoconstriction, cell proliferation, and vascular leakage and eventually, pulmonary fibrosis (12) . These properties of SARS-CoV-2 contribute to the development of acute respiratory distress syndrome (ARDS) and as a result may lead to lung failure, as seen among many severely-ill patients (14) .

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In parallel to the ability of the virus to induce hyper-stimulation of the immune system, recent findings pointed out a homology of primary sequence between humans and components of SARS-CoV-2 (22) . In contrast, this homology was not found in mammals unaffected by SARS-CoV-2 (22) . As the acquired immune system produces antibodies cross-reacting with common molecules among pathogens and self-components, molecular mimicry readily contributes to the production of autoantibodies that possibly result in the new onset of an AID. In this regard, Table 1 documents a list of heptapeptides, the linear sequence of which is shared between SARS-CoV-2 and the human proteome with high pathological potential. Indeed, the viral versus human peptide overlaps involve human proteins that, if altered, mutated, deficient, or improperly functioning, can lead to severe pathologies. Examples are: cerebellum-2, alterations of which associate with MS (23); follistatin-related protein 1 that protects against hypoxiainduced pulmonary hypertension (24) ; and the protein solute carrier family 12 member 6, alterations of which may associate with areflexia and severe progressive neuropathy often accompanied by psychiatric symptoms and olfactory receptor 7D4, which is specific for smell (25, 26) . These results correlate with the long-standing claim that identity of sequences between self-and viral proteins display a potential major role in the pathophysiology of AIDs (27) . In addition to the remarkable results shown in Table 1 identified by using linear sequences of 7 contiguous residues (7-mer), other possible identities may occur when the self-and viral proteins are folded in the secondary and tertiary structure.

Neutrophil extracellular traps (NET) activation and release, or NETosis, is a dynamic process that plays a critical role in innate immunity. It represents a beneficial antimicrobial mechanism of neutrophils, which intervenes by trapping and killing invading pathogens while minimizing damage to the host cells.

NETs are networks of extracellular fibers, primarily composed of DNA and chromatin that are expelled from neutrophils and bind pathogens. However, NETs can also serve a source of self-antigens resulting in J o u r n a l P r e -p r o o f Journal Pre-proof autoimmune conditions. Thus, excessive NET formation has been involved in the autoinflammatory response in SLE, RA, myositis and MS, for example (28) (29) (30) . NET-derived neutrophil proteases, such as elastase, may cause the release of peptidylarginine deiminases (PADs) that enhance citrullination of selfproteins (e.g. histones, cartilage proteins, others), rendering them autoreactive and promoting pathogenic inflammatory cascade in these autoinflammatory diseases. NET formation has also been associated with thrombosis in antiphospholipid syndrome (31) . It is thus thought that excessive NETosis is implicated in early vascular ageing and increased risk of cardiovascular disease, a severe complication of SLE.

Autoantibodies to NETs have been claimed to represent potential serological biomarkers in RA (32) .

Excessive NET formation and neutrophil-associated cytokine responses have also been associated with SARS-CoV-2 pathogenesis (33). Numerous clinical reports indicate a progressive rise in neutrophilia in SARS-CoV-2-infected non-survivors compared to survivors (34, 35) . Activated neutrophils undergo degranulation and release NETs, which deliver their content in chromatin, DNA and histones, as well as toxic enzymes and proteases, which exacerbate lung tissue damage and may directly cause the lethal complications of COVID-19 (Fig. 2) . Coagulation dysfunction and widespread thromboses have been observed in adverse outcomes of the SARS-CoV-2-infection (36) (37) (38) (39) (40) that resembles what has longbeen revealed in lupus patients.

These findings led to the conclusion that there is a crucial necessity to prevent excessive neutrophil recruitment, activation, degranulation and NET release, and control coagulation (i.e. "lupus" anticoagulant) in SARS-CoV-2-infected patients (40, 41) . A few drugs might give some promise in this line of therapeutic development. It is the case, for example, of the autophagy regulator peptide P140, which inhibits NET formation (42) and also shows efficacy without toxicity among lupus patients (43).

It had been established long ago that many viruses trigger an autoimmune response, a phenomenon that includes both the production of autoimmune antibodies, as well as AIDs. For instance, beta2 glycoprotein I (β2GPI) (44) . These antibodies bind to proteins on the cell membrane leading to coagulation dysfunction. As COVID-19 patients with severe illness are seen to produce blood clots that damage various organs, as mentioned earlier, it was found that many of them carry APLA (39, 45) . It was found that 31 out of 66 (47%) severely-ill SARS-CoV-2-infected patients had produced β2GPI or/and aCL circulating autoantibodies (46). Additionally, patients with severe COVID-19 had significantly higher aCL autoantibody levels than patients with moderate disease (47). Evidence show also high concentrations of LAC among COVID-19 patients enduring coagulation disorders (48). Though, there is a well-established link between LAC and common inflammation indices (49,50). Due to the acute inflammation COVID-19 patients present, there is a possibility that a high concentration of LAC is caused by the inflammatory response, and not as a direct outcome of SARS-CoV-2.

Phosphatidylserine/prothrombin (aPS/PT) autoantibodies are also associated with higher prevalence of thrombotic events, and usually found in some APLA carriers (51). A study that included 172 hospitalized patients with SARS-CoV-2-infection reported that 24% carried aPS/PT IgG (52). Additionally, antiheparin-PF4 (aPF4), a platelet-activating antibody that is used as a marker for heparin-induced thrombocytopenia (HIT), were identified in severely-ill COVID-19 patients who ordeal HIT. In some patients aPF4 had been recognized without a pre-exposure to heparin, thus strengthening the hypothesis that SARS-CoV-2 has the ability cause coagulation disorders though an autoimmune mechanism, particularly in severely-ill patients (53, 54).

A recent study showed that 101 of 987 patients (10.2%) with life-threatening COVID-19 pneumonia had neutralizing autoantibodies against type I interferons (IFNs), in contrast to individuals with asymptomatic or mild SARS-CoV-2 infection that these autoantibodies were absent (55). IFNs are a large subtype of cytokines that are crucial for adequate regulation of the immune response, thus autoantibodies against them may, in some individuals, contribute to the development of severe COVID- 19 . Furthermore, out of the 101 patients that carried IFNs neutralizing autoantibodies 94% were men, providing an explanation for the higher prevalence of mortality and severe disease in men (55).

Noteworthy to point out a report that inspected the presents of multiple autoantibodies in 29 severely-ill COVID-19 patients, randomly chosen with no history of AID, that found antinuclear antibodies (ANA), antibodies to β2GPI, aCL, p-ANCA and to c-ANCA in 34.5%, 34.5%, 24.1%, 6.9% and 6.9% of the patients, respectively (56) . p-ANCA and c-ANCA autoantibodies are frequently detected among patients with autoimmune vasculitis, which is seen in severely-ill patients and will be discussed later.

Importantly, anti-Ro52 and anti-Ro60 antibodies were discovered in severely-ill COVID-19 patients, with the prevalence of 20% and 25% respectively (57) . These autoimmune antibodies are linked to certain autoimmune disorders, such as SLE, subacute cutaneous LE (SCLE), neonatal lupus and primary biliary cirrhosis (58) .

Lastly, a study that categorized SARS-CoV-2-infected patients based on C-reactive protein (CRP) concentration, a general marker for inflammation, found that more patients with high CRP produced ANA in comparison to patients with low CRP. Moreover, the titer of the ANA was significantly higher in patients with high CRP, reaching up to 1:640, which is considered a significant titer. Rheumatoid factor (RF) autoantibody was also measured and was only detected only among patients with high CRP (59) .

Although some of the studies presented include only a few dozen patients, their results may illustrate that the COVID-19 is not merely a reviler of pre-existing state, but a significant magnitude of autoimmunity. It is noteworthy that additional studies identified several more autoantibodies, such as J o u r n a l P r e -p r o o f Journal Pre-proof contactin-associated protein 2 (anti-CASPR 2) (60), anti-cyclic citrullinated peptide (anti-CCP) (56) and

anti-annexin-V (61).

All the autoantibodies described were identified mostly in severely-ill patients in comparison with those with mild or moderate disease. These findings are consistent with the claim that SARS-CoV-2 has the ability to hyper-stimulate the immune system, as discussed above. The development of autoantibodies has a significant clinical importance considering that a substantial portion of patients displays pathogenic properties. Furthermore, systemic autoimmunity is known to arise from generalized polyclonal B cell activation, thus the existence of autoantibodies in patients may indicate a pre-AID (4,62,63).

Alongside the evidence presented regarding the ability of SARS-CoV-2 to initiate a hyperstimulated state of the immune system, leading to the synthesis of autoantibodies, there is also evidence for new-onsets of AIDs among patients with the infection.

It had been suggested that COVID-19 has an association with the immune-mediated neuropathy Gillian-Barré syndrome (GBS). In August 2020, about 31 documented cases of GBS that followed a SARS-CoV-2-infection were reported, since then, even more cases of the disease are disclosed (64) (65) (66) .

GBS is characterized by damage to the myelin sheath of peripheral nerve cells. Multiple viruses are already known to be linked to the development of GBS, thus it may be less surprising that COVID-19 may be an additional origin (64) (65) (66) (67) . Likewise, acute onset of Miller Fisher syndrome (MFS) and

Polyneuritis cranialis (PNC), rare variants of GBS, were also described in COVID-19 patients (68,69).

Autoimmune endocrine diseases had also been described, as evidence accumulates mostly regarding an autoimmune thyroiditis disorder. A recent study that included 191 individuals with COVID-19-infection had shown abnormalities in thyroid function of 13.1% (70) . Furthermore, case reports of Graves' disease after COVID-19 infection had been described, as well as atypical thyroiditis with characteristic features of autoimmune thyroiditis (71, 72) .

Journal Pre-proof ACE-2, a crucial viral fusion protein of SARS-CoV-2 discussed earlier, is widely expressed by vascular endothelial cells (12, 73) . Therefore, it had been proposed that SARS-CoV-2 invades the vascular endothelium, causing endothelial damage and vasculitis (74) . A recent study showed the presents of anti-ACE-2 IgM antibodies in 27% of severely-ill patients, in comparison with 3.8% among patients who were not ventilated, thus some argue that vascular damage may occur also as a result of T-independent immune response toward the antibodies in severely-ill patients (75) .

COVID-19 often has a mild course among children in comparison to adults (76) . Nevertheless, recent evidence demonstrates autoimmune disorders triggered by COVID-19 in children as well. For instance, Kawasaki disease (KD) is an immunologic reaction that presents as an acute, self-limited vasculitis, that mainly occurs in children younger than 5 years of age (77) . Cases of SARS-CoV-2infection followed by an acute onset of KD were documented worldwide, described in 36 different articles, reporting the sum of 320 children. (78) . Additionally, recent studies had shown an increment of new-onset diabetes type 1 in healthcare centers during the current pandemic, as well as case reports of SARS-CoV-2-infection followed by new-onset of diabetes type 1 in children (79) (80) (81) .

Autoimmune hemolytic anemia (AIHA) is a relatively rare disease that is characterized by autoantibodies targeting erythrocytes causing hemolysis (82) . Articles had been published describing AIHA onset after SARS-CoV-2-infection, with both warm and cold IgG, thus enhancing the possibility that antibodies directed toward SARS-CoV-2 were acting also as AIHA autoantibodies to a specific protein on the surface of erythrocytes (82) (83) (84) (85) . As discussed, molecular mimicry might be at the root of severe COVID-19 and contribute specifically also to the onset of AIHA in those patients. In fact, it has to be underlined that the potential risk of cross-reactivity between SARS-CoV-2 and human proteins is much higher when considering that a pentapeptide represents the minimal immune determinant unit (86) .

Therefore, if one analyzes the viral versus human commonalities at the 5-mer level, the extent of the peptide sharing would increase exponentially by two orders of magnitude and involve a highest number of human proteins. As regards AIHA, the Ankyrin-1 (ANK1) protein, which can be found on the erythrocyte membrane, has a putative 5-mer immunogenic epitope (amino acid residues LLLQY) in J o u r n a l P r e -p r o o f Journal Pre-proof common with SARS-CoV-2 spike protein, thus supporting the possibility that molecular mimicry may influence AIHA onset in SARS-CoV-2-infected patients (87) . An additional humoral-related autoimmune response triggered by SARS-CoV-2-infection, which was reported in multiple case reports, is immune thrombocytopenic purpura (ITP) (88, 89) . ITP is characterized by a reduction of platelets in the blood, leading to coagulation dysfunction. Other studies suggest additional autoimmune-related disorders that have an association with SARS-CoV-2 infection, such as SLE (90, 91) , post orthostatic tachycardia syndrome (POTS) (92), viral arthritis (VA) (93, 94) , myasthenia gravis (95) and others (Fig. 3) .

The autoimmune disorders discussed may occur as a result of an aberrant immune response toward SARS-CoV-2. Most of the findings were published in the literature only as case reports, and therefore it is necessary to further investigate the subject in order to assess the prevalence of the phenomenon and its implication. Nevertheless, we should take into consideration that many AIDs may break out only after years of the onset of autoantibody formation (96) . Hence, there is a possibility that the incidence of AIDs as a result of SARS-CoV-2-infection will significantly increase in the time to come.

One of the common initial symptoms in COVID-19 patients is anosmia, the complete loss of the ability to sense smell, and other olfactory alterations (97) (98) (99) (100) (101) . These manifestations had been described in patients from the broad spectrum of mild to critically severe COVID-19 illness and surprisingly, even in individuals with no respiratory clinical presentation at all (102, 103) . Early in the pandemic, a study performed in London reported 2428 patients with new-onset of anosmia, being at 17% an isolated symptom and in 51% related to other COVID-19 clinical manifestations, such as fever or cough (104) . In addition, almost 25% of 202 COVID-19 subjects of an Italian study reported olfactory changes as the first or only symptom during the disease course (105) . Indeed, in an American study, near 75% of 237 COVID-19-confirmed patients presented with anosmia, some of them even prior to diagnosis (99) . When comparing 60 COVID-19 patients to 60 matched for gender and age controls, by applying quantitative J o u r n a l P r e -p r o o f Journal Pre-proof smell testing, a much higher incidence of olfactory dysfunction, 98% of the overall incidence, were upon the infected population, while more than 50% of them were classified with severe hyposmia or anosmia (106) .

Olfactory symptoms following COVID-19 infection are already considered as a known symptom of the disease and in many countries as an indication for self-isolation, but the exact mechanism through which SARS-Co-2 leads to hyposmia/anosmia is still not well-defined. Different hypotheses had been raised (107) .

The ACE-2 receptor, crucial viral fusion proteins of the SARS-CoV-2 and abundantly seen in the nasal mucosa, is known to take on a part in the inflammatory response in the respiratory system, such as partly controlling the bradykinin levels (108, 109) . Since the olfactory symptoms of COVID-19 are usually not associated with rhinitis as in other respiratory virus infections, it is reasonable to conceive that the symptom is not induced by local inflammation and congestion, but instead by some level of damage of the olfactory pathways (97, 98, 110) . In fact, when infecting transgenic mice for the human ACE-2 receptor with the SARS-CoV-1, there was no local inflammation in the nasal tract that could explain the olfactory findings (111) .

It has been indicated that neuronal death could be caused as a result of the increased proinflammatory cytokines, referred to as a cytokine storm, especially IL-6 (111, 112) . On the other hand, the fact that COVID-19 patients usually regain the olfactory function after some weeks and that other neurologic symptoms are not common in the course of the disease, do not corroborate with the neuronal definitive damage hypothesis (95) (96) (97) (98) (99) 113, 114) .

proposed to be responsible for the olfactory symptoms following the infection. Some of those cells include olfactory epithelium sustentacular cells, microvillar cells, Bowman's gland cells, horizontal basal cells and olfactory bulb pericytes (115) . Indeed, all those cell types express 2 genes that are essential for the SARS-CoV-2 entry and that are not found in olfactory sensorial neurons (115) .

Moreover, the immune response was already associated with olfactory changes in other diseases, most of them being autoimmune diseases, such as SLE, Myasthenia Gravis and systemic sclerosis (116) (117) (118) (119) . For example, olfaction changes were shown to be more common in SLE patients than in control groups (120) . Moreover, olfaction manifestations had been linked to the disease activity level, with a higher incidence in active SLE patients, and, interestingly, in patients positive for anti-ribosomal P autoantibody, a specific marker of SLE (121, 122) .

In fact, the nose and the immune system share some mutual characteristics (123) : both have to differentiate the self to non-self-molecules and depend on the major histocompatibility complex (MHC).

In animal models, olfactory bulbectomy led to an alteration in the cellular immunity, such as reduced neutrophil phagocytosis and lymphocyte mitogenesis, and increased leukocyte aggregation, monocyte phagocytosis and acute-phase-reaction proteins, suggesting a direct association between smell and immune-mediated process (124) .

Inflammatory cytokines, such as IL-1, play a role both in the immune and in the nervous system.

In animal models, receptors for this cytokine were shown to be moderately present in the primary olfactory cortex and highly seen in the olfactory bulb (125) , indicating a role of IL-1 in the olfaction and possibly explaining why an immune imbalance could contribute to dysfunction in sensation.

COVID-19 had been described together with other autoimmune conditions, as the synthesis of various autoantibodies, Kawasaki disease, anti-phospholipid syndrome and Guillain-Barre syndrome (67, 126, 127) . Since smell loss has been described and linked to many autoimmune conditions (116) , it is possible that hyposmia/anosmia in COVID-19 patients may be induced, at least partly, by autoimmune mechanisms.

An effective vaccine against SARS-CoV-2 may be the best solution in dealing with the ongoing 

In a similar manner to many viruses, such as EBV, CMV, HIV and HTLV-1, SARS-CoV-2 may have the ability to contribute to autoimmunity. Numerous records demonstrate the likelihood of COVID- J o u r n a l P r e -p r o o f P-ANCA 56 10 Anti-Ro60 57 11 Anti-Ro52 57 12 RF 59 13 Anti-CASPR 2 60 14

Anti-CCP 56 15 Anti-Annexin V 61 16 Anti-ACE-2 75 17 Anti-MuSK 95 

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