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Molecular mimicry, hyperactive immune system, and SARS-COV-2 are three prerequisites of the autoimmune disease triangle following COVID-19 infection

SARS-CoV-2 infection can produce a variety of clinical manifestations, which are either directly related to viral tissue damage or indirectly induced by the antiviral immune response. Molecular mimicry enables this virus to undermine self-tolerance in a host's immune system also immune system's attempts to eliminate SARS-COV-2 may trigger autoimmunity by hyper-activating the innate and adaptive immune systems. Auto immune diseases include Systemic lupus erythematosus, autoimmune thyroid diseases, Guillain‐Barre syndrome, Immune thrombocytopenic purpura, and the detection of autoantibodies are the cues to the discovery of the potential of COVID‐19 in inducing autoimmunity. As COVID-19 and autoimmune diseases share a common pathogenesis, autoimmune drugs may be an effective treatment option. Susceptible patients must be monitored for autoimmune symptoms after contracting CVID-19. In light of the SARS-COV-2 virus' ability to induce autoimmunity in susceptible patients, will the various COVID-19 vaccines that are the only way to end the pandemic induce autoimmunity?


Introduction
Pathogen infection and autoimmune disease' may imply that pathogens are suspected of causing autoimmune diseases. Pathogens of all kinds, including viruses, bacteria, and parasites, can cause direct damage to organs and tissues, which stimulates the body's immune system to destroy the foreign invader. As a consequence of pathogen infections, several inflammatory cascades occur that result in the attraction, differentiation and expansion of cells of the innate and adaptive immune systems. A number of mechanisms have also been implicated in the breakdown of self-tolerance, including molecular mimicry [1], epitopespreading [2], superantigen production [3], direct cytotoxicity [4], Innate immunity activation [5], persistent or recurrent viral infection [6] bystander activation, pathogen-induced necroptosis, and cross-linking or molecular mimicry [7,8]. New evidence on type 1 diabetes (T1D) pathogenesis highlights the role of recurrent viral infections in autoimmunity. Different types of viral infections such as coxsackievirus B (CVB) [9,10] cytomegalovirus (CMV), and enteroviruses [11,12] have been postulated to be associated with type 1 diabetes. Systemic lupus erythematosus (SLE), as the most common type of lupus has been suggested to be associated with hepatitis C virus (HCV) [13,14], CMV [15], dengue virus [16], parvovirus B19 [17], EBV [18,19] and Torque Teno Virus (TTV) [20]. Furthermore, Epstein-Barr virus (EBV) [21,22] Measles virus [23], and Varicella-zoster virus (VZV) [24,25] have been attributed to triggering the immune system to attack the brain and spinal cord, thereby leading to Multiple Sclerosis(MS) ( Table 1).
Coronavirus disease 2019 (COVID- 19) is an infectious disease caused by severe acute respiratory syndrome (SARS) associated coronavirus 2 . While most infected individuals are asymptomatic, some develop severe diseases involving multiple organs with COVID-19 [26]. Certain medications used to treat autoimmune rheumatologic diseases may have therapeutic effects in patients with severe COVID-19 infections, highlighting the link between COVID-19 and autoimmune disease [27,28]. SARS-CoV-2 may also trigger autoimmune disorders in genetically predisposed people [29].
genetics, microbiota exposure, and environmental chemicals [34]. Molecular mimicry has been proposed as a cause of the autoimmune phenomena observed in COVID-19 [35,36]. As a result of analyzing tissues from COVID-19 victims, they identified cellular and molecular patterns that lead to the damage of epithelial and other structures resulting in death, which underscores the role of autoimmunity brought on by molecular mimicry in the pathology of COVID-19 [37]. Another study supported this idea, that self-reactivity against proteins involved in activation/development of B-and T-cells can be explained by molecular mimicry. Moreover, accordingly, the extent of immunosuppression is determined by the extent of immune responses themselves. An immunosuppression that is more severe is caused by cross-reactions against human immunodeficiency-related proteins when the immune response triggered by SARS-CoV-2 immunization is higher. As a result, SARS-CoV-2-induced immunosuppression can be considered a molecular mimicry syndrome [38].
The autoimmune theory is supported by many clinical reports from covid-19 patients. Some have suggested that molecular mimicry may be responsible for immunological cross-reactivity between viral and human molecules, and thus play a role in the generation of autoimmunity in COVID-19 [35,39]. In addition to being highly conserved, heat shock proteins (many of which are molecular chaperones) are capable of intracellular localization [40,41], and the introduction of autoimmunity caused by antigenic epitopes responding to microbial chaperones has already been documented in various diseases as well as the immune response [42,43].
One study compared amino acid sequences of all SARS-CoV-2 proteins with heat shock proteins, many of which are molecular chaperones, to see if they share amino acids with antigenic potential, which can elicit cross-reactive antibodies and effector immune cells capable of damaging and destroying cells by autoimmunity [44]. A sequence analysis of 20,365 human proteins revealed 3781 proteins with at least six amino acids (≥6 mer) similar to SARS-CoV-2 proteins, and 17 of those are molecular chaperones. 17 human chaperones and viral proteins share peptides that are likely to trigger an autoimmune reaction if recognized by the human immune system. Stress (shear and/or metabolic) associated with COVID-19 causes chaperone molecules to translocate from their intracellular location to the plasma-cell membrane and extracellular space, which results in autoimmunity [44].

Hyperactivation of the immune system during covid-19 infection
There is no doubt that viruses can trigger or exacerbate autoimmunity in genetically predisposed individuals, likely by aberrantly activating immune pathways involving either the innate or adaptive immune system.In covid-19 infection the innate and adaptive immune systems attempt to eliminate the virus, the virus sometimes interacts with the body in a way that stimulates immune and non-immune cells, leading to a hyperactive immune response [45].
Some patients experiencing severe COVID-19 develop an overactive cytokine storm or "cytokine release syndrome" characterized by the release of cytokines from macrophages, dendritic cells, and monocytes, such as interleukin 1 (IL1) and interleukin 6, interleukin 10 (IL10), tumor necrosis factor alpha (TNF-α), tumor necrosis factor beta (TNF-β) and ferritin [46,47]. The presence of these cytokines causes eosinopenia and lymphocytopenia characterized by low numbers of eosinophils, CD8+ T cells, natural killer (NK) cells, and nave T-helper cells, while simultaneously activating nave B-cells, increasing T-helper cell 17 (Th17) lymphocyte differentiation, and stimulating monocyte and neutrophil recruitment. An acute respiratory distress syndrome (ARDS) results from a generalized, nonspecific hyperinflammatory response in the lungs with consequent activation of nonspecific inflammatory response in the circulatory system and other organs, sometimes leading to multiorgan failure, leaky vasculature, coagulopathies, or strokes [48,49].

The role of innate immunity in triggering an autoimmune response in SARS-CoV-2 infections
For any new infection, the initial immune response is provided by the innate immune system, which is highly visible in both respiratory and intestinal mucosa, and continuously seeks out and counteracts potential threats through a complex interaction of cells and soluble mediators [50]. In addition, resident macrophages and monocytes, natural killer (NK) cells, innate lymphoid cells, polymorphonuclear and dendritic cells, and cytokines, chemokines, and the complement system all participate in the process [51].
There are potentially a number of TLRs that participate in COVID-19 infection, such as TLR2, TLR3, TLR4, TLR6, TLR7, TLR8, and TLR9.We should also consider both the beneficial and harmful effects of TLRs when dealing with COVID-19 infection. The TLRs could be used to control the infection in the early stages of disease, however; it can also harm the host due to persistent inflammation and tissue destruction [53]. Type 1 IFN plays an important role in SARS-CoV-2 as the production of type 1 IFN is mediated by TLRs, they could play a crucial role in COVID-19 disease. An infection with COVID-19 could activate the TLRs, leading to the production of pro-inflammatory cytokines, such as IL-1β and type 1 IFN [54] Many autoimmune diseases, such as systemic lupus erythematosus (SLE) [55], primary Sjögren's syndrome (SS) [56], Kawasaki syndrome,and behcet's disease [29] are characterized by hyper-production of IFN (mainly type I), which may be linked to primitive viral infections [57,58].
Other studies on SARS-CoV2 have indicated that excessive inflammation resulting in NETosis and inflammasome activation is caused by excessive TLR4 activity in COVID-19 patients [59,60]. In addition, TLR agonists could be used as prophylactic drugs for SARS-CoV-2 [61].

The inflammasome pathway
In addition to IFN response, viral proteins and nucleic acids can lead to systemic pro-inflammatory effects through IL-1 and IL-18 production after activation of the inflammasome system in cells belonging to the monocyte-macrophage system [62]. As well as RNA viruses, viral pathogen-associated molecular patterns (PAMPs) of RNA viruses, including SARS-CoV-2, can activate pyrin-containing NOD receptor 3 (NLRP3), while their RNA fragments can activate RIG-I, MDA5, and the mitochondrial antiviral signaling pathway (MAV).Through intranuclear translocation of nuclear factor kB (NF-kB), transcription of pro-IL-1 and pro-IL-18 genes, and the conversion of these precursors into active cytokines through inflammasome-driven caspases, these events culminate in the production of pro-inflammatory cytokines such as IL-1 and IL-18 [58]. (Figure 1.B) Through activation of NLRP3 inflammasomes and the release of pro-inflammatory cytokines from cells through Gasdermin-pores commonly found in cell death by pyroptosis, the SARS-CoV-2 infection may potentiate or accelerate pre-existing systemic inflammation of individuals with obesity [63]. There is a strong association between inflammation and auto-inflammatory syndromes, a group of genetically induced rheumatic disorders characterized by recurrent episodes of fever and other systemic manifestations triggered by external infections [64] Studies suggest autoinflammation contributes to a number of multifactorial rheumatic diseases, including Behçet's syndrome, seronegative arthritis, and Still's disease [29,65]. The monocyte-macrophage system is controlled by pattern recognition receptors, including the endosomal toll-like receptors (TLR), and the nucleotide oligomerization domain-like receptors (NLR) that helps trigger an antiviral response, mainly explicated through the production of IFNλ. Viral proteins and nucleic acids can activate the inflammasome platforms in cells belonging to the monocyte-macrophage system with the following production of IL-1 and IL-18. C. Neutrophils release a number of active molecules when they form NETs, including cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and histone H3 citrulline (Cit-H3), which increase the concentration of these autoantigenes in plasma, leading to autoantibodies against the NETs. D. The SARS COV-2 can activate classical, and mannose-binding protein pathways, which are products of both C3a and C5a pathways. Dysregulation of the complement system can result in an imbalance between the host's defenses and the inflammatory response.

Neutrophil extracellular traps (NETs)
Increased neutrophil counts have been described as an indicator of severe respiratory symptoms in COVID-19 [66]. Among effector mechanisms of neutrophils in inflammatory diseases, neutrophil-derived extracellular traps (NETs) are some of the most important. NETs are networks of extracellular fibers composed of DNA containing histones and granulederived enzymes, such as myeloperoxidase (MPO) and elastase. The process of NET formation by neutrophils, called NETosis, has been widely studied. In general, the process starts with neutrophil activation by pattern recognition receptors or chemokines, followed by ROS production and calcium mobilization, which leads to the activation of protein arginine deiminase 4 (PAD-4), an intracellular enzyme involved in the deamination of arginine residues on histones [67].
Based on studies the concentration of NETs increases in the plasma, tracheal aspirate, and lung tissue specimens of autopsies from COVID-19 patients. Indeed, inflammatory processes are accelerated by NETs when they release a range of active molecules like danger associated molecular patterns (DAMPs), histones, and enzymes that induce further inflammatory responses in the extracellular space. Cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3) are NETosis markers, however; Myeloperoxidase-DNA is the most specific marker of NETosis [68][69][70][71]. It is important to note that both cellfree DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air Furthermore, Yu Zuo and colleagues found that circulating neutrophils are infected with SARS-CoV-2 and release high levels of NETs [68].
Indeed, as a consequence of the SARS-CoV-2, healthy neutrophils are capable of releasing NETs, which is mediated by the ACE2-serine protease axis, virus replication, and PAD-4 signaling. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial apoptosis. Novel cellular and molecular mechanisms involved in the production of NETs by SARS-CoV-2 infection as well as their possible detrimental role in the pathophysiology of COVID-19 are described here [72] NETs may, therefore, serve as an additional source of auto-antigens against which autoantibodies may be directed by a wide range of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), psoriasis, and gout [73,74] (Figure 1.C). The over-production of NET by CVID-19 can lead to autoimmune diseases in genetically predisposed people. Therefore, the An adaptive immune response can follow either a cellular or humoral pathway depending on the antigenic nature (intracellular versus extracellular), however, a disturbed and over-activated immune response may be counterproductive, causing autoimmune response. A. Th1 recognizes the peptides of SARS COV-2 and produces inflammatory cytokines, including MCP1, IFNλ, IL1B, IL8, andIL17.Also, Th1 produce large amounts of interferon IFNλ, which activates macrophages, resulting in delayed hypersensitivity. B. The Th17 subset responds to SARS COV-2 by producing cytokines, such as IL-17A, IL-17F, IL-21, and IL-22 and recruited neutrophils by T helper 17 cell can lead to autoimmunity reactions by excessive neutrophil extracellular trap formation C. As a result of digestion of intracellular antigens, epitopes are usually delivered to CD8 + T lymphocytes, which ultimately act by way of a direct cytotoxic mechanism and produce inflammatory products such as Granzyme B, IFNλ, and TNF-alpha. D. Th2 lymphocytes cooperate with B cells in supporting the final maturation in plasma cells and the secretion of specific antiviral antibodies. inhibition of NET release or actions could represent a potential therapeutic target for COVID-19 [75].

The complement system
The complement system is one of the earliest immune responses to infection,which takes part in the antiviral response through several mechanisms: opsonizing viruses and virus-infected cells (including lysing them), inducing an antiviral immunoinflammatory state, and boosting virus-specific immune responses [76,77]. Pathogens induce an inflammatory response and complement activation at the site of infection in early infection. Depending on the severity of the initial injury and the length of exposure, the complement cascade could be activated excessively or underregulated, leading to additional damage to tissues and cells. SARS-CoV-2 infection activates complement cascade in a similar manner. The glycoprotein S of SARS-CoV can bind to mannose binding lectin and trigger the complement cascade, resulting either in a direct (cytolysis of infected cells) or indirect (immune complexmediated) viral clearance [78]. Disseminated thrombotic phenomenon, cytokine release syndrome, and the overactive complement system are among the pathological mechanisms that contribute to the worsening of critical conditions of patients requiring intensive care [79,80].
In a histological examination of patients with COVID-19, Magro C and colleagues found spike glycoproteins along with C4d and C5b-9 in the interalveolar septa and cutaneous microvasculature of patients with SARS-CoV-2 [81] as well as, according to a recent preprint study, the highly pathogenic coronavirus N protein aggregated the lung injury caused by SARS-CoV-2 by binding to mannan-binding lectin-associated protease (MASP-2), a serine protease that directly activates the complement cascade [82]. Since SARS-CoV-2 pathogenesis and severity is strongly influenced by complement activation and an overactive complement system may lead to adverse consequences, including fibrosis and inflammation in the musculoskeletal system [78] (Figure 1.D). Dysregulation of the complement system can generate an imbalance between host defense and inflammatory response that leads to autoimmunity. For instance, as a hallmark of SLE, the complement system cascade is hyperactive triggered by autoantibodies and immune complexes through the classical pathway [83,84].

The role of adaptive immunity in triggering an autoimmune response in SARS-CoV-2 infections
A functional adaptive immunity is essential for the ultimate clearance of viral infections and for preventing re-infections. Based on the nature of the antigen (intracellular vs extracellular), the adaptive immune response can take a cellular or humoral approach, with T and B lymphocytes leading the way in each case.

Cellular immunity
Dendritic cells act as connectors between the innate and adaptive immune system. A number of epitopes are present on SARS-CoV-2 envelope proteins, including S, E and M, which can trigger an adaptive immune response once dendritic cells recognize them. Each component of adaptive immunity plays a different role in controlling viral infections, so CD4+ and CD8+ T cells may play different roles [85]. The fact that T lymphocytes can initiate a cytokine storm, which can affect the outcome of COVID-19 patients, should not be overlooked.
In fact, CD4+ T cell responses to SARS-CoV-2 are more prominent than CD8+ T cell responses [86]. One study showed that, patients with severe disease had a lower proportion of IFNγ -producing type 1 helper (Th1) cells [83]; however, type 1 helper T cells (Th1) are capable of producing large amounts of interferon (IFN)γ and activating macrophages, causing delayed hypersensitivity reactions [84] (Figure 2,A). Study results show that patients with severe COVID-19 disease have a complex and overexuberant inflammatory response. ICU patients with COVID-19 had higher plasma levels of IL1, IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα compared to non-ICU patients with COVID-19. COVID-19 patients were noted to have high amounts of IL1B, IFNγ, IP10 and MCP1 which were leading to activation of T-helper-1 (Th1) responses and the resulting cytokine storm was associated with disease severity [83]. In addition, increasing evidence suggests that Th17 cells play an important role in the pathogenesis of COVID-19, not only by activating cytokine cascade but also by inducing Th2 responses, inhibiting Th1 differentiation and suppressing Treg cells. Also, recruited neutrophils by T helper 17 cells (Th17) can lead to autoimmunity reactions [86] (Figure 2,B). COVID-19 lung specimens from patients with increased levels of serum IL-17, IFNγ and multinucleated giant cells are indicative of an activated Th1 and Th17 response [87].
One study evaluated the interplay between Th1 and type 2 helper (Th2) cells in covid-19 patients. They demonstrated for the first time that Th2/Th1 cytokine imbalance in the airway is associated with major COVID-19 risk factors such as age, sex, high ACE2 expression phenotype, and smoking. Based on this study there is also a possible association between worse outcomes and higher Th17 in all patients [85]. The immune system is regulated by cytokines, and inflammatory cytokines cause a deregulation of the immune system and immunopathology. It is possible for people with COVID-19 to develop autoimmune diseases as a result of the cytokine storm syndrome Indeed, Infection with SARS-CoV-2 may result in cytokine storms due to an inadequate immune response to the virus [87]. Furthermore, Blanco-Melo and colleagues demonstrate that infected cells are incapable of producing interferons, which are key mediators of a proper host response against viral infections. They also produce high levels of neutrophil-and macrophage-recruiting chemokines [88]. According to Jiadi Lv et al., innate immune systems may not be able to effectively clear infected cells in the first phase of infection, which could favor virus replication. SARS-CoV-2 survives and replicates inside macrophages [89]. The immune system would regain the ability to fight the virus in a second phase, but since it had been able to replicate undisturbed, an exaggerated reaction of adaptive immune system would result. Moreover, renin-angiotensin-aldosterone system (RAAS), the main receptor used by SARS-CoV-2 to enter human cells can mediate pro-inflammatory, prothrombotic, and profibrotic effects [90,91].

Humoral immunity
Th2 lymphocytes are involved in the final maturation of plasma cells as well as the release of specific antiviral antibodies that may belong to different isotypic classes (IgM, IgG, IgA). Furthermore, follicular dendritic cells can stimulate B cells in a MHC-independent manner by causing their B cell receptors (BCR) to cross-link in response to multimerized antigens [92]. (Figure 2,D) There is evidence that the SARS-CoV-2 virus has a critical and pivotal effect on human immunity, and its capability to trigger autoimmune diseases in genetically predisposed individuals, based on the reported inflammatory and autoimmune symptoms, the presence of circulating autoantibodies, and the diagnosis of defined autoimmune diseases in a subgroup of SARS-CoV-2-infected patients [93][94][95][96].

Autoantibodies in SARS-CoV-2-infected patients
Researches were conducted to examine the presence of antinuclear antibodies in COVID 19 patients. According to them, ANA-positive patients have a worse prognosis than the negative ones with regards to COVID-19 disease, but a number of limitations prevent conclusions from being drawn, including the small number of patients studied, the different methods for autoantibodies detection, and the genetic heterogeneity of the patients involved. These findings strongly suggest an autoimmune response in these patients [97,98].
Researchers have studied the antiphospholipid (aPL) profile in critically ill COVID-19 patients and found that Intensively ill COVID-19 patients have profound hypercoagulability, leading to complicated venous thrombosis [99,100]. Some studies, however, have claimed that there is no correlation between aPL positivity and disease outcomes such as thrombosis, invasive ventilation, and mortality. It remains to be determined the clinical and pathological importance of aPL in COVID-19 [101,102] (Table 2).

Reports of the most prevalent autoimmune conditions associated with COVID-19
There have been a growing number of reports describing autoimmune reactions associated with COVID-19 infection. The time between symptoms of viral illness and onset of autoimmune symptoms ranged from 2 days to 33 day [114]. For instance, the first case of systematic lupus erythematosus (SLE) following covid-19 infection was reported by Batool Zamani in Iran. The patient was a 39-year-old Iranian/Persian man who had been infected with SARS-CoV-2 two months ago. He complained of fever, scaling on the palms of his hands and feet, lower extremity edema, and ankle swelling and patient had proteinuria and was positive for SLE laboratory tests [115]. It is challenging to diagnose SLE in patients who have been infected by SARS-CoV-2. We know from the present series that severe thrombocytopenia, serositis, and kidney damage are clinical indicators that could aid in differential diagnosis. In the presence of such findings, immunological markers should be determined to confirm or rule out the presence of SLE. SLE activity should be diagnosed promptly so that specific treatment can be initiated without delay [116].
A COVID-19 infection can produce neurological symptoms by affecting the central nervous system (CNS) (headache, dizziness, consciousness disorder, acute brain disease, seizures, and ataxia) [117], the peripheral nervous system (PNS) (anosmia, ageusia, visual impairment, nerve pain), and the skeletal muscles [118]. The acute polyneuropathy characterized by SARS-CoV-2 has been documented in a few case reports [119]. Studies have shown that the days between COVID-19 symptoms and GBS onset can vary between 3 and 30 days in different cases. There have been 73 cases of Guillain-Barre following covid-19 reported throughout the world so far [120]. One of the most curious reports regarding GBS following COVI-19 infection was released by Sepideh Paybast in Iran, which revealed the familial occurrence of GBS following COVID-19 infection in one father and his daughter [121].
There are several studies, which documented the occurrence of Graves' thyrotoxicosis following mild symptomatic COVID-19. These reports may align with the theory of a viral link in the development of autoimmune thyroid disease in those with genetic predisposition. An overview of the recent reports regarding the most prevalent autoimmune conditions associated COVID-19 is provided in Table 3.

The effect of some autoimmune disease drugs on the clinical course of patients with COVID-19
COVID-19 and autoimmune diseases share a common pathogenesis, making autoimmune drugs a possible treatment option. In several studies, drugs commonly used to treat autoimmunity were found to be effective in covid-19 patients as well. For example, in Th17 cell differentiation, STAT3 is activated by IL-6 and IL-23 through JAK2 and JAK1. SLE and COVID-19 patients' clinical conditions can be improved by regulating JAK2, which is a bridge to differentiation and function of Th17 cells [147]. Chloroquine (CQ) can interfere with the glycosylation of the ACE2 by binding to the virus and inhibiting respiratory syndrome in COVID-19 patients. Rheumatoid arthritis patients may benefit from Anti-GD1b antibodies anti-Caspr2 autoantibodies [109] Anti-heparin PF4 complex antibody Anti-AT1 antibody/Anti-ACE-2 antibody 1 [96,113] 1 Angiotensin type-1 receptors (AA-AT1) and autoantibodies against ACE2 (AA-ACE2).  Baricitinib, a reversible oral inhibitor of the Janus kinases JAK1 and JAK2.This drug interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also inhibit angiotensinconverting-enzyme-2 upregulation by targeting host factors that viruses rely on for entry into cells. However, during acute viral infections, Baricitinib's immunosuppressive effects may delay viral clearance and increase vulnerability to secondary infections [148]. Another effective drug, which is common between COVID-19 and Multiple sclerosis is Tocilizumab, which is a IL-6 receptor blocker and can reduce cytokine storm and hyperactivation of immune system.Infact, the blocking of interleukin-6 would benefit COVID-19 patients with enhanced inflammation, as demonstrated by increased levels of certain inflammatory biomarkers [149]. In patients with COVID-19, immunosuppressive drugs are either beneficial or detrimental. In the initial phase of COVID-19, immunosuppressive drugs may be harmful. In this phase, the host immune response is necessary to inhibit viral replication. However, immunosuppressive drugs might have a beneficial effect in the later, more severe phase of COVID-19 due to cytokine storm. In fact, using immunosuppression to treat hyperinflammation in COVID-19 is a double-edged sword [150]. This table (Table 4) presents some effective autoimmune disease drugs on the clinical course of COVID-19 patients.
A treatment approach based on immune cells is also available for both COVID-19 and autoimmune diseases. The adoptive immune cell therapy to recover cell-mediated immunocompetence, represents a promising treatment for patients with COVID-19. It is imperative to use an effective treatment strategy such as immuno-cell therapy to modulate the immune system's over-activation and increase its ability to kill the COVID-19 virus. These approaches are particularly focused on targeting inflammatory processes, and raising the effective immune response against the SARS-CoV-2 by using adaptive immune system cells such as NK, Treg,specific T cell, DC, Monocyte [151].

Conclusion
SARS-CoV-2, like many viruses like EBV, CMV, HIV, and HTLV-1, is capable of causing autoimmunity. Several mechanisms are thought to be capable of contributing to the development of autoimmunity in COVID-19, including SARS-CoV-2 ′ s ability to perturb the immune system, excessive NETosis formation with neutrophil-associated cytokine responses, and the molecular resemblance between host components and the virus [154]. There have been several reports of autoimmune manifestations in patients with SARS-CoV-2. This suggests that COVID-19 is capable of causing autoimmune diseases in vulnerable patients. After contracting CVID-19, physicians must monitor susceptible patients for autoimmune symptoms. Since there are no specific medicines for COVID-19, studies suggest autoimmune drugs as a potential treatment because autoimmune diseases and COVID-19 share a common pathogenesis.However, vaccination is the best remedy for dealing with this pandemic, but concerns have been raised about triggering autoimmune diseases like previous virus vaccinations [155]. How likely is it that the Covid-19 vaccines will cause autoimmune disease?

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability
No data was used for the research described in the article.