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Andalib A R, Radandish M. Immunological and Clinical Aspects of Immune Responses to SARS-CoV-2. Journal of Inflammatory Diseases. 2021; 24 (6) :592-613
URL: http://journal.qums.ac.ir/article-1-3104-en.html
1- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. , andalib@med.mui.ac.ir
2- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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1. Introduction
he Coronavirus Disease 2019 (COVID-19) caused by a coronavirus named SARS-CoV-2 from the family Coronaviridae, was first reported in December 2019 in China [1]. The disease have mild or severe symptoms such as fever, chills, cough, shortness of breath, body aches, and gastrointestinal symptoms, followed by severe inflammation, cytokine storm, acute respiratory distress syndrome, and dysfunction of other organs. Most people infected with this virus return to normal life, although tissue damage caused by the virus may remain in their body [4]. In this study, we hypothesize that innate and acquired immune responses play an important role in resistance to SARS-CoV-2.
2. Materials and Methods
This is a narrative review study. The search was conducted on related studies published during January- October 2020 in Google Scholar, PubMed, Embase, and Scopus databases using the keywords Covid-19, Immunology, and Immunopathogenesis. Among abundant and mostly repetitive information, the immunological aspects were selected. Having knowledge of the immunopathogenesis and progression of COVID-19 can help the medical staff develop appropriate interventions for the patients. Therefore, the content is designed by describing clinical cases and immunological aspects involved in the disease process and the use of intervention facilities based on immunological findings. 
3. Results
The SARS-CoV-2 can enter the cell by binding to the Angiotensin-Converting Enzyme 2 (ACE2) receptor and Trans-Membrane Protease Serine 2 (TMPRSS2) on the surface of lung epithelial cells [18]. The main pathogenic mechanism of infection with SARS-CoV-2 is the stimulation of inflammatory response followed by damage to the alveoli of lung tissue. In uncontrolled immune responses, the infiltration of macrophages, monocytes, neutrophils, and inflammatory T cells into the alveoli increases which leads to tissue damage in the lungs and other organs by overproduction of inflammatory cytokines such as Interleukin 6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), interleukin 6 (IL-8), Interferon gamma (IFNγ), etc. [7, 17]. Therefore, the severity of the disease in individuals is correlated to the host’s uncontrolled inflammatory/immune response.
Immunological aspects
As shown in Figure 1, SARS-COV-2 stimulates the pyroptosis of alveolar cells, leads to immune cells infiltration into the infection site. 

Then, 7-14 days after infection, the amount of antibodies in the blood can be detected. The increased IgM, IgG, IgA antibodies can be detected by laboratory methods [41]. B cells first make antibodies in response to N antigen and then against S antigen of SARS-CoV-2 [42]. Specific antibody against S protein Receptor-Binding Domain (RBD) inhibit the virus from binding to the ACE2 receptor which is called neutralizing antibody [43]. Following pyroptosis of the infected cells, the NOD Like Receptor family Pyrin domain containing 3 (NLRP3) inflammasome activation can enhance the production of inflammatory cytokines. Damage-Associated Molecular Patterns (DAMPs) are detected by Pattern Recognition Receptors (PRRs) of alveolar macrophages which causes the production of cytokines and chemokines [13], and the migration of monocytes, macrophages, and T cells from the peripheral blood into the alveoli, leading to disruption in lung function. Lack of control of this process challenges the patient’s health by causing damage to the lung tissue [24]. Due to the association of the severity of COVID-19 with the host’s immune response, targeting any of the immunopathological pathways to inhibit inflammatory responses can cause patient survival. With an appropriate immune response, alveolar macrophages can prevent ectopic immune responses by phagocytosis of apoptotic cells and the viruses neutralized by antibodies [19]. However, in some cases, following the production of CXCL9/10/11 chemokines by active monocytes in the lung, Natural Killer (NK) cells traffic to the site of infection which leads to lysis of virus-infected cells. When antibodies are produced, the NK cell is activated in response to antibody-coated cells, cause Antibody Dependent Cell Cytotoxicity (ADCC) and Antibody Dependent Enhancement (ADE), and produces perforin, granzymes, and pro-inflammatory cytokines and chemokines [29, 30]. The NK and T cell dysfunction, lymphopenia, and infection of immune cells such as monocytes with ADE mechanism are factors causing the body’s failure in resistance to SARS-CoV-2 [13]. 
The increased lymphocyte cytokines of Th1, Th2, and Th17 cells in COVID-19 patients are involved in activating Cytotoxic T lymphocytes (CTLs) for the lysis of virus-infected cells including the cytokines of Th1 cell such as IL-12, IFNγ, TNFα and etc. Th2 cells also induce antibody production by delivering viral antigens to B cells [38]. Although the number of Th17 cells is lower than that of other cells, their number in COVID-19 patients is higher; the uncontrolled increase of their IL-17 cytokine can result in increased inflammation [39]. The increase in GM-CSF-producing TCD4+ T cells play an essential role in polarization and stimulation of inflammatory macrophages and increased lung damage [37]. Reduced regulatory T cell phenotypes observed in severe stages of the disease have correlation with immunopathogenesis [13].
Clinical aspects
The COVID-19 diagnosis is based on the clinical symptoms and the results of molecular tests (such as Polymerase Chain Reaction test), or computerized tomography scan followed by serological tests and measuring biochemical factors in the blood (e.g. lymphocyte and platelet counts, C-reactive protein, dimerized plasmin fragment D, lactate dehydrogenase, serum amyloid A, procalcitonin, urea, creatinine, and direct bilirubin) can also help monitor the disease. Their abnormal changes have correlation the with disease progress or severity [51, 67, 69]. Furthermore, intervention of IFN types I and III can effectively cause the resistance of healthy cells to the virus and inhibit virus replication and accumulation in the infected cells. The use of immune system regulators such as chloroquine, corticosteroids, inflammatory cytokine blockers such as anti-IL-6, anti-IL-1, and immune or stem-cell therapy at the right time can have an enhanced effect on the recovery of the disease or inhibit the disease progression [85, 90, 102].

Ethical Considerations
Compliance with ethical guidelines

Ethical approval was not sought for the present study because this article does not contain any studies with human or animal subjects

Funding
This study was supported by the Deputy of Isfahan Medical School.

Authors' contributions
The authors contributed equally in preparing this article.

Conflict of interest
The authors declare no conflict of interest.

Acknowledgments
The authors would like to acknowledge the encouragement provided by the Head of School of Medicine, Isfahan University of Medical Sciences.

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Type of Study: Review article | Subject: Immunology

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