On the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than >70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with <70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of <70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).
Fig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is >70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with <70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.