Does SARS-CoV-2 Induce IgG4 Synthesis to Evade the Immune System?

Abstract

SARS-CoV-2, the virus that causes the COVID-19 disease, has been shown to cause immune suppression in certain individuals. This can manifest as a reduced ability of the host’s immune system to effectively control the infection. Studies have reported that patients with COVID-19 can exhibit a decline in white blood cell counts, including natural killer cells and T cells, which are integral components of the immune system’s response to viral pathogens. These cells play critical roles in the immune response to viral infections, and their depletion can make it harder for the body to mount an effective defense against the virus. Additionally, the virus can also directly infect immune cells, further compromising their ability to function. Some individuals with severe COVID-19 pneumonia may develop a “cytokine storm”, an overactive immune response that may result in tissue damage and organ malfunction. The underlying mechanisms of immune suppression in SARS-CoV-2 are not entirely understood at this time, and research is being conducted to gain a more comprehensive understanding. Research has shown that severe SARS-CoV-2 infection promotes the synthesis of IgG4 antibodies. In this study, we propose the hypothesis that IgG4 antibodies produced by B cells in response to infection by SARS-CoV-2 generate immunological tolerance, which prevents its elimination and leads to persistent and chronic infection. In summary, we believe that this constitutes another immune evasion mechanism that bears striking similarities to that developed by cancer cells to evade immune surveillance.

SARS-CoV-2-Specific Immune Responses in Vaccination and Infection during the Pandemic in 2020–2022

“…The difference in IgG peak levels between the second and third doses could be influenced by factors such as the age distribution of vaccine recipients, the timing of sampling, and the method of measurement. Interestingly, recent studies demonstrated that the IgG4 subclass antibody was upregulated in repeated vaccination of SARS-CoV-2 mRNA [ 37 , 38 ], indicating the IgG4 class switch mechanism for immune regulation [ 39 , 40 ]. Nevertheless, it is important to note that vaccine effectiveness against Delta variants increased significantly after the third vaccination [ 34 , 35 , 36 , 41 ].…”

Current German Recommendations and International Research on the Use of COVID-19 Boosters among Health Care Providers in 2024: A Narrative Review

“…SARS-CoV-2 may employ evasion mechanisms to avoid immune surveillance and attack, including inhibition of interferon (IFN) synthesis, disruption of Ag presentation, evasion of Ab through nanotube construction, and induction of lymphopenia through syncytial generation [ 15 ]. Evidence indicates that changes in IFN-γ level dynamics after the booster dose are less pronounced than the humoral dynamics.…”

“…Furthermore, individuals who have received three doses of Comirnaty Original may experience a reduction in Ab-mediated phagocytic activity and complement deposition. This could potentially increase the risk of other opportunistic infections [ 15 , 22 , 23 , 24 ].…”

“…The Fab arm exchange can reduce the overall antiviral efficacy of IgG4 antibodies, including viral clearance, compared to IgG1 and IgG3. Elevated ratios of IgG4 to IgG1 are associated with unfavourable disease outcomes, potentially leading to prolonged viral persistence and increased susceptibility to the spike protein of SARS-CoV-2 [ 15 , 22 , 23 , 24 ].…”

“…It is crucial to acknowledge that IgG4 may not be the sole pathway for SARS-CoV-2 clearance. Other innate immune mechanisms stimulated by hybrid and herd immunity might prove more effective against SARS-CoV-2 [ 15 , 22 , 23 , 24 ].…”