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.

Keywords: IgG4; SARS-CoV-2; Tregs; immune tolerance; long COVID.

Figure 1

SARS-CoV-2 infects a permissive cell, and its ORF-8 protein induces interleukin 6 (IL-6) synthesis. This cytokine then stimulates the activation and excessive proliferation of regulatory T cells (Tregs), which in turn release interleukin 10 (IL-10). In adequate concentrations, IL-10 exerts anti-inflammatory functions. However, in higher concentrations, it exerts pro-inflammatory effects. IL-10 then induces IgG4 antibody production. These antibodies can block normal antiviral responses, such as complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell phagocytosis (ADCP), thus favoring viral replication and persistence in the host. Created with BioRender.com.

Figure 2

(A) Under normal conditions, the IgG3 antibody binds to the spike protein via its variable region. This antibody has a constant region (Fc) that is recognized by the corresponding receptor found on macrophages and other immune cells. This mechanism is called “opsonization” and marks foreign pathogens for phagocyte destruction. (B) SARS-CoV-2 induces IL-6 production, altering the normal phenotype of B cells, and making them produce IgG4 antibodies (depicted in red). The constant region of the IgG4 antibody binds to the constant region of IgG3, thus preventing the binding of said antibody to its receptor located on the macrophage. In this way, IgG3 effector functions are blocked. Created with BioRender.com.

Figure 3

Schematic representation of the hypothesized mechanism for immune evasion by cancer cells using B lymphocyte-produced IgG4. Long-term contact with tumor antigens induces B cells to switch classes and produce IgG4. Due to its unique structural and biological characteristics, increased IgG4 in the cancer microenvironment creates an effective immune evasion mechanism for the disease. The terms antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and natural killer cells (NK) are abbreviations of these processes. Adapted from [65]. This article is open access and is distributed under the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which enables others to distribute, remix, adapt, and build upon it for non-commercial purposes and to license their derivative works under different conditions as long as the original work is properly cited, due credit, any changes are noted, and the use is for non-commercial purposes.