How the Immune System Makes the Fatal Choice in COVID-19

The immune system’s first line of defense, innate immunity, may be responsible for SARS-CoV-2 immunosuppression by over producing TNF alpha (tumor necrosis factor) https://www.cell.com/action/showPdf?pii=S0092-8674%2820%2931067-9. This could explain recent reports of re-infection. TNF is the first cytokine to appear in the blood within minutes after an injury or stress. Other pro-inflammatory mediators like IL-1 or IL-6 appear later. The name “tumour necrosis factor” came from the cytokine’s causing vascular activation and thrombosis resulting in necrosis of subcutaneous tumors in mice. TNFR1, also known as p55, a TNF receptor present on all cells, when cross-linked by TNF, generates a pro-inflammatory response. It activates NF-κB, mitogen-activated protein kinases, anti-apoptotic responses, and generation of other pro-inflammatory cytokines such as IL-1, IL-6, and GM-CSF. When not acting appropriately, TNF binding to TNFR1, yields such autoimmune diseases as rheumatoid arthritis. An alternative receptor for TNF, TNFR2 has positive beneficial effects. TNFR2, also known as p75, has restricted tissue distribution and activates different signalling pathways. It is important for repair and homeostasis, and the cells with the highest expression of TNFR2 are T regulatory lymphocytes. TNRF2 gene knockout mice have enhanced pathology, such as poor survival following coronary artery damage. However, several monoclonal specific ant-TNF antibodies, which counteract the negative effects of TNF, have been FDA approved over the years for rheumatoid arthritis, which may reduce the lethality and long term adverse effects of COVID, if TNF is the proven cause of the severe effects. There are five approved anti-TNFs: (1) infliximab, a chimaeric IgG anti-human monoclonal (Remicade®); (2) etanercept, a TNFR2 dimeric fusion protein, with an IgG1 Fc (Enbrel®); (3) adalimumab, a fully human monoclonal antibody (mAb) (Humira®); (4) golimumab, a fully human mAb (Simponi®) and (5) certolizumab, a PEGylated Fab fragment (Cimzia®). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279876/. Another piece of evidence that TNF and its receptor TNFR1 are important in COVID is that children seem to be resistant to the severe effects, except in some instances when they display multiple organ inflammation, Kawasaki-like syndrome, because they produce a lot of the anti-inflammatory cytokine IL10. The responses of neonates compared to adults change from increased IL-10 as neonates to balanced IL-10/T helper type 1 (Th1)/Th2/Th17 cytokine levels early in life. This allows protection from pathogens but reduces the chances of a cytokine storm https://www.nature.com/articles/s41390-020-0881-y.pdf. In 1995, in my book Type B Cytochromes: Sensors and Switches, pointed out the importance of IL10 to reduce the effects of TNF which was linked to the oxidative burst which produced superoxide, hydrogen peroxide by the enzyme NADPH oxidase, and alternatively nitric oxide (NO) by nitric oxide synthase enzyme (NOS) by white blood cells: “Lymphokines provide extra-macrophage regulation of NO production. IL-10, produced by CD4 + lymphocytes of the Th-2 subset, not only inhibits synthesis of gamma-interferon by both T cells and NK cells, but also inhibits the synthesis of NOS by mouse macrophages. Another lymphokine, IL-13, inhibits TNF production, generally downregulates macrophage LPS responses, but assists in upregulating gamma-interferon production. This interleukin also inhibits HIV replication in vitro and immunity to tranplanted tumors. Also, NOS induction is directly involved in allograft rejection in transplantation, as one of the earliest events noted. Even though NO has been shown to be generally immunosuppressive for lymphocyte proliferation, human lymphocytes can produce picomolar concentrations of NO that are essential as a messenger initiating lymphocyte responses, including DNA synthesis.” Thus a measured NO response is beneficial but a large amount can lead to immunosuppression or failure to develop immune memory. This level could perhaps be adjusted to optimal by treatment with such NO traps as 3-amino-L-tyrosine. Recently, a paper has appeared to contradict this scenario. Severity in adult COVID-19 appears to be related to a combination rise in IP-10, IL-6 and IL-10. IP-10 causes inflammation induced by gamma interferon. The combination may be an indicator of immune exhaustion in adults or merely concomitant effect rather than cause. However, based on depletion of certain immune cells (basophils migrating to the lungs and lymphocytes and dendrocytes) and a left shift of lymphocytes to more immature and replicating forms, noted in the paper, this confusion over what COVID does to the immune system is time and tissue related (when and where measured). TNF not changing generally, as noted in this recent paper, https://www.nature.com/articles/s41591-020-1038-6.pdf, can be because it’s produced very locally and affects only lymph nodes and other lymphoid tissues, without generalized rise in levels and effect.