First new research published connecting the severe respiratory failure with immune dysfunction

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We studied immune responses of 54 COVID-19 patients, 28 of whom had severe respiratory failure (SRF). All SRF patients displayed either macro****e activation syndrome (MAS) or very low human leukocyte antigen (HLA)-DR expression accompanied by profound depletion of CD4-lymphocytes, CD19- lymphocytes and natural killer cells. TNF and IL-6 production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.

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https://www.cell.com/pb-assets/products/coronavirus/CHOM2296_s50.pdf

Kind of restates what we already know, but good established evidence now. They also make the connection about HLA expression, which I might have seen before but didn't make the connection. There are a bunch of different DR serotypes out there....wondering if certain serotypes are more prone than other? Would help explain in part why some have mild disease vs others. Could mean your reaction to SARS-COV-2 is in part based on genetics....a lot of DR serotypes also related to other illnesses and comorbidities.....

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A perspective (like a review, not research, just making sense of what we know)
My comments in bold to try and help explain what they are saying

https://marlin-prod.literatumonline.com/pb-assets/products/coronavirus/immuni4349_S5.pdf

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ACE2 is a membrane protein and inactivator of angiotensin 2 (AngII). Importantly, ACE2 is endocytosed together with SARS-CoV, resulting in the reduction of ACE2 on cells, followed by an increase of serum AngII (Kuba et al., 2005) (ACE2 gets taken up along with the virus meaning its no longer on the cell to complete its function). Because ACE2 is also downregulated in lung-injury models and recombinant ACE2 suppressed ARDS development (Imai et al., 2005), severe lung inflammation itself might induce dysregulation of the renin-angiotensin pathway followed by ARDS development after SARS-CoV-2 infection. Indeed, SARS-CoV-induced ARDS in an animal model is prevented by inhibitors of angiotensin receptor type 1 (AT1R) (Kuba et al., 2005).

AngII acts not only as a vasoconstrictor but also as a pro-inflammatory cytokine via AT1R (Eguchi et al., 2018). WHEN ACE2 IS NOT AROUND TO TAKE CARE OF ANGII, ANGII STARTS CYTOKINE SIGNALING AS CONSEQUENCE The AngII-AT1R axis also activates NF-B and disintegrin and metalloprotease 17 (ADAM17), which generates the mature form of epidermal growth factor receptor (EGFR) ligands and TNF, two NF-B stimulators (Eguchi et al., 2018). ADAM17 induction also processes the membrane form of IL-6R to the soluble form (sIL-6R), followed by the gp130-mediated activation of STAT3 via the sIL-6R-IL-6 complex in a variety of IL-6R-negative nonimmune cells including fibroblasts, endothelial cells, and epithelial cells (Murakami et al., 2019). STAT3 is required for full activation of the NF-B pathway, and the main stimulator of STAT3 in vivo is IL-6, especially during inflammation, although there are nine other members of IL-6 family cytokines that can activate STAT3, at least in vitro (Murakami et al., 2019). ANGII ACTS ON SEVERAL CYTOKINE OR PRO INFLAMMATORY REGULATORS THAT IN TURN AMPLIFIES THEMSELVES SO YOU GET A SUPER STRONG CASCADE Therefore, SARS-CoV-2 infection in the respiratory system can activate both NF-B and STAT3, which in turn can activate the IL-6 amplifier (IL-6 Amp), a mechanism for the hyper-activation of NF-B by STAT3, leading to multiple inflammatory and autoimmune diseases (Murakami et al., 2019). The IL-6 Amp induces various proinflammatory cytokines and chemokines, including IL-6, and recruits lymphoid cells and myeloid cells, such as activated T cells and macro****es, in the lesion to strengthen the IL-6 Amp in a positive feedback loop (Figure 1). Importantly, because IL-6 is a major functional marker of cellular senescence, the age-dependent enhancement of the IL-6 Amp might correspond to the age-dependent increase of COVID-19 mortality. FIRST TIME I HAVE SEEN THIS EXPLANATION FOR AGE-RELATED MORTALITY

Indeed, the ARDS seen with SARS-CoV-2 infection is a cytokine release syndrome (CRS), which is a disorder induced by cytokine storms. The lethal side effect of CRS found with chimeric antigen receptor (CAR)-T cell therapies for leukemia and lymphoma is also associated with elevated inflammatory cytokines (Neelapu et al., 2018). It is possible that the enhanced pro-inflammatory cytokines are induced by the IL-6 Amp. Considering that the anti-IL-6R antibody tocilizumab is an effective treatment for CRS in CAR-T cell therapies (Neelapu et al., 2018), researchers might want to consider drugs with a similar mechanism of action for CRS in COVID-19. WHAT WE ALREADY KNOW

Taken together, all evidence supports the idea that the ARDS observed in COVID-19 is a CRS induced by the AngII-AT1R axis and PRR pathway as well as the IL-6-STAT3 axis, suggesting that IL-6/gp130 signaling pathways could be therapeutic targets to treat COVID-19.

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