Cytokine Overproduction and Immune System Dysregulation in alloHSCT and COVID-19 Patients

Abstract

The COVID-19 pathomechanism depends on (i) the pathogenicity of the virus, (ii) ability of the immune system to respond to the cytopathic effect of the virus infection, (iii) co-morbidities. Inflammatory cytokine production constitutes a hallmark of COVID-19 that is facilitated by inability of adaptive immunity to control virus invasion. The effect of cytokine release syndrome is deleterious, but the severity of it depends on other confounding factors: age and comorbidities. In this study, we analyze the literature data on the post-transplant course of allogeneic hematopoietic stem cell transplanted (alloHSCT) patients, which is affected by generated inflammatory cytokines. The sequence of events boosting cytokine production was analyzed in relation to clinical and laboratory data highlighting the impact of cytokine generation on the post-transplant course. The collected data were compared to those from studies on COVID-19 patients. The similarities are: (i) the damage/pathogen-associated molecular pattern (DAMP/PAMP) stage is similar except for the initiation hit being sterile in alloHSCT (toxic damage of conditioning regimen) and viral in COVID-19; (ii) genetic host-derived factors play a role; (iii) adaptive immunity fails, DAMP signal(s) increases, over-production of cytokines occurs; (iv) monocytes lacking HLADR expression emerge, being suppressor cells hampering adaptive immunity; (v) immune system homeostasis is broken, the patient’s status deteriorates to bed dependency, leading to hypo-oxygenation and malnutrition, which in turn stimulates the intracellular alert pathways with vigorous transcription of cytokine genes. All starts with the interaction between DAMPs with appropriate receptors, which leads to the production of pro-inflammatory cytokines, the inflammatory process spreads, tissue is damaged, DAMPs are released and a vicious cycle occurs. Attempts to modify intracellular signaling pathways in patients with post-alloHSCT graft vs host disease have already been undertaken. The similarities documented in this study show that this approach may also be used in COVID-19 patients for tuning signal transduction processes to interrupt the cycle that powers the cytokine overproduction.

Virlaza™ Inhibits Sars-COV-2-induced Inflammatory Response of Bronchial Epithelial Cells and Pulmonary Fibroblast

“…Among the factors underlying the development of the severe and critical forms of COVID-19, advanced age [3], comorbidities [3], hyperactivation of the immune system [3,4] are proven to have a central role, hyperactivation of the immune system results in the cytokine storm, which is characterized by the synthesis and release of high levels of proinflammatory cytokines [3,4]. In this way, cytokine storm plays a major role in Covid-19 pathogenesis [3,4].…”

Individual genetic variability mainly of Proinflammatory cytokines, cytokine receptors, and toll‐like receptors dictates pathophysiology of COVID‐19 disease

“…Moreover, 7p15.3 ( IL6 –174C allele) has been related to the severity of pneumonia and COVID‐19. IL6 also affects the CD4 + T cells' fate and causes the COVID‐19 severity 61–63 . In addition, IL6 , IL10 , and IL12B SNPs have been associated with daily death rates mainly due to hypertension, cardiovascular diseases, obesity, and asthma 64–67 .…”

“…IL6 also affects the CD4 + T cells' fate and causes the COVID‐19 severity. 61 , 62 , 63 In addition, IL6 , IL10 , and IL12B SNPs have been associated with daily death rates mainly due to hypertension, cardiovascular diseases, obesity, and asthma. 64 , 65 , 66 , 67 In a study, among severely ill COVID‐19 patients ( n = 100), the IL6 gene was significantly expressed higher compared to that in the control population ( n = 324) which was correlated to the higher mortality rate.…”

Interplay between lymphocyte subpopulation, inflammatory cytokines and their correlation with oxidative stress parameters in COVID-19

“…The humoral and cellular immunity uses T cells, B cells, natural killer (NK) cells in fighting viral infections and an effective immune response depends on the activation of cytotoxic CD8+ T cells through killing the infected cells. 3 Results reported since the onset of pandemic showed that more than half of the patients had decreased lymphocyte counts, and pathological findings showed that patients who died of this disease had higher levels of pro-inflammatory CCR6 + Th17 + CD4 + T cells. 4 This infers that the overactivation of T-cells united with the high CD8 T cells cytotoxicity is partially responsible for the observed severe immune injuries in COVID-19 patients.…”