NKG2A Expression among CD8 Cells Is Associated with COVID-19 Progression in Hypertensive Patients: Insights from the BRACE CORONA Randomized Trial

Abstract

Cardiovascular comorbidities and immune-response dysregulation are associated with COVID-19 severity. We aimed to explore the key immune cell profile and understand its association with disease progression in 156 patients with hypertension that were hospitalized due to COVID-19. The primary outcome was progression to severe disease. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and immune cell subsets associated with the primary outcome. Obesity; diabetes; oxygen saturation; lung involvement on computed tomography (CT) examination; the C-reactive protein concentration; total lymphocyte count; proportions of CD4+ and CD8+ T cells; CD4/CD8 ratio; CD8+ HLA-DR MFI; and CD8+ NKG2A MFI on admission were all associated with progression to severe COVID-19. This study demonstrated that increased CD8+ NKG2A MFI at hospital admission, in combination with some clinical variables, is associated with a high risk of COVID-19 progression in hypertensive patients. These findings reinforce the hypothesis of the functional exhaustion of T cells with the increased expression of NKG2A in patients with severe COVID-19, elucidating how severe acute respiratory syndrome coronavirus 2 infection may break down the innate antiviral immune response at an early stage of the disease, with future potential therapeutic implications.

New Insights on the Mechanisms of Myocardial Injury in Hypertensive Patients With COVID-19

“…We found marked lymphopenia, particularly of T lymphocytes, in patients with myocardial injury. We previously proposed lymphopenia as a biomarker of COVID-19 progression risk in hypertensive patients [ 13 , 14 ] and the present results demonstrate that it is also an important predictor of myocardial injury in these patients. Similarly, immunologic dysregulation with lymphopenia was described in children with multisystem inflammatory syndrome (MIS-C) associated with COVID-19, and the presence of myocardial injury was also reported in these patients [ 25 ].…”

“…Lymphocytes and monocytes were quantified by photometry using an automized ABX Micros 60 system (Horiba Medical, Montpellier, France). To obtain peripheral blood mononuclear cells (PBMCs), density gradient centrifugation (Ficoll-Paque; GE Healthcare, Piscataway, NJ, USA) was performed, as previously described [ 14 ].…”

“…To quantify the immune cell populations in the PBMCs, 1 × 10 6 cells were stained with various combinations of fluorophore-conjugated antibodies, as previously described [ 14 ]. The following profiles were quantified: total monocytes, total lymphocytes, B lymphocytes, T lymphocytes, natural killer (NK) cells, CD4 + T cells, CD8 + T cells, CD4/CD8 cell ratio, CD8 + CD38 + T cells [percentage and CD38 mean fluorescence intensity (MFI)], CD8 + human leukocyte antigen DR isotope (HLA-DR) + T cells (percentage and HLA-DR MFI), CD8 + natural killer group 2A (NKG2A) + T cells (percentage and NKG2A MFI), CD8 + HLA-DR + CD38 – T cells, CD8 + HLA-DR + CD38 + T cells, CD8 + HLA-DR – CD38 + T cells, and CD8 + HLA-DR – CD38 – T cells.…”

“…Among the comorbidities associated with COVID-19 and myocardial injury, hypertension is particularly important due to its high prevalence and global burden, but the mechanism of this association and the reasons for clinical progression have not been elucidated clearly [ 10 , 11 ]. Considering that myocardial injury due to direct SARS-CoV-2 infection is rare and that the immune system is often dysregulated in patients with COVID-19, and cytokine storm and lymphopenia are important immune markers of progression to severe disease [ 12 – 14 ], we investigated the immune profile of hypertensive patients with COVID-19 and myocardial injury aiming to obtain a better understanding of the immune dysregulation and to provide new insights on the mechanism of myocardial injury in hypertensive patients with this disease.…”

Troponin in COVID-19: To Measure or Not to Measure? Insights from a Prospective Cohort Study

“…In the context of COVID-19, myocardial injury is more likely to occur in older patients, those with chronic cardiovascular conditions, and those with severe presentations [ 2 , 3 ]. The increased risk of myocardial injury in patients with cardiovascular comorbidities is probably related to a dysregulated immune response and a greater angiotensin-converting enzyme 2 expression [ 8 , 9 , 10 , 11 , 12 ]. This enzyme, which is expressed in many organs, such as the heart, lungs, and kidneys, is a key regulator of the renin-angiotensin-aldosterone system, and a cell-surface functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 13 , 14 ].…”