Hallmarks of immune response in COVID-19: Exploring dysregulation and exhaustion

Abstract

One and half year following the occurrence of COVID-19 pandemic, significant efforts from laboratories all over the world generated a huge amount of data describing the prototypical features of immunity in the course of SARS-CoV-2 infection. In this Review, we rationalize and organize the main observations, trying to define a “core” signature of immunity in COVID-19. We identified six hallmarks describing the main alterations occurring in the early infection phase and in the course of the disease, which predispose to severe illness. The six hallmarks are dysregulated type I IFN activity, hyperinflammation, lymphopenia, lymphocyte impairment, dysregulated myeloid response, and heterogeneous adaptive immunity to SARS-CoV-2. Dysregulation and exhaustion came out as the trait d’union, connecting abnormalities affecting both innate and adaptive immunity, humoral and cellular responses.

High-affinity FcγRIIIa genetic variants and potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) responses contributing to severe COVID-19

“…This is in agreement with recently published ex vivo studies that found a higher NK cell activation status in severe than in mild COVID-19, which was hallmarked by the high-level expression of perforin and evidenced a status of NK cell exhaustion. 9 , 17 Another ex vivo study analyzed the potential of peripheral blood mononuclear cells derived from patients with COVID-19 to induce an ADCC response against rituximab-coated Raji cells. 18 The authors found a considerably defective ADCC response in hospitalized patients with COVID-19, which also shows exhaustion of ADCC mediating cells in these patients.…”

From COVID-19 to Sarcoidosis: How Similar Are These Two Diseases?

“…Hematological analysis of COVID-19 patients has been reported to show lymphopenia, which is an important indicator of severe SARS-CoV-2 infection and poor prognosis ( 76 – 78 ), suggesting a defect in their adaptive immune system. Multiple sets of clinical data show that the absolute number of circulating lymphocytes is significantly lower in COVID-19 patients in the ICU than in patients with mild to moderate infection ( 79 ). However, the immune mechanism in COVID-19 patients is complex and still unclear, especially about potentially orchestrated acute mortality.…”

“…However, the absolute number of peripheral circulating T cells was significantly reduced in COVID-19 patients, which may be because of increased lymphocytosis locally recruited to lung tissue or increased lymphocyte adhesion to the endothelium ( 84 ). Moreover, elevated levels of cytokines IL-6, IL-10, and TNF-α were observed in severe COVID-19 patients, directly affecting T-cell subsets and indirectly affecting dendritic cells and neutrophils, thereby reducing lymphocyte count ( 79 , 85 ).…”

“…Mazzoni et al. ( 79 ) reported that an early dysregulated type I IFN response induced a series of immune response dysregulations, including cytokine storm, lymphocyte impairment, and the whole SARS-CoV-2 highly heterogeneous adaptive immune response.…”

“…Specific manifestations are highly elevated clinical inflammatory biomarkers and correspondingly elevated serum cytokine levels, including IL-1β, IL-1RA, IL-2, IL-4, IL-6, IL-7, IL-10, IL-19, G-CSF, TNF-α, and IFN-γ ( 114 – 117 ). Dysregulated immune responses involving increased cytokine levels and immune system hyperactivation include a potentially life-threatening systemic inflammatory syndrome with consequent systemic inflammatory response syndrome (SIRS) and MODS ( 79 ).…”