Unraveling the thread of uncontrolled immune response in COVID-19 and STEMI: an emerging need for knowledge sharing

Abstract

The outbreak of severe acute respiratory syndrome coronavirus 2 that first emerged in Wuhan in December 2019 has resulted in the devastating pandemic of coronavirus disease 2019, creating an emerging need for knowledge sharing. Meanwhile, myocardial infarction is and will probably remain the foremost cause of death in the Western world throughout the coming decades. Severe deregulation of the immune system can unnecessarily expand the inflammatory response and participate in target and multiple organ failure, in infection but also in critical illness. Indeed, the course and fate of inflammatory cells observed in severe ST-elevation myocardial infarction (neutrophilia, monocytosis, and lymphopenia) almost perfectly mirror those recently reported in severe coronavirus disease 2019. A pleiotropic proinflammatory imbalance hampers adaptive immunity in favor of uncontrolled innate immunity and is associated with poorer structural and clinical outcomes. The goal of the present review is to gain greater insight into the cellular and molecular mechanisms underlying this canonical activation and downregulation of the two arms of the immune response in both entities, to better understand their pathophysiology and to open the door to innovative therapeutic options. Knowledge sharing can pave the way for therapies with the potential to significantly reduce mortality in both infectious and noninfectious scenarios.

Keywords: coronavirus disease 2019; immunity; myocardial infarction.

Figure 1.

Temporal evolution of circulating white blood cells after MI and COVID-19. In a cohort of 650 reperfused ST-segment elevation patients with MI (A) and 103 patients with COVID-19 (B), this figure shows the dynamics of neutrophils (top), monocytes (top middle), lymphocytes (bottom middle), and neutrophil-to-lymphocyte ratio (bottom) (×1,000 cells/mL) according to the extent of structural damage (larger IS and MVO) in case of MI or bilateral pneumonia in case of COVID-19. Patients with a more damaged structure display higher neutrophils, monocytes, and total leukocyte counts and a lower number of lymphocytes. C: in a controlled experimental model of reperfused MI, the infiltration of neutrophils (top), monocytes (middle), and lymphocytes (bottom) in myocardial tissue with MVO is higher than in those regions without MVO. COVID-19, coronavirus disease 2019; IS, infarct size; MI, myocardial infarction; MVO, microvascular obstruction.

Figure 2.

Deregulation of the innate and adaptive immune system correlates with poorer outcomes after MI and COVID-19. A: in both entities, analyses of blood cell subtypes indicate that excessive activation of innate immunity (principally due to neutrophilia and monocytosis) and uncontrolled decline in adaptive immunity (reflected by a marked lymphopenia) are associated with massive injury in target organs (lung and heart) and worse clinical outcomes. However, a controlled immune reaction is observed in patients with better prognosis and less structural tissue damage. B: DAMPs secreted by ischemic cardiomyocytes and PAMPs after SARS-CoV-2 infection lead to neutrophil degranulation and proinflammatory monocyte activation and main cellular components of innate immunity. Both neutrophilia and monocytosis are demonstrated to be associated with a more structural damage and higher rate of adverse events after STEMI and COVID-19, probably due to massive cell apoptosis and adverse ECM remodeling. Afterward, proinflammatory situation turns into anti-inflammatory and proregenerative milieu, mainly driven by lymphocytes, key players in adaptive immunity. Clinical studies have demonstrated a clear association between lymphopenia (lower activation of adaptive immunity) and more structural damage and worse prognosis in both COVID-19 and STEMI. COVID-19, coronavirus disease 2019; DAMP, damage-associated molecular pattern; ECM, extracellular matrix; Ig, immunoglobulin; MI, myocardial infarction; PAMP, pathogen-associated molecular pattern; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STEMI, ST-segment elevation MI; Treg, regulatory T cells. Created with Biorender.com and published with permission.

Figure 3.

Pathophysiology of the innate and adaptive immune reaction after SARS-CoV-2 infection and MI. The massive arrival of PAMPs after infections (viral fragments in case of COVID-19) and DAMPs in sterile situations (necrotic cells and damaged extracellular matrix elements after infarction) is recognized by toll-like receptors in APCs (mainly macrophages and dendritic cells). Activated APCs secrete high amounts of proinflammatory cytokines (e.g., TNF-α, IL-1, and IL-6) in a so-called cytokine storm. As a consequence, transmigration of neutrophils as well as NK cells takes place to remove necrotic cells (in case of MI) and viruses (in case of COVID-19). Acting as a link between innate and adaptive immunity, APCs capture, process, and present extracellular and intracellular antigens to naive T lymphocytes in lymph node. For T-cell activation, two principal interactions are needed: First, TCR binds to the antigen presented in the peptide-binding groove of MHC I, and second, costimulatory molecule CD28 on T cells binds to CD80 or CD86 on the APC. However, the interaction of CTLA-4 to CD80/CD86 provokes inhibition of T lymphocytes, resulting in apoptosis. Moreover, binding of PD-1 on T lymphocytes to PD-L1 on the surface of APC, upregulated by IL-6 secretion, contributes to T-cell apoptosis. As a result of this double interaction, APCs secrete high amounts of IL-12 to promote Th1 lymphocytes. Activation of Th1 cells promotes cell-mediated inflammatory responses by inducing macrophages to eliminate opsonized microorganisms, B cells to secrete IgG to induce opsonization and become APC, and CD8⁺ cells to eliminate infected microorganisms and cells. An uncontrolled immune reaction can result in deleterious effects. Therefore, modulating several steps in the inflammatory cascade, including proinflammatory cytokines (IL-1 and IL-6), immune checkpoints (PD-1 and CTLA-4) as well as regulatory T cells, is a key to regulate the immune response after MI and SARS-CoV-2 infection. APC, antigen-presenting cell; COVID-19, coronavirus disease 2019; CTLA-4, cytotoxic T lymphocyte antigen 4; DAMP, damage-associated molecular pattern; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; Ig, immunoglobulin; IL, interleukin; MHC, major histocompatibility complex; MI, myocardial infarction; NK, natural killer; PAMP, pathogen-associated molecular pattern; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TCR, T cell receptor; TFGβ, transforming growth factor-β; TNF-α, tumor necrosis factor-α. Th1:, lymphocyte T helper-1; Treg, regulatory T cell. Created with Biorender.com and published with permission.

Figure 4.

Mechanism of T-cell activation and implication of immune checkpoints CTLA-4 and PD-1. A: for T cell activation, two principal interactions are needed: first, TCR binds to the antigen presented in the peptide-binding groove of MHC I, and second, costimulatory molecule CD28 on T cells binds to CD80 or CD86 on the APC. As a result of this double interaction, APCs secrete high amounts of IL-12 to activate T lymphocytes. B: CTLA-4, structurally similar to CD28, binds with greater affinity and avidity than CD28 to CD80/CD86. CTLA-4 induces an inhibitory signal to T cell, thus reducing lymphocyte activation and minimizing the inflammatory response. The administration of anti-CTLA-4 neutralizing antibody favors the interaction of CD28 to CD80/CD86, thus boosting T lymphocyte activation and cytotoxic T cell proliferation. C: PD-1 to PD-L1 binding on the surface of APC induces T-cell apoptosis. Administration of anti-PD-1 antibodies avoids PD-1 interaction to PD-L1, and thus lymphocyte activation occurs. APC, antigen-presenting cell; CTLA-4, cytotoxic T lymphocyte antigen 4; IL, interleukin; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TCR, T-cell receptor. Created with Biorender.com and published with permission.

Figure 5.

Potential therapeutic options after COVID-19 (left) and MI (right). Top. As primary prevention, vaccine, social distancing, frequent handwashing, wearing masks (in COVID-19), and gaining control over cardiovascular risk factors (obesity, diabetes, smoking, dyslipidemia, atherosclerosis) (in STEMI) are the first-line defense mechanisms before the main event. Top central: antivirals soon after SARS-CoV-2 infection and coronary revascularization, mainly by primary angioplasty, once the thrombotic occlusion takes places are the gold standard approaches to diminish structural damage and improve prognosis. Bottom central: in both scenarios, thrombotic events (such as distal thrombi in COVID-19 and MVO in MI) occur. Antithrombotic drugs and dual antiplatelet therapy are essential to reduce the incidence of microvascular events. Bottom: following COVID-19 and MI, uncontrolled immune reaction results in adverse events at acute (bilateral pneumonia and edema and extensive infarction) and chronic (pulmonary fibrosis and adverse remodeling) phases in target tissues. Therapeutic alternatives to reduce innate immunity (via neutralization of the proinflammatory cytokines IL-6 and IL-1) and potentiate adaptive immune cells (by blocking the immune checkpoints CTLA-4 and PD-1 to reduce lymphocyte apoptosis) using specific monoclonal antibodies could potentially promote a controlled immune response, thus minimizing target organ damage. COVID-19, coronavirus disease 2019; CTLA-4, cytotoxic T lymphocyte antigen 4; CV, cardiovascular; IL, interleukin; MI, myocardial infarction; MVO, microvascular obstruction; PD-1, programmed death-1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STEMI, ST-segment elevation MI. Created with Biorender.com and published with permission.