File Name: cellular and molecular immunology 7th .zip
- Medical Physiology Question Bank
- Cellular and molecular immunology
- Cellular and Molecular Immunology
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Cellular and Molecular Immunology takes a comprehensive yet straightforward approach to the latest developments in this active and fast-changing field. Abul K. Abbas, Andrew H. Lichtman, and Shiv Pillai present sweeping updates in this new edition to cover antigen receptors and signal transduction in immune cells, mucosal and skin immunity, cytokines, leukocyte-endothelial interaction, and more.
Medical Physiology Question Bank
The severe acute respiratory syndrome caused by the new coronavirus SARS-CoV-2 , termed COVID, has been highlighted as the most important infectious disease of our time, without a vaccine and treatment available until this moment, with a big impact on health systems worldwide, and with high mortality rates associated with respiratory viral disease. The medical and scientific communities have also been confronted by an urgent need to better understand the mechanism of host-virus interaction aimed at developing therapies and vaccines.
Since this viral disease can trigger a strong innate immune response, causing severe damage to the pulmonary tract, immunotherapies have also been explored as a means to verify the immunomodulatory effect and improve clinical outcomes, whilst the comprehensive COVID immunology still remains under investigation. In this review, both cellular and molecular immunopathology as well as hemostatic disorders induced by SARS-CoV-2 are summarized.
The immunotherapeutic approaches based on the most recent clinical and nonclinical studies, emphasizing their effects for the treatment of COVID, are also addressed. The information presented elucidates helpful insights aiming at filling the knowledge gaps around promising immunotherapies that attempt to control the dysfunction of host factors during the course of this infectious viral disease. The identification of the first patients reported with COVID also identified a common history associated with the local market for seafood in Huanan, where wild animals are traded.
The genomic characterization of the new virus identified a close similarity to two bat coronaviruses SARS-CoV and pangolin coronavirus linking the origin of SARS-CoV-2 with the wholesale market and indicating its zoonotic origin [ 1 , 3 ].
SARS-CoV-2, responsible for the current pandemic declared on March, 11th by the WHO, has been overwhelming on a global scale, presenting high transmission rates with a large number of deaths, bringing severe effects to health services and economies worldwide. For this reason, it is being widely used in current studies, in an attempt to gain a better knowledge and understanding of this disease and also in the search for treatment and vaccine options for COVID [ 6 — 8 ].
COVID is a disease that may remain asymptomatic, or may present light symptoms, evolving to a more severe disease and can eventually lead to death. Many studies present asymptomatic cases as probable sources of infection, playing an important role in the spread of these viruses [ 9 ]. However, further studies should be carried out to assess both the amount and infectivity of viral load in asymptomatic individuals to better understand the course of the disease and the necessary methods to fight it [ 11 ].
The great challenge of this disease is the lack of knowledge about the SARS-CoV-2 virus, its adaptation, and its effects on the human body, especially as there is no effective drug, vaccine, or treatment available against COVID until this date July Therefore, intervention measures to contain the pandemic are limited to social behavioral interventions, such as the use of masks, social distancing, self-isolation, quarantine, and even blocking entire territories and communities, to contain or, at least, mitigate the burden of the ongoing pandemic [ 12 ].
The search for a vaccine or an effective treatment is evading laboratories around the world, and several articles have been published daily to share the knowledge obtained. So far, during the onset of COVID symptoms, it has been known that a dysfunction of the immune response is part of the virus-host interaction process and can lead to disease severity and poor outcomes [ 13 — 16 ].
Protective immunity after the infection is not guaranteed. Despite the cross-reactivity with other human common cold coronaviruses in those with previous contact, protection against SARS-CoV-2 infection cannot be confirmed [ 17 ].
Furthermore, there is little information regarding immunity [ 1 , 6 ], raising questions that still have no answers, such as which pathway in the immune response can be the key to attempt to control the immune dysfunction?
How can immunotherapy be effective in all subjects affected? In this review, we aim to gather information on the main immune responses described in the literature, as well as to offer insights into the promising immunotherapies that can be helpful for the scientific community thus assisting in the delivery of solutions for the urgently needed near-future breakthroughs. There is a great discussion regarding the adaptive immune responses to SARS-CoV-2, whether these are protective or pathogenic, or whether both scenarios are possible.
The management and knowledge of immune response composition, kinetics, and magnitude can determine the real protection against this pathogen [ 17 ]. In this context, the search for correlates of protection biomarkers and reliable immunological parameters has become the key to eliminating this disease [ 18 ].
Knowledge of the nature and extent of B cell memory response becomes of great importance, given that the protection from reinfection has directed medical and social initiatives, including the search for vaccine strategies and the return to regular activities.
Studies from countries that were in the epicenter of the pandemic showed that, despite a large number of identified cases, the percentage of people who developed antibodies to SARS-CoV-2 is less than expected, like During infection, follicular helper T cells Tfh are important and crucial for initiating the antibody response at the germinal center for affinity maturation and humoral memory response [ 23 , 24 ].
In COVID, a drop on T cell numbers have been described in the acute phase and even in mild cases, without antibody production or diminishing of IgG antibody detection in the recovery phase [ 25 , 26 ]. The remaining question is whether the generated antibodies confer long-lasting immunity.
Due to the pandemic being a recent event, it is not possible to obtain this response yet; however, it can be predicted based on what is learned from the study of other human coronaviruses [ 30 ].
In general, studies have shown that the antibody response among coronaviruses is rarely detected in the acute phase of the disease until the 7th day. Since , studies have been carried out in order to better understand the activity of this virus. A follow-up study of 34 healthcare professionals infected with SARS-CoV-1 also shows that virus-specific IgG decreased after several years; however, after 12 years of infection, the authors observed specific detectable IgG [ 33 ].
These and other studies of human coronaviruses demonstrate a tendency of antibody response against these viruses to decrease over time. It was observed that IgG and neutralizing antibody levels in convalescent patients decrease within 2 to 3 months after infection. Although many discussions about cross-immunity are taking place, they are still at odds. The correlation between the level of antibodies produced and the severity of the disease even for other coronaviruses is still unclear [ 8 ].
While IgM appears both in severe and nonsevere cases at the same time, IgG appears 2 to 3 days earlier in severe cases [ 37 , 38 ]. Moreover, S protein mutations may be responsible for viral resistance to antibody recognition and consequent aggressiveness [ 29 ].
Caution is needed since the total measurable antibody is not precisely the same as protective. Virus-neutralizing antibodies are presumed to be an important mechanism of action in COVID since high titers of these antibodies have been related to severe cases of the disease.
In addition, some patients present low or very low titers of COVID neutralizing antibodies up to 2 weeks after hospital discharge [ 38 , 39 ]. Studies report successful plasma convalescent therapy as a source of therapeutic polyclonal antibodies, indicating monoclonal antibodies as an excellent therapeutic possibility [ 40 ].
One of the findings that support this hypothesis is that patients who developed responses against protein S earlier are related to the worse prognosis of the disease [ 41 ]. Another possibility is that the virus-specific nonneutralizing IgG could facilitate the entry of viral particles into cells that express Fc receptors FcR , leading to the inflammatory activation of these cells, such as macrophages and monocytes [ 30 ]. This event was also observed during the SARS-CoV-1 epidemic, where deceased patients presented much higher neutralizing antibody titers when compared to patients who recovered [ 41 ].
However, this hypothesis must be validated by further scientific research and also by longer time intervals in order to assess an effective and safer concentration of antibodies. With regard to vaccine aspects, the role of follicular helper T cells in the production of antibodies should also be considered to guarantee comprehensive protection. Juno et al. The immunological scenario regarding COVID indicates a secondary role of humoral response in terms of effectiveness, suggesting the importance of innate and cellular response.
Some studies described that the acute phase of COVID is divided into two aspects: benign and severe, and it is correlating with immune dysfunction alterations [ 13 — 16 ]. A highly activated innate immune response may be the cause of disease progression, as well as poor outcome, including death [ 2 , 47 , 48 ].
Wang et al. T lymphocytes are also involved in the immune imbalance during COVID, with a massive decrease of CD4 and CD8 total numbers in the initial phase [ 37 ], and with CD4 T helper cells found in the pulmonary tract [ 45 ], showing a possible effect of SARS-CoV-2 on lymphocyte lysis and an important function of CD4 T helper cells in the lung damage in the acute phase [ 2 , 45 ] Figure 1. Natural killer cells, macrophages, and immature T cells can produce these components, being chemoattractant to neutrophils in the lung compartments, inducing a reduction of blood vessels, and subsequently, in the blood circulation, leading to oxygen impairment and facilitating thrombosis activation [ 45 , 47 , 52 ] Figures 1 — 3.
Among these, type I and III interferons IFNs are considered the most important for antiviral defense, which mediate the onset of the innate immune response. Upon activation of pattern recognition receptors PRRs , downstream signaling cascades trigger the secretion of cytokines [ 53 ]. Interferon cytokines affect several other processes, including those regulating cell growth, differentiation, and apoptosis, as well as the modulation of the immune response.
Phosphorylation recruits the signal translation and transcription activators STAT1 and 2 , forming a heterodimer of interferon regulatory factor IRF. However, the transcription of these genes is regulated over time, since type I IFNs are expressed and resolved quickly, while type III IFNs present late, sustained, and tissue-specific induction. It also plays a role in mediating protection against viral infections, especially long-term control of viral infection.
However, SARS-CoV-2 present several evasion mechanisms of the innate immune response, and the genome viral load encodes a protein open reading frame ORF3b that inhibits the induction of type I interferon [ 58 ]. Analysis of the virus sequences isolated from two patients with severe COVID disease showed a variant that further increased the ability of ORF3b to suppress interferon induction [ 59 ].
The key point in SARS-CoV-2 infection could be the effect of viral evasion of the host defenses, related to the innate immune response. Even with the current limitation of serological assays related to antibody detection, some studies have shown that memory T cells are emerging from peripheral blood to contribute to virus elimination and complete recovery [ 61 — 63 ] Figure 1. Despite those findings, there are challenges concerning the full protection from possible reinfection.
Considering the above, more studies are necessary, and at the same time, new information is appearing daily with regard to immunity against the new coronavirus. Patients with severe COVID commonly exhibit signs of systemic activation of the coagulation system that relies on increased rates of thrombotic events and elevated plasma levels of D-dimer, a known marker of thrombogenesis [ 64 — 67 ]. In clinical observations, nonsurvivors present significantly higher levels of D-dimer and fibrin degradation products as well as longer prothrombin and activated partial thromboplastin compared to survivors on admission, thus meeting the criteria for disseminated intravascular coagulation [ 57 , 67 ].
Therefore, there is strong evidence that the exacerbated procoagulant responses account for organ failure and the increased mortality in critically ill COVID patients [ 71 ]. In this context, treatment with anticoagulants may improve the progress of severe COVID [ 72 , 73 ]. The crosstalk between inflammation and coagulation has long been described [ 74 ]. Therefore, these cells infiltrate massively into the lungs, as demonstrated in fatal cases of COVID [ 36 , 47 ].
These cells, still inside capillaries, probably express Tissue Factor TF , as demonstrated largely in a number of viral infections, such as HIV and dengue, as well as microbial and other types of sepsis [ 78 — 80 ]. In the absence of tissue damage, TF expressed by activated monocytes initiates TF-dependent coagulation with the conversion of prothrombin to thrombin Coagulation Extrinsic Pathway , in an uncontrolled manner, leading to disseminated intravascular coagulation.
An increase in Protease-Activated Receptor 1 PAR-1 expression in endothelial cells after viral infections is one of the consequences observed [ 81 ]. Although the main function of thrombin is to promote the formation of clots through the activation of platelets and the conversion of fibrinogen to fibrin, this protease exerts several cellular effects and may increase the inflammation process through the activation of PAR receptors, mainly PAR The activation of PAR-1 in endothelial cells promotes proinflammatory responses, resulting in the rupture of the endothelial barrier and an increase of cell permeability.
These defects in procoagulant-anticoagulant mechanisms during inflammation may be responsible for predisposition of the development of microthrombosis, disseminated intravascular coagulation, and multiple organ failure in patients with severe COVID pneumonia and in nonsurvivors [ 83 ] Figure 3. On the other hand, PAR-1 might be activated by the anticoagulant serine protease, activated protein C APC , which binds to its coreceptor, endothelial protein C receptor EPCR , and exerts cytoprotective and anticoagulant responses.
Recombinant APC has been used as a drug to treat severe sepsis, a pathological condition characterized by exacerbated clotting and inflammation responses. However, the mechanism by which APC-activated PAR-1 promotes cytoprotective responses is still poorly understood [ 82 ].
In this context, PAR-1 antagonists and other coagulation protease inhibitors, in addition to modulators of the protein C pathway, may play an important role in the treatment of critically ill patients with COVID [ 84 ]. Still, in the context of hemostatic disorders, platelets are also an important hub of classical crossover between the inflammatory and coagulation process [ 85 — 87 ]. This event is most likely due to platelet consumption leading to the formation of pulmonary thrombi, which highlights the importance of monitoring platelet count during hospitalization [ 89 , 90 ].
Besides, low count leads to platelet deposition in damaged pulmonary blood vessels in SARS patients [ 91 , 92 ]. It has been described that activated platelets play a critical role in hemostasis and in coagulation, as well as in angiogenesis, inflammation, and even immune response, as demonstrated in other viral infections, like dengue and influenza.
Furthermore, resting platelets from COVID patients increased P-selectin expression, both basally and upon activation [ 94 ].
These functions are achieved through direct interaction with endothelial cells, as well as monocytes, lymphocytes platelet-leukocyte aggregates PLA and neutrophils platelet-neutrophil aggregates PNA in a process regulated by P-selectin [ 93 , 98 , 99 ].
The formation of PNA leads to C3 release from platelets and formation of Neutrophil Extracellular Traps NETs , a mechanism that tightly regulates host immune responses and complement system responses, but can also promote thrombosis and damage lung capillaries [ , ]. In COVID patients, it has been demonstrated that circulating platelet-neutrophil, platelet-monocyte, and platelet-T-cell aggregates were all significantly elevated, enhancing the hypothesis that P-selectin blockade may be warranted in treating COVID patients [ 94 , , ] Figure 3.
Immunotherapy is described as a helpful tool to attempt to control immune dysfunction. However, to this moment, therapeutic intervention has been limited to severe cases, in order to minimize the risk of death, and also in combined therapies. Beyond therapies addressed to severe cases, it should be relevant to consider the differences on gender, age, pregnant condition, diabetes, hypertension, autoimmune diseases, heart diseases, cancer, and obesity during nonclinical and clinical studies, as well as the management for mild cases to avoid the worst outcome, since some comorbities are under risk of fatal COVID [ 48 , — ].
Actually, the surveillance of the immune events and their behavior should also be included in the guidelines for immunotherapies to treat COVID, once the immune response is crucial to the clinical evolution of the patient Figure 1. It is worth noting that some potential immunotherapies are very specific when targeting immune events and pathways, and they are designed to avoid adverse events, to be used exclusively to minimize the inflammation process induced by the viral disease, such as COVID Therefore, immunotherapy approaches are developed to be useful in any situation, regardless of comorbity conditions.
In this manuscript, we summarize some commercially available immunotherapeutic components with their mode of action and immunological impact in attempting to control the immune dysregulation during COVID, already used in clinical trials human Tables 1 a and 1 b and nonclinical studies in vitro and in vivo animal models for treatment purposes Table 2.
Cellular and molecular immunology
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Cellular and Molecular Immunology
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The severe acute respiratory syndrome caused by the new coronavirus SARS-CoV-2 , termed COVID, has been highlighted as the most important infectious disease of our time, without a vaccine and treatment available until this moment, with a big impact on health systems worldwide, and with high mortality rates associated with respiratory viral disease. The medical and scientific communities have also been confronted by an urgent need to better understand the mechanism of host-virus interaction aimed at developing therapies and vaccines. Since this viral disease can trigger a strong innate immune response, causing severe damage to the pulmonary tract, immunotherapies have also been explored as a means to verify the immunomodulatory effect and improve clinical outcomes, whilst the comprehensive COVID immunology still remains under investigation. In this review, both cellular and molecular immunopathology as well as hemostatic disorders induced by SARS-CoV-2 are summarized. The immunotherapeutic approaches based on the most recent clinical and nonclinical studies, emphasizing their effects for the treatment of COVID, are also addressed. The information presented elucidates helpful insights aiming at filling the knowledge gaps around promising immunotherapies that attempt to control the dysfunction of host factors during the course of this infectious viral disease.
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