O papel das respostas imunológicas inata e adaptativa ao SARS-CoV-2: Revisão de literatura / The role of the innate and adaptative immune responses to SARS-CoV-2: Literature review

Introdução: O vírus SARS-CoV-2, causador da COVID-19, tornou- -se a representação de ameaça global ao que diz respeito à saúde pública, à medida que se espalha facilmente. A COVID-19 pode gerar desde um quadro assintomático até sinais e sintomas envolvendo os sistemas respiratório, hepático, neurológico, podendo, inclusive, levar à morte. O sistema imunológico possui papel fundamental no combate às infecções e sua atuação pode definir o quadro clínico, seja assintomático, leve, grave ou fatal. Objetivo: Descrever o papel das respostas imunológicas inata e adaptativa ao SARS-CoV-2. Metodologia: O estudo caracterizou-se por levantamento bibliográfico utilizando-se artigos científicos indexados nas bases de dados online PubMED, Medline, Scielo e Google Acadêmico, no período compreendido entre 2019 e 2020 Para a filtragem das publicações foram utilizados os seguintes descritores em português/inglês: COVID-19, SARS-CoV-2, Sistema imunológico, Resposta inata e Resposta adaptativa. Após filtragem, 42 artigos científicos foram selecionados. Resultados: O SARS-CoV-2 infecta as células do indivíduo ao reconhecer a enzima ECA2 ou a proteína CD147 e suas proteínas virais prejudicam a resposta imune à medida que diminuem a síntese de IFN1, ativam a via NF-kB, aumentam a síntese de citocinas pró-inflamatórias e aumentam a necroptose. Linfócitos T CD4+ possuem papel essencial na ativação de Linfócitos B e sua consequente síntese de anticorpos monoclonais. Linfócitos T CD8+ citotóxicos são capazes de dizimar células infectadas. Entretanto, estes eventos podem levar à resposta inflamatória exacerbada e à tempestade de citocinas, o que pode ser prejudicial nas infecções por SARS- -CoV-2, já que agravam sintomas e promovem alterações sistêmicas. Conclusão: Conhecido que Linfócitos T e B são ativados por peptídeos virais e que esta ativação promove a liberação de mediadores inflamatórios-chave e anticorpos monoclonais, e sabendo-se que a tempestade de citocinas inflamatórias pode agravar o quadro clínico do paciente infectado, faz-se necessário reconhecer a importância do sistema imunológico no combate à infecção da COVID-19.

Introduction: The SARS-CoV-2 virus, which causes COVID-19, has become the representation of global threat to public health, as it spreads easily, without efficient resources to control its spread until the present moment. COVID-19 can generate from an asymptomatic condition to signs and symptoms involving the respiratory, hepatic, neurological systems, and can even lead to death. The immune system has a fundamental role in fighting infections and its performance can define the clinical condition, either asymptomatic, mild, severe or fatal. Objective: To describe the role of innate and adaptive immune responses to SARS-CoV-2. Methodology: The study was characterized by a bibliographic survey, using scientific articles indexed in the online databases PubMED, Medline, Scielo and Google Scholar, in the period between 2019 and 2020. For filtering publications, the following descriptors were used in Portuguese/ English COVID-19, SARS-CoV-2, Immune system, Innate response and Adaptative response. After filtering, 42 scientific articles were selected. Results: SARS-CoV-2 infects the individual's cells by recognizing the ECA2 enzyme or the CD147 protein and its viral proteins impair the immune response as they decrease IFN1 synthesis, activate the NF-kB pathway, increase pro cytokine synthesis -inflammatory and increase necroptosis. CD4 + T lymphocytes play an essential role in the activation of B lymphocytes and their consequent synthesis of monoclonal antibodies. Cytotoxic CD8 + T lymphocytes are capable of decimating infected cells. However, these events can lead to an exacerbated inflammatory response and a cytokine storm, which can be harmful in SARS-CoV-2 infections, as they worsen symptoms and promote systemic changes. Conclusion: Known that T and B lymphocytes are activated by viral peptides and that this activation promotes the release of key inflammatory mediators and monoclonal antibodies, and knowing that the storm of inflammatory cytokines can worsen the clinical condition of the infected patient, it is necessary to recognize the importance of the immune system in combating the infection of COVID-19.

Activated Leukocyte Cell Adhesion Molecule Modulates Th2 Immune Response in Atopic Dermatitis

PURPOSE: Activated leukocyte cell adhesion molecule (ALCAM), a member of the immunoglobulin superfamily, is highly expressed on dendritic cells. ALCAM and its receptor CD6 are co-stimulatory molecules in the immunological synapse; their interaction is required for T cell activation. While atopic dermatitis (AD) is recognized as a T helper 2 (Th2)-mediated allergic disease, the role of ALCAM in its pathogenesis is unclear. METHODS: ALCAM levels were measured in the serum of AD patients and AD-induced murine model by ovalbumin treatment. We next investigated transepidermal water loss, clinical score, Th2-immune responses, skin barrier gene expression and T-cell activation using wild-type (WT) and ALCAM deficiency mice. An oxazolone-induced AD-like model was also established and analyzed using WT- and ALCAM-deficient mice. RESULTS: We found that serum ALCAM levels were elevated in pediatric AD patients as well as WT AD mice, whereas Th2-type cytokine production and AD symptoms were suppressed in ALCAM-deficient mice. In addition, CD4+ effector T-cell counts in murine skin and skin-draining lymph nodes were lower in ALCAM-deficient mice than in their WT counterparts. ALCAM deficiency was also linked to higher expression of skin barrier genes and number of lamellar bodies. CONCLUSIONS: These findings indicate that ALCAM may contribute to AD pathogenesis by meditating a Th2-dominant immune response and disrupting the barrier function of the skin.

Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body's immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CAR-modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cytotoxic cell-mediated immunotherapies are urgently needed. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the formation of the immunological synapse (IS) between CAR-modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat cancer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV), and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-mediated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.

Actin Engine in Immunological Synapse

T cell activation and function require physical contact with antigen presenting cells at a specialized junctional structure known as the immunological synapse. Once formed, the immunological synapse leads to sustained T cell receptor-mediated signalling and stabilized adhesion. High resolution microscopy indeed had a great impact in understanding the function and dynamic structure of immunological synapse. Trends of recent research are now moving towards understanding the mechanical part of immune system, expanding our knowledge in mechanosensitivity, force generation, and biophysics of cell-cell interaction. Actin cytoskeleton plays inevitable role in adaptive immune system, allowing it to bear dynamic and precise characteristics at the same time. The regulation of mechanical engine seems very complicated and overlapping, but it enables cells to be very sensitive to external signals such as surface rigidity. In this review, we focus on actin regulators and how immune cells regulate dynamic actin rearrangement process to drive the formation of immunological synapse.

Adenosin deaminasa como molécula coestimuladora y marcador de inmunidad celular / Adenosine deaminase as costimulatory molecule and marker of cellular immunity

La adenosin deaminasa (ADA), es una enzima del metabolismo de las purinas que ha sido objeto de mucho interés debido a que el defecto congénito de esta enzima causa el síndrome de inmunodeficiencia combinada severa. Una de las tres isoformas de la enzima (ecto-ADA) es capaz de unirse a la glicoproteína CD26 y a los receptores de adenosina A1 y A2B. La interacción ADA-CD26 produce una señal coestimuladora en los eventos de activación de las células T y en la secreción de IFN-g, TNF-a e IL-6. Durante dicha activación la actividad de la enzima está regulada de manera positiva por IL-2 e IL-12 y negativamente por IL-4, basado en un mecanismo de translocación. Diversos estudios señalan que los niveles séricos y plasmáticos de ADA se elevan en algunas enfermedades causadas por microorganismos que infectan principalmente a los macrófagos; así como en trastornos hipertensivos, lo cual podría representar un mecanismo compensatorio como consecuencia de la elevación de los niveles de adenosina y la liberación de mediadores hormonales e inflamatorios estimulados por la hipoxia.

Adenosine deaminase (ADA) is an enzyme of purine metabolism which has been the subject of much interest because the congenital defect of this enzyme causes severe combined immunodeficiency syndrome. One of the three isoforms of the enzyme (ecto-ADA) is capable of binding to the glycoprotein CD26 and adenosine receptors A1 and A2B. ADA-CD26 interaction produces a costimulatory signal in the events of T cell activation and secretion of IFN-g, TNF-a and IL-6. During this activation, the enzyme activity is regulated positively by IL-2 and IL-12 and negatively by IL-4, based on the mechanism of translocation. Diverse studies suggest that seric and plasmatic levels of ADA rise in some diseases caused by microorganisms infecting mainly the macrophages and in hypertensive disorders, which may represent a compensatory mechanism resulting from increased adenosine levels and the release of hormones and inflammatory mediators estimulated by hipoxia.

Leukocyte synapse: structure, function and significance / 中国实验血液学杂志

Neuronal synapse is the critical structure of neuronal network. Immune system is mainly consisted of invisible network. Recently, evidence showed that leukocyte synapses between immune cells named as immunological synapses (IS), were formed under some functional conditions to form temporal local network. In fact, they are dynamic structures, which can be classified into synapse and kinase. Different leukocytes have different synapses. Inflammatory and leukemic cells showed special patterns of IS. Similar structure is also observed in some viral infected lymphocytes, which is called virological synapse (VS). This is one of the mechanisms for viral transmission, not only enhancing the transmission efficiency but also mediating the escape from antibody neutralization, leading persistent infection. Recently the flower-like poly synapses was reported by French scientists. This is a multi-tunneling nanotube flower-like structure on cell surface. We had observed this kind of structure in EB virus infected human leukemic cell line J6-2. In this paper, the structure and function of leukocyte synapses are reviewed combined with authors' own work. Their significance is discussed.