Revisión del concepto de inmunidad poblacional, a propósito de la epidemia COVID-19 y del desarrollo de vacunas / Review of the concept of herd immunity, in the context of COVID-19 epidemic and the development of vaccines

Resumen Se revisa brevemente el concepto de inmunidad de grupo, poblacional o efecto "rebaño", mostrando que algunas ideas popularizadas no corresponden al concepto original. Se establece la relación con los números reproductivo básico y efectivo, enfatizándose que el umbral para el efecto rebaño no indica el número de individuos que se contagiarán en una epidemia. Se establece la relación con el umbral de vacunación efectiva y su relación con la efectividad de la vacuna. Se analiza el efecto reductor del umbral de inmunidad de rebaño producido por la heterogeneidad de transmisión y mezcla en la población y la existencia de subpoblaciones aisladas lo que podría llegar a ser importante y que podría explicar los bajos niveles de seroprevalencia post-epidemia de algunos lugares, ayudando a mitigar nuevos brotes.

Abstract The concept of herd immunity is briefly reviewed, showing that some popularized ideas do not correspond to the original concept. The relationship with the basic and effective reproductive numbers is established. It is pointed out that the threshold for the herd effect does not indicate the number of individuals that will be infected in an epidemic. The relationship with the effective vaccination threshold and its relationship with the effectiveness of the vaccine are established. The reducing effect of the herd immunity threshold produced by the heterogeneity of transmission and mixing in the population and the existence of isolated subpopulations are analyzed, which could be important and could explain the low levels of post-epidemic seroprevalence in some places helping to mitigate new outbreaks.

Imunização na gravidez, puerpério e amamentação / Immunization in pregnancy, puerperium and breastfeeding

A vacinação materna representa uma ferramenta promissora na melhoria da saúde materna e infantil para diversas condições infecciosas. A maior susceptibilidade das gestantes às condições infecciosas, assim como a capacidade da mãe transferir anticorpos através da placenta, oferecendo proteção vital a seus conceptos antes que os mesmos sejam vacinados, têm despertado atenção maior à imunização materna. A FEBRASGO, em conformidade com a Sociedade Brasileira de Imunizações e Ministério da Saúde, recomenda três vacinas de rotina para todas gestantes: influenza, difteria - tétano -coqueluche acelular (dTpa), além da vacina de hepatite B, disponíveis no sistema público na totalidade. Esta revisão descreve as vacinas recomendadas na gestação, além de vacinas e imunoglobulinas de uso específico, e contraindicações da imunização na gestação e puerpério. Aborda, ainda, estratégias de melhoria de adesão à imunização pela gestante, visando alcançar altas taxas de cobertura vacinal, uma estratégia fundamental em saúde pública, com objetivo de reduzir a morbimortalidade infecciosa de gestantes e recém-nascidos.(AU)

Análise da reemergência da coqueluche no Brasil / Analysis of the reemergence of pertussis in Brazil

A coqueluche, doença infectocontagiosa, atualmente vem apresentando um perfil reemergente. Fatores como diminuição da imunidade, anos após a vacinação, mudanças no genótipo da bactéria e maior susceptibilidade entre jovens e adultos são considerados como contribuintes para o aumento da taxa da incidência da doença. Assim, esse estudo teve como objetivos verificar a distribuição espacial dos casos confirmados de coqueluche entre o período de 2007 a 2015; identificar o comportamento da série histórica da taxa de incidência da coqueluche durante o período de 2001 a 2015 no Brasil e verificar a associação da vacina contra coqueluche e a ocorrência da doença no estado do Rio Grande do Norte. Dessa forma, o caminho metodológico da pesquisa foi dividido em três partes. A análise da distribuição espacial considerou como unidade de análise as 482 Regiões Imediatas de Articulação Urbana e utilizou o software Terraview para construção dos mapas temáticos. Para se verificar a tendência da série optamos por utilizar o ajuste de uma função polinomial no tempo, utilizando-se assim modelos de regressão polinomial. Em relação a associação foi estabelecido como critério de inclusão a confirmação do caso de acordo com os critérios estabelecidos pelo Ministério da Saúde, sendo excluídos aqueles cujas fichas não encontravam-se devidamente preenchidas ou que estivessem com algum tipo de dúvida que comprometesse a coleta dos dados. Os resultados demonstraram que a doença apresentou uma distribuição espacial democrática em todo território nacional, formando pequenos clusters com altas taxas de incidência nas regiões de articulação urbana presentes nas regiões sul e sudeste. Identificamos também que houve, na série histórica, uma tendência crescente da doença ao longo de 15 anos. E por fim, os resultados apontam que independentemente do estado vacinal os indivíduos estão adoecendo por coqueluche, o que não gerou evidência científica suficiente para medir a efetividade da vacina. Os achados sugerem que aspectos relacionados a vacinação precisam ser melhor investigados para que se possa garantir o controle da doença. É necessário também que ocorram melhorias nas ações de vigilância, o que pode garantir uma representação epidemiológica fidedigna da doença (AU).

Pertussis, an infectious-contagious disease, is currently presenting a reemerging profile. Factors such as decreased immunity years after vaccination, changes in the genotype of the bacteria and increased susceptibility among young and adults are considered to have contributed to increase the disease incidence rate. Therefore, this study aimed to verify the spatial distribution of confirmed pertussis cases between 2007 and 2015; to identify the patterns in the time-series of pertussis incidence rates during the period 2001 to 2015 in Brazil and to verify the association of pertussis vaccine with the occurrence of the disease in the state of Rio Grande do Norte. Thus, the methodological path of the research was divided into three parts. The analysis of the spatial distribution considered the 482 Regions Immediate Urban Articulation as unit of analysis and used the Terraview software to construct the thematic maps. In order to verify the trend in the series we chose to use the adjustment of a polynomial function in time, using polynomial regression models. Regarding the association, the confirmation of the case was established as inclusion criteria in accordance with the criteria established by the Ministry of Health, being excluded those files that were not properly filled or had any uncertainties that could compromise the data collection. The results suggests that the disease has a democratic spatial distribution throughout the country, forming small clusters with high incidence rates in the urban articulation present in the South and Southeast regions. It was also identified in the time-series an increasing tendency of the disease over a period of 15 years. Finally, the results indicate that regardless of vaccination status individuals are being infected with pertussis, which did not generate enough scientific evidence to measure the effectiveness of the vaccine. The findings suggest that aspects related to vaccination need further investigation in order to guarantee disease control. There is also a need for improvements in surveillance actions, which can ensure a reliable epidemiological representation of the disease (AU).

Regulatory T cells: A review.

Regulatory T cells (Tregs) play a pivotal role in the homeostasis of the immune system and in the modulation of the immune response. Tregs have emerged as key players in the development and maintenance of peripheral immune tolerance. Broadly speaking, CD4+ T cells possessing the ability to suppress immune responses can be divided into two types: naturally occurring (nTreg) and inducible (iTreg) or adaptive regulatory cells. Naturally occurring thymus-derived CD4+CD25+ Tregs are a subset of T cells which have immunosuppressive properties and are 5%–10% of the total peripheral CD4+ T cells. In normal conditions, Tregs regulate ongoing immune responses and prevent autoimmunity. Imbalanced function or number of these cells, either enhanced or decreased, might lead to tumour development and autoimmunity, respectively. These cells thus play a major role in autoimmune diseases, transplantation tolerance, infectious diseases, allergic disease and tumour immunity. These natural properties make Tregs attractive tools for novel immunotherapeutic approaches. The in vivo manipulation or depletion of Tregs may help devise effective immunotherapy for patients with cancer, autoimmunity, graftversus- host disease, infectious diseases and allergic diseases. It is crucial to understand the biology of Tregs before attempting therapies, including (i) the injection of expanded Tregs to cure autoimmune disease or prevent graft-versus-host disease or (ii) the depletion or inhibition of Tregs in cancer therapy. Recent findings in murine models and studies in humans have opened new avenues to study the biology of Tregs and their therapeutic potential. This overview provides a framework for integrating these concepts of basic and translational research.

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.

Caracterización de eventos adversos asociados a vacunas que inmunizan contra enfermedades infecciosas: años 2006-2007 / Characterization of adverse events associated with vaccines immunizing against infectious diseases: 2006-2007

Se realizó un estudio descriptivo, transversal y retrospectivo para caracterizar los eventos adversos temporalmente asociados con las vacunas que se emplean en la prevención y el control de las enfermedades infecciosas, y que fueron notificados a la Unidad Coordinadora Nacional de Farmacovigilancia entre los años 2006-2007. Se determinó su comportamiento de acuerdo con la edad, sexo, procedencia de la notificación, personal que reporta, localización y severidad. Se identificaron además los principales eventos reportados y las vacunas implicadas en su aparición. La fiebre constituyó el 60 por ciento del total de eventos notificados. Estos últimos se distribuyeron de igual forma entre uno y otro sexos, en tanto los lactantes resultaron ser los más afectados (46,8 por ciento). Se destacó en el reporte la Atención Primaria de Salud con 812 notificaciones. Los médicos fueron los profesionales que más reportaron (36 por ciento). El comportamiento en cuanto a severidad no se diferenció de lo reportado en la literatura, pues afortunadamente predominaron los eventos leves (66,4 por ciento). Sin embargo, contrario a lo que se esperaba, los eventos sistémicos fueron los de mayor cuantía (80,2 por ciento). La vacuna pentavalente estuvo implicada en el 29,6 por ciento de los eventos adversos temporalmente asociados a vacunación

A descriptive, transversal and retrospective study was conducted to characterize the adverse events temporarily associated with vaccines used in prevention and control of infectious diseases and that were notified to National Coordinator Unit of Pharmacosurveillance between the 2006-2007 years. Its behavior was determined according to the age, sex, notification origin, reporting staff, location and severity. Also, it was possible to identify the leading events reported and the vaccines involved in its appearance. Fever accounted for the 60 percent of total of reported events. These latter were distributed equally between both sexes where the infants were the most affected (46.8 percent).Report from Health Primary Care report was the more significant with 812 notifications. The most reports came from physicians (36 percent). The behavior as regards severity was not different from that reported in literature, since fortunately there was predominance of slight events (66.4 percent). However, contrary to expected, the systemic events had the greatest amount (80.2 percent). pentavalent vaccine was related to 29.6 percent of adverse events temporarily associated with vaccination

Implications of infectious diseases and the adrenal hypothesis for the etiology of childhood acute lymphoblastic leukemia

Acute leukemia is the most frequent cancer in children. Recently, a new hypothesis was proposed for the pathogenesis of childhood acute lymphoblastic leukemia (ALL). The so-called "adrenal hypothesis" emphasized the role of endogenous cortisol in the etiology of B-cell precursor ALL. The incidence peak of ALL in children between 3 to 5 years of age has been well documented and is consistent with this view. The adrenal hypothesis proposes that the risk of childhood B-cell precursor ALL is reduced when early childhood infections induce qualitative and quantitative changes in the hypothalamus-pituitary-adrenal axis. It suggests that the increased plasma cortisol levels would be sufficient to eliminate all clonal leukemic cells originating during fetal life. Because Brazil is a continental and tropical country, the exposure to infections is diversified with endemic viral and regionally non-viral infections, with some characteristics that support the recent adrenal hypothesis. Here we discuss this new hypothesis in terms of data from epidemiological studies and the possible implications of the diversity of infections occurring in Brazilian children.

Conceptos emergentes de tolerancia y autoinmunidad: Nuevos enfoques terapéuticos / Tolerance and autoimmunity: Novel therapeutic approaches

La función primaria del sistema inmune es resguardar al individuo de los patógenos potencialmente dañinos que invaden el medio ambiente en el cual nos desarrollamos. Este cuenta con dos grandes ramas, la inmunidad innata y la adaptativa, ambas con la propiedad de diferenciar lo peligroso de aquello inofensivo. Estos procesos se hallan regulados por mecanismos homeostáticos que constituyen la tolerancia inmunológica, a los fines de limitar aquellos procesos prolongados y silenciar los potencialmente autoagresivos. Ante la falla de estos mecanismos de control, surgen las enfermedades autoinmunes. Avances en el conocimiento de la fisiopatología de estas entidades, han abierto un nuevo capítulo en el terreno de la inmunofarmacología. Su prometedor potencial actualmente nos ofrece novedosas herramientas terapéuticas para controlar y atenuar el daño causado por este tipo de respuestas. No obstante, debe continuarse la investigación en el campo de los agentes biológicos, ya que ninguno de ellos se encuentra libre de inconvenientes. Seguramente, futuros hallazgos se concretarán en futuros aciertos. Y los aciertos, en Medicina, equivalen a esperanza.

The main function of the immune system is to protect the individual against potentially dangerous pathogens. It comprises innate and adaptive cellular and soluble components, both with the capacity to discriminate between harmful and harmless. These processes are regulated by homeostatic mechanisms that constitute the so-called immunological tolerance, which aims to limit the prolonged action of immune mediators and to silence the generation of potentially autoaggressive components. Failure to silence self-reactive T and B cells results in the generation of autoimmune disease. Recent advances in our knowledge of these pathological entities have opened a new chapter in the pharmacology of the immune system. Its promising potential currently offers new therapeutic agents to control and attenuate pathological tissue damage. Nevertheless, further research regarding these biologic agents is required, since they are not free from inconveniences. It is without question that upcoming findings in this field will instill hope into the quest for the "magic bullet".

Estudo do papel de células T reguladoras e moléculas co-estimulatórias ma regulação da resposta imune em doenças infecciosas e tumor de cabeça e pescoço / The role of the regulatory T cells and PD-1 molecules in the modulation of the immune response in chronic infections and head and neck tumors

O sistema imune serve como uma barreira contra os patógenos e ao crescimento anormal de células. Para impedir as respostas imunes excessivas ou indiscriminadas que podem comprometer a sobrevivência do organismo, diversos mecanismos regulatórios são ativados visando manter o delicado balanço entre início e término de uma resposta imune. As celular T reguladoras (Treg) parecem desempenhar papel central na regulação da resposta imune em infecções crônicas e durante o desenvolvimento de tumores. Outro mecanismo importante no controle da resposta imune é desempenhado por moléculas co-estimulatórias, dentre as quais estão CTLA-4 e PD-1, todas associadas à função das células T reguladoras. Um aspecto importante é q a sobrevida de tecido tumoral e de transplantes tem sido associada à função das células T reguladoras. Assim, buscamos definir o envolvimento de células T reguladoras e PD-1 na modulação da resposta imune L. braziliensis, ao fungo P. brasiliensis, à doença periodontal e ao tumor de cabeça e pescoço. Baseado nos resultados já publicados e em dados preliminares, as hipóteses são que: (a) a interação do parasita (ou célula tumoral) com o hospedeiro leva à migração de linfócitos T e efetores e células T reguladoras para o local da lesão; (b) a dinâmica do acúmulo dessas células em tais sítios determina a eficiência da eliminação do patógeno ou tumor. No caso das parasitoses, há o desenvolvimento de imunidade concomitante; (c) as células T regulam a resposta imune local de forma contato dependente e modulando a função de APC através da liberação de IL-10 e/ou TGF-β; (d) infecção e progressão tumoral levam à modulação da expressão de PD-1 nos leucócitos e seus ligantes nos órgãos; (e) a interação PD-PDL-1 regula a resposta imune local de forma a favorecer a persistência do patógeno e os mecanismos de escape tumoral.

The immune system serves as a barrier against pathogens and abnormal cellular growth. To avoid tissue and organ damage during immune response several regulatory mechanisms are activated to limit, terminate and attenuate T-cells response. Regulatory T cells (Treg) play a central role in the regulation of the immune response in chronic infections and tumor-specific immunity. Programmed death-1 (PD-1) is a transmembrane protein that acts as a negative regulator in effector T cells, modulating the delicate balance between effective antimicrobial immune defenses and immune-mediated tissue damage. However, recent data suggest that the PD-1:PD-L1 pathway can also block antitumor immune responses even when tumor antigens can be recognized. An important aspect it that the survival of tumor and transplant tissues has been associated with the function or regulatory T cells. Thus, we discuss the role of Treg cells and PD-1 molecules in the modulation of the immune response to L. braziliensis, P. brasiliensis, periodontal disease and head and neck tumors. Based on published results and preliminary data, the hypotheses are that: (a) the interaction of the parasite (or tumoral cells) with the host leads to the migration of effector T lymphocytes and Treg cells to the local; (b) the dynamics of cells accumulation in such sites determinate the elimination efficiency of tumors. In infectious disease, there is the development of concomitant immunity; (c) Treg cells regulate the local immune response, modulating the APC function through the release of IL-10 and/or TGF-β; (d) infection and tumor progression leads to the modulation of PD-1 expression in the leukocytes and their ligands in the tissue; (e) PD-PDL-1 interactions regulate the immune response and may mediate the persistence of pathogen and contribute to immune evasion by cancers.T.

Associação do sistema de histocompatibilidade humano com patologias ginecológicas e reprodutivas / Association of the human histocompatibility antigens with gynecological and reproductive disorders

Mecanismos imunes são atualmente aventados como componentes fundamentais nas etapas de fertilização, implantação e manutenção da gravidez, bem como na fisiopatologia de doenças infecciosas e neoplásicas do trato genital feminino. As moléculas do sistema de histocompatibilidade humano (HLA) permeiam estes aspectos, interferindo na susceptibilidade a patologias e atuando na manutenção da fisiologia reprodutiva. Este trabalho se propõe a atualizar o conhecimento sobre estrutura e função das moléculas de histocompatibilidade, métodos de detecção, nomenclatura e mecanismos imunogenéticos que associam o HLA com a reprodução humana e algumas patologias ginecológicas. Na pesquisa bibliográfica utilizamos os bancos de dados MEDLINE e LILACS, privilegiando os estudos mais recentes de cada tema. Conclui-se que o HLA desempenha papel importante na reprodução humana e doenças ginecológicas, mas ainda pouco estudado. O melhor conhecimento dos fatores imunorregulatórios envolvidos nestes aspectos são áreas promissoras de pesquisa.

Immunogenetics and infectious diseases: special reference to the mayor histocompatibility complex

Many studies have tried to identify genetic markers for infectious diseases, some of them have focused on human leukocyte antigens (HLA). The products of HLA genes interact with surface-specific receptors of T lymphocytes, resulting in activation of the host's immune response. Association of bacterial, viral, parasitic and fungal infections with the host's HLA has been widely investigated. The type and strength of this association differs among distinct populations, as well as among racial and/or ethnic groups. The new molecular methods for the identification of the HLA alleles, and the resulting new nomenclature, have contributed to a better understanding of this system. Unfortunately, this information has not been adequately transmitted to clinicians, which hampers the understanding of the association between the HLA system and diseases. We revised relevant studies on the association of HLA genes with infectious diseases, demonstrating their importance in the pathogenic mechanisms, through increased susceptibility or protection against infections and their complications.

Imunomodulação materna no ciclo gestatório normal e patológico / The Maternal immunomodulation in normal and pathological pregnancy

O conhecimento sobre as mudanças imunoendócrinas às quais as gestantes são condicionadas ajuda a entender muito da relação materno-fetal envolvida na aceitação e rejeição de um corpo semi-estranho. Este trabalho teve por objetivo trazer à comunidade científica a discussão sobre a imunobiologia materna no ciclo gestatório normal e patológico. Nesse contexto, uma rede de citocinas participa de todas as etapas da gestação. Enquanto as citocinas inflamatórias, como TNF-a, IL-1b e o IFN-y, estão envolvidas na fase de implantação e no pré-parto, a produção de citocinas antiinflamatória é responsável pela sobrevivência do feto na cavidade uterina. Muitos pesquisadores acreditam que níveis elevados de estrogênio e, principalmente, de progesterona induzem uma resposta imune materna mediada por células T reguladoras dos tipos 1 e 3, que garante a não responsividade às estruturas fetais. Estes linfócitos T reguladores, quando ativados, produzem IL-10 e TGF-b que contra-regulam os efeitos embriotóxicos das citocinas inflamatórias na interface decídua-trofoblasto. A presença de cortisol em tempos mais tardios da gestação auxilia na manutenção sistêmica desse fenótipo por, dentre outras funções, amplificar a secreção da IL-10 no sangue periférico materno. Esse equilíbrio é tênue e pode ser quebrado por algumas intercorrências, como na pré-eclâmpsia, infecções e nas doenças auto-imunes

Cross- reaction of sera from patients with various infectious diseases with Leishmania infantum

To compare and evaluate the application of indirect fluorescent antibody [IFA] and counterimmunoelectrophoresis [CIEP] for laboratory identification of visceral leishmaniasis. Materials and Serum samples from patients with malaria [Plasmodium vivax, n = 86; Plasmodium falciparum, n = 38], brucellosis [n = 26], tuberculosis [n = 31] and typhoid fever [n = 35] were examined for the presence of antibody to Leishmaniainfantum antigen using IFA and CIEP tests. Using IFA, false-positive results were malaria [P. vivax 19.8%, P. falciparum 13.2%], tuberculosis [6.4%], brucellosis [3.8%], and typhoid fever [2.8%]. Using CIEP, a lower percentage of false-positives was observed only among malaria patients [P. vivax 2.3%, P. falciparum 2.6%]. Serum samples from patients with other infectious diseases were negative in the CIEP test. Based on the results of this study, the CIEP technique is recommended for immunodiagnosis of visceral leishmaniasis, especially in regions where malaria, brucellosis and tuberculosis are prevalent

Trp-Lys-Tyr-Met-Val-Met stimulates phagocytosis via phospho-lipase D-dependent signaling in mouse dendritic cells

Dendritic cells (DCs) play a key role in activating the immune response against invading pathogens as well as dying cells or tumors. Although the immune response can be initiated by the phagocytic activity by DCs, the molecular mechanism involved in this process has not been fully investigated. Trp-Lys-Tyr-Met-Val-Met-NH2 (WKYMVM) stimulates the activation of phospholipase D (PLD) via Ca2+ increase and protein kinase C activation in mouse DC cell line, DC2.4. WKYMVM stimulates the phagocytic activity, which is inhibited in the presence of N-butanol but not t-butanol in DC2.4 cells. Furthermore, the addition of phosphatidic acid, an enzymatic product of PLD activity, enhanced the phagocytic activity in DC2.4 cells. Since at least two of formyl peptide receptor (FPR) family (FPR1 and FPR2) are expressed in DC2.4 as well as in mouse bone marrow-derived dendritic cells, this study suggests that the activation of FPR family by WKYMVM stimulates the PLD activity resulting in phagocytic activity in DC2.4 cells.