UNIVERSIDADE FEDERAL DO RIO GRANDE DO NORTE
CURSO DE GRADUAÇÃO EM FARMÁCIA
Júlia Kandisse Vieira de Almeida
PERFIL INFLAMATÓRIO DAS PARASITOSES INTESTINAIS CAUSADAS POR
HELMINTOS: UMA REVISÃO
Natal-RN
2019
Júlia Kandisse Vieira de Almeida
PERFIL INFLAMATÓRIO DAS PARASITOSES INTESTINAIS CAUSADAS POR
HELMINTOS: UMA REVISÃO
Artigo apresentado à Coordenação do Curso de Farmácia da
Universidade Federal do Rio Grande do Norte, para inscrição do
Trabalho de Conclusão do Curso (TCC), como requisito parcial
para conclusão da graduação em Farmácia.
ORIENTADORA: Profª Drª Aldilane Gonçalves da Fonseca
Natal - RN
2019
Júlia Kandisse Vieira de Almeida
PERFIL INFLAMATÓRIO DAS PARASITOSES INTESTINAIS CAUSADAS POR
HELMINTOS: UMA REVISÃO
Artigo apresentado à Coordenação do Curso de Farmácia da
Universidade Federal do Rio Grande do Norte, para inscrição do
Trabalho de Conclusão do Curso (TCC), como requisito parcial
para conclusão da graduação em Farmácia.
ORIENTADORA: Profª Drª Aldilane Gonçalves da Fonseca
Banca de Avaliação:
Presidente: Profa Aldilane Gonçalves da Fonseca, Dra. – Orientadora, UFRN
Membro: Profa. Ana Claúdia Galvão Freire Gouveia, Dra., UFRN
Membro: Profa. Marcela Abbot Galvão Ururahy, Dra., UFRN
Natal, 05 de novembro de 2019
AGRADECIMENTOS
A Deus, pela confiança, pela paciência e sabedoria concedida durante esta travessia, pelo
seu amor grandioso e misericordioso para conosco. A Ele, toda minha gratidão.
À minha mãe, Regina, pela perseverança e esforços para que esta conquista fosse alcançada,
por acreditar e aceitar minhas decisões, pelo seu amor incondicional.
Ao meu pai, Carlos Antônio, pelo amor, pelo carinho, pelo aconchego e por todo o apoio de
sempre.
Ao meu namorado, Pedro, por me ajudar em todas as horas de desespero, pelo amor e
ternura de sempre.
À minha orientadora, Profª Drª Aldilane, por me acolher, acreditar e confiar, além de toda
atenção e paciência concedida.
Aos demais professores que contribuíram para minha formação.
Aos meus amigos que durante os últimos anos partilharam muitos momentos de aflição, mas
também de grandes alegrias. Por estarem estimulando o meu crescimento pessoal e
profissional.
A todos o meu muito obrigada!
Perfil inflamatório das parasitoses intestinais causadas por helmintos: uma revisão
Inflammatory profile of intestinal parasites caused by helminths: a review
Júlia Kandisse Vieira de Almeida1; Aldilane Gonçalves da Fonseca1
1 Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade
Federal do Rio Grande do Norte, Av. General Gustavo Cordeiro de Farias, s/n, CEP 59012-
570. Natal, RN, Brasil.
Autor de Correspondência:
Aldilane Gonçalves da Fonseca
Rua General Gustavo Cordeiro de Farias, S/N, Petrópolis, Natal/RN
CEP: 59012-570
Tel: +55 84 3342-9835
E-mail: [email protected]
RESUMO
Os helmintos infectam bilhões de pessoas em todo o mundo, quando transmitidos para o
hospedeiro causam uma agressão, através de ações espoliadora, tóxica, mecânica ou localização
ectópica, desencadeando uma resposta imune e inflamação. Diante disto, esta revisão aborda os
mecanismos imunológicos e imunorregulatórios relacionados a estes parasitos, com objetivo de
compreender melhor as patogenias envolvidos nas helmintíases. Para todos os helmintos
intestinais foi encontrado perfil inflamatório semelhante: a resposta inata, seguida da ativação
da via alternativa do sistema complemento, que estimula o C3b (opsonização) e C5a (ativa
mastócitos, basófilos e inflamação). Assim como a resposta adaptativa (Th2), onde partes do
parasito, os Padrões moleculares associados à patógenos (PAMP), são reconhecidas pelas
células apresentadoras de antígenos (APC) e via Complexo Principal de Histocompatibilidade
de classe II (MHC II), é apresentado para o TCD4, também chamado de Th0, a Interleucina-4
(IL-4) produzida por mastócitos e eosinófilos, transforma Th0 em Th2, assim o Th2 passa a
produzir várias substâncias como IL-13, IL-4, IL-5. Todos os mecanismos discutidos nesta
revisão colaboraram para uma melhor compreensão da patogenia das helmintíases, bem como
para nortear novas pesquisas.
Palavras-chaves: Helmintos. Inflamação. Imunorregulação.
ABSTRACT
Helminths infect billions of people worldwide, when transmitted to the host cause aggression
through spoiling, toxic, mechanical or ectopic localization, hence an immune response and
inflammation. Thus, this review addresses the immunological and immunoregulator
mechanisms of these parasites in order to better understand how the pathogens are applied by
helminths. For all intestinal helminths, a similar inflammatory profile was found: the innate
response, followed by activation of the alternative complement pathway, which stimulates C3b
(opsonization) and C5a (activates mast cells, basophils and inflammation), as well as the
adaptive response (Th2), where parts of the parasite, the associated molecular patterns
Pathogens (PAMP), are recognized by antigen presenting cells (APC) and via Class II Main
Histocompatibility Complex (MHC II) pathway, it is presented for TCD4, also called Th0, turns
Th0 into Th2, so Th2 now produces various substances like IL-13, IL-4, IL-5. All the
mechanisms discussed in this review contributed to a better understanding of the pathogenesis
developed, as well as to guide new research.
Keywords: Helminths. Inflammation. Immunoregulation.
8
1 INTRODUÇÃO
As infecções parasitárias são eventos comuns em nosso meio e ocorrem em todas as
faixas etárias e níveis socioeconômicos [1]. Apresentam alta prevalência nas comunidades
socioeconomicamente desfavorecidas, principalmente em países tropicais e subtropicais [2],
com variações de acordo com o ambiente e espécie de parasito envolvido [3]. Parasitoses,
principalmente as causadas por helmintos, desencadeiam centenas de milhares de mortes
evitáveis a cada ano e estão entre as doenças infecciosas mais recorrentes do mundo. Trata-se
de um problema de saúde pública com cerca de 3,5 bilhões de pessoas infectadas em todo o
planeta [2], onde o Ascaris lumbricoides, os ancilostomídeos e o Trichuris trichiura infectam
cerca de 1.450 milhões, 1.300 e 1.050 milhões de pessoas, respectivamente, enquanto a
esquistossomose intestinal afeta mais de 200 milhões de pessoas, segundo estimativa realizada
pela OMS [4].
No Brasil, em 2014, dados do Departamento de Informática do Sistema Único de Saúde
(DATASUS) mostraram que as doenças infeciosas e parasitárias representaram a sexta causa
de morbidade no país, totalizando 776.358 internações, o que corresponde a 7,28% da
morbidade hospitalar no período [5].
Os helmintos compreendem um grupo diverso de organismos metazoários que infectam
bilhões de pessoas e animais domésticos em todo o mundo. Em grande parte, as helmintíases
são causadas por membros do filo Nematoda (cilíndricos) e Platyhelminthes (achatados).
Espécies pertencentes a ambos os filos ocupam numerosos nichos dentro de seus hospedeiros
mamíferos, variando desde o lúmen intestinal até locais intravasculares e mesmo
intracelulares [6].
A infecção no hospedeiro gera um processo inflamatório, com recrutamento de
fagócitos, leucócitos do sangue periférico e proteínas plasmáticas no local da infecção. O fluxo
sanguíneo e a permeabilidade vascular aumentam, principalmente no endotélio para permitir a
transmigração de leucócitos e a entrada de proteínas plasmáticas, sistema complemento, fatores
de coagulação e anticorpos [7]. Durante a infecção, os mecanismos imunológicos também são
ativados como a resposta imune adaptativa ou especifica, que ocorre contra microrganismos ou
antígenos previamente reconhecidos pela resposta inata, havendo predomínio da resposta
adaptativa para parasitoses intestinais. A resposta imune inata ou inespecífica, a qual é a
primeira linha de defesa do hospedeiro, apresenta métodos de proteção preexistentes, incluindo
as barreiras naturais (pele e mucosa), secreções, neutrófilos, macrófagos, mastócitos e células
9
natural killer (NK). Os macrófagos participam tanto como células apresentadoras de antígeno
quanto como células efetoras, via liberação de citocinas ditas pró-inflamatórias (p.ex.: fator de
transformação do crescimento beta [TGF-β] e Interleucinas IL-1, IL-10, IL-12 e IL-23),
quimiocinas, espécies reativas de oxigênio, produção de prostanóides e metaloproteinases da
matriz extracelular [8].
Parasitos, particularmente helmintos, podem modular a resposta imune e propiciar um
ambiente anti-inflamatório que favoreça sua sobrevivência dentro do organismo do hospedeiro,
ou seja, suprimem respostas imunes pró-inflamatórias para manter seu ciclo vital. Nestas
infecções, embora o complemento e outros fatores da resposta imune inata possam atuar na
defesa, predomina a resposta imune adaptativa ou específica com a produção de anticorpos e
citocinas. As células T CD4+ e TCD8+ do tipo 2 são produtoras de citocinas como IL-4, IL-5
e IL-13 que, entre outras funções, induzem a produção de IgE pelas células B e ativação de
eosinófilos, mastócitos e basófilos, respectivamente; componentes fundamentais na defesa
contra os parasitas, citocinas reguladoras como IL-10 e TGF-β também estão presentes na
resposta. Anticorpos da classe da imunoglobulina IgE ligam-se aos basófilos circulantes ou
mastócitos teciduais, induzindo a liberação de histamina e outros mediadores da reação de
hipersensibilidade imediata, que leva à destruição de helmintos. Eles também inibem
Interferon-gama (IFN-γ), IL-1 e IL-17 e suprimem a resposta imune inflamatória de células Th1
e Th17 [7, 8, 9, 10].
Helmintos secretam produtos excretórios-secretórios (ES) (Figura 1), como a ES-62,
que são glicosilados e induzem citocinas Th2 e expansão de células T regulatórias. Ademais, a
quantidade de células T regulatórias (CD4+CD25+FOXP3+) que produzem IL-10 e TGF-β
aumenta após a infecção por helmintos, contribuindo para sua permanência dentro do
organismo hospedeiro. A homeostase gerada por essas respostas imunes previne uma reação
exagerada contra os parasitas que também prejudicariam o hospedeiro, garantindo a
sobrevivência dos helmintos [7].
O principal objetivo desta revisão é discutir sobre o perfil inflamatório nas principais
helmintíases intestinais e os mecanismos que são desencadeados. Isso irá contribuir na
perspectiva da elucidação de mecanismos de patogenia e pesquisas de novas alternativas
terapêuticas.
10
Figura 1: Efeito dos produtos excretor / secretório de helmintos (ES) nas células
imunológicas do hospedeiro.
Fonte: (Smallwood et al., 2017).
2 METODOLOGIA
2.1. Critério de eleição
A seleção dos estudos a serem incluídos neste estudo baseou-se no seguinte: (1) o estudo
deve ser sobre inflamação decorrente de parasitoses intestinais; (2) o estudo deve ser publicado
em língua inglesa ou portuguesa; (3) os estudos devem apresentar o perfil inflamatório nas
parasitoses intestinais; (4) os estudos devem ser publicados entre 1999 e 2019; (5) os estudos
não devem tratar de pesquisas com tratamentos. Os critérios de exclusão para o propósito desta
revisão foram estudos não relacionados à inflamação decorrente de parasitoses intestinais.
2.2. Estrategia de busca
A busca foi eletrônica, visando estudos que discorreram sobre inflamação decorrente de
parasitoses intestinais. Isso produziu 1087 referências, mas apenas 61 foram incluídas na
revisão usando os critérios de inclusão/exclusão. Os artigos foram extraídos por busca
11
eletrônica do PubMed, NCBI, LILACS e outros periódicos relevantes. Várias palavras-chave
utilizadas na estratégia de busca incluíram o seguinte: inflamação, parasitoses intestinais, perfil
inflamatório, helmintos intestinais, ascaridíase, ancilostomose, tricuríase, enterobíase,
estronloidíase, esquistossomose e teníase. Várias combinações de palavras-chave foram feitas
usando “AND” e “OR” como operadores booleanos.
Uma abordagem prática para a inflamação em parasitoses intestinais decorrente desta
revisão e da experiência dos autores é apresentada aqui.
3 RESULTADOS
Esta revisão encontrou 1087 artigos relacionados ao tema pesquisado, dos quais 53
foram selecionados de acordo com os critérios estabelecidos para nossa análise e comparação.
Ao final desta sessão, o Quadro 1 resume estes achados.
3.1 Ascaridíase e inflamação
A revisão encontrou 43 artigos relacionados ao tema pesquisado, onde 7 foram
escolhidos de acordo com os critérios de eleição. Weatherhead e colaborares (2018)
encontraram IL-4, IL-5, IL-13 aumentadas e IL-10 ligeiramente elevada, resultando em um
aumento das citocinas do tipo 2. Em contraste, para a resposta Th1, não foi notado TNF-α ou
IFN-γ, significando uma redução ou ausência [11]. Já Zavala e colaradores (2018), notaram IL-
10 regulando TNF-α e IL‐ 6 na inflamação [12]. Gazzinelli-Guimaraes e colaboradores (2019)
demonstraram aumento significativo dos níveis de IL-4, IL-13, IL-13Rα2, IL-1β e TNF-α, em
contraproposta, níveis de IL-5 e IL-6 mostraram um padrão bastante diferente da IL-4, IL-13,
IL-33, além dos aumentos acentuados nas quimiocinas CCL-11 (eotaxina ou proteína
quimiotática eosinófila), CCL-2 (proteína quimioatraente 1 de monócitos ou MCP-1) e CXCL-
10 (Proteína 10 induzida por interferon gama ou IP-10), também encontrou-se um pequeno
acúmulo, mas mensurável, de células Th2 efetoras de CD4 +, eosinófilos ativados e macrófagos
alternativamente ativados (M2) [13]. Em um estudo anterior Gazzinelli-Guimaraes (2013)
havia observado somente o aumento de IL-5, IL-6 e TNF-α [14]. Nogueira e colaboradores
(2016), além de observaram o aumento de IL-4, IL-5, IL-6, IL-10 e TNF-α como já visto em
outros estudos, também notaram o aumento de IL-17A e a intensa inflamação pulmonar
associada a uma resposta imune Th2/Th17 sistêmica polarizada durante as múltiplas exposições
12
ao Ascaris lumbricoides, já que este verme também pode desenvolver sua patogenia no sistema
pulmonar [15].
Ainda, Aceved e colaborados (2013), compararam e demonstraram a forte indução de
IgE por estes parasitas em relação a alérgenos [16], o que também foi comprovado por Pitrez e
seus colaboradores (2015) em relação aos eosinófilos, assim como a produção de IL-10 e a
redução de IL-5 nos individuos já sensibilizados [17].
3.2 Ancilostomose e inflamação
Encontrou-se 88 artigos, onde 10 foram designados para esta revisão, levando-se em
consideração os critérios estabelecidos. Além da resposta imune inata, interleucinas como IL-
33, IL-25, células apresentadoras de antígenos (células dendríticas) e células linfóides inatas
(ILC2), levaram a um aumento na liberação das citocinas tipo 2 IL-4, IL-5 e IL-13, sinalizadas
através da via IL-4Rα/Stat6 [18, 19]. Damle (2016) destaca a produção de IgE, assim como
por consequência o aumento da produção de muco, hiperplasia das células caliciformes,
eosinofilia e estimulação do nervo entérico, para facilitar a expulsão do verme intestinal [20].
Navarro e colegas (2016) identificaram uma proteína secretada por ancilóstomos,
proteína anti-inflamatória-2 (AIP-2), que suprimiu a inflamação, assim como reduziu a
expressão de marcadores co-estimulatórios em células dendríticas humanas (DCs) e suprimiu
células T [21].
Ferreira e colaboradores (2017) analisaram a proteína anti-inflamatória recombinante
(AIP-1), secretada em abundância por ancilóstomos na mucosa intestinal e notaram que com a
presença da proteína a infiltração local de células inflamatórias reduziu, apresentando perda
mínima de células caliciformes e a arquitetura mucosa sendo preservada. Ainda, o tratamento
com AIP-1 promoveu a produção de interleucinas no cólon IL‐ 10, TGF‐ β e linfopoietina do
estroma do timo (TSLP), resultando na supressão do fator de necrose tumoral (TNF)‐ α, IL‐
13 e IL‐ 17 A, caracterizando um acúmulo de células T reguladoras no cólon [22].
Jang (2015) também afirma a supressão das citocinas Th2 por RELMα, ainda acrescenta
que a expressão das resinas trata-se de uma resposta inata a múltiplos helmintos, onde promove
o recrutamento de monócitos e um ambiente de citocina pró-inflamatória tipo 1, levando a uma
diminuição do clearance de helmintos e a uma inflamação exacerbada associada à infecção [23].
Pesce e colaboradores (2009) e Fitzsimmons e colaboradores (2014) sugerem que a
imunidade de Th2 é aumentada durante a infecção pelo helminto [24, 25], assim como a IL-17
inicialmente contribuiu para a inflamação, enquanto a sinalização subsequente do receptor de
13
IL-4 (IL-4R) reduziu elevações nos níveis de mRNA da IL-17, embora outros estudos
demonstrem que IL-17 medeia o curso da inflamação. IL-10 aumentou sua expressão e
estimulou o desenvolvimento de macrófagos M2, os quais contribuíram para a rápida resolução
do dano tecidual [26].
Chenery e companheiros (2019) abordam um marcador de ativação alternativo, o Ym1
derivado dos macrófagos alveolares (Mφs), que pode conduzir o recrutamento de neutrófilos
inatos dependente do receptor IL-1R durante a infecção pelo nematoide, também discute o
aumento da eosinofilia e das proteínas inflamassomas como a NLRP3, que apresentam uma
importante função pró-inflamatória [27].
3.3 Tricuríase e inflamação
Na revisão localizou-se 65 artigos, dos quais 7 foram eleitos de acordo com os critérios
determinados para nossa análise e comparação.
Assim como Yang (2017), Duque-Correa (2019) observou a resposta Th1 inicialmente,
seguida por fator de crescimento transformador (TGF –β), IL-35 e IL-10, macrófagos e células
T em resposta a antígenos parasitários excretores-secretórios (ES) [28, 29]. Jang (2015)
reafirma esta resposta acrecentando o equilíbrio entre citocinas Th2 e citocinas pró-
inflamatórias do tipo 1, como IFNγ e TNFα, considerando a contra-regulação entre elas. Por
exemplo, a inibição de IFNγ promove a expulsão de Trichuris muris, permitindo o
desenvolvimento de uma resposta imune protetora Th2 [23].
Urban e colaboradores (2000), em estudos com ratos infectados com Trichuris muris,
bloqueando as interações do ligante B7, inibiu a imunidade protetora, suprimiu a produção de
IL-4 e aumentou a produção de IFN-γ, mas inesperadamente não inibiu a produção da citocina
Th2, IL-13. O bloqueio de IFN-γ e B7 restaurou a imunidade protetora, que dependia de IL-13,
mas não restaurou IL-4 ou respostas de IgE associadas. Embora a IL-13 fosse necessária para
a expulsão de vermes em camundongos nos quais o IFN-γ e o B7 estavam bloqueados, a IL-4
poderia mediar a expulsão na ausência de IL-13 e IFN-γ [30].
Nair e colegas (2008), usando um modelo natural de inflamação intestinal induzida por
infecção crônica com helminto gastrointestinal Trichuris muris, identificou funções duplas para
RELMβ no aumento das respostas das células CD4+ Th1 e na promoção de inflamação
intestinal induzida por infecção, associada à produção robusta de IFN-γ [31]. Foi confirmado
por Chen (2016), que o RELMβ promove ativação de macrófagos e células T, levando ao
14
aumento da inflamação intestinal e à diminuição da resposta imune Th2 [32]. Por outro lado, a
função de RELMβ durante a infecção por helmintos pode ser dependente do parasito [33].
3.4 Enterobíose e inflamação
Para este termo encontrou-se 38 artigos, dos quais 3 foram selecionados de acordo com
os critérios estabelecidos para nossa análise e comparação. No estudo de Panidis e
colaboradores (2011) pode-se observar acentuado número de leucócitos e neutrófilos [34]. Th2
como resposta imune predominante e a elevação de IL-4 e IL-13, notando que IL-13 apresenta
um papel mais dominante que IL-4, ainda, a ausência das citocinas do tipo 1 IFN-γ e IL-12 e a
diminuição dos níveis de IgA-S secretor (SigA) no intestino [35, 36].
3.5 Estrogiloidíase e inflamação
Noventa artigos relacionados ao tema pesquisado foram encontrados, 6 foram
selecionados de acordo com os critérios especificados. Bleay (2007) explica a resposta imune
dos vertebrados a este helminto, mostrando que a resposta é tipicamente uma resposta T-helper
tipo 2 (Th2), ao invés de uma resposta inflamatória do tipo Th1 que é gerada em resposta a
microparasitas. Uma resposta imune do tipo Th2 é caracterizada pela produção das citocinas
IL-4, IL-5, IL-13, IgA e IgE [37], acompanhada de mastócitos intestinais, eosinófilos, células
caliciformes, proliferação de enterócitos e contratilidade intestinal, e ainda secreção de IL-9 por
citocinas Th2, segundo Sipahi (2017). Outras vias acessórias são ativadas, incluindo o aumento
da expressão de células T reguladoras e IL-10 e/ou a transformação dos níveis do fator de
crescimento beta, levando a uma resposta predominantemente anti-inflamatória [38]. Ainda, foi
comprovado por Anuradha (2015) o papel das células T CD4 + na expressão das citocinas Th1,
Th2 e Th17 na infecção humana por S. stercoralis, que demonstrou uma diminuição nas células
funcionais Th1 e Th17 e um aumento nas células funcionais Th2, em comparação com
indivíduos não infectados. A regulação das células Th1, Th2 e Th17 foi predominantemente
dependente da IL-10, enquanto que a regulação das células Th2, mas não Th1 ou Th17, também
foi dependente do TGFβ. Descobriu-se níveis circulantes significativamente menores de
citocinas pró-inflamatórias (interferon gama, fator de necrose tumoral alfa e IL-1) e níveis
significativamente mais altos de citocinas anti-inflamatórias (IL-4, IL-5, IL -9, IL-10, IL-13,
IL-27, IL-37 e TGF-β) [39]. Rajamanickam (2016) também acrescenta marcadores
15
inflamatórios (metaloproteinase da matriz 1 [MMP-1] e heme oxigenase 1 [HO-1]), e citocinas
pró-inflamatórias (IL-6, IL-8, proteína quimioatraente 1 de monócitos [MCP-1] e IL-1β [40]).
Pace (2018) afirma o aumento da produção de Th2 e interleucinas, destacando IL-4
como responsável por ativar o fator de transcrição STAT6 e sua importância clínica [39]. Em
estudo, Reitz (2018), usa camundongos deficientes em receptor de IL-9 infectados
com Strongyloides ratti e comprova que os animais deficientes em receptor de IL-9 exibiram
uma carga parasita intestinal aumentada e uma infecção prolongada. O aumento da carga
parasitária foi correlacionado com uma degranulação precoce reciprocamente reduzida de
mastócitos da mucosa, redução da expressão intestinal de IL-13 causada por deficiência do
receptor de IL-9 em células hematopoiéticas [41].
3.6 Esquistossomose e inflamação
Segundo critérios, esta pesquisa encontrou 598 artigos, dos quais 13 foram utilizados
para os resultados. Estudos comprovam que a infecção produz respostas Th2 maiores, seguidas
por uma resposta Th1 precoce que pode estar associada a uma resposta Th17. A fase aguda da
infecção é caracterizada pela produção de citocinas regulatórias como interleucina (IL)-10, que
é capaz de inibir citocinas pró-inflamatórias como interferon (IFN)-γ, fator de necrose tumoral
(TNF)-α e óxido nítrico (NO) [36, 42, 43]. Estudos anteriores, realizados por MacDonald e
companhia (2002), abordaram a imunorregulação por IL-13 e IL-12, assim como Weinstock
(2014), estudou a supressão da produção de esplenócitos e células do sistema nervoso central
(SNC) de IL12p40, IFNγ e TNFα enquanto aumenta TGFβ, IL10 e IL4 [6, 44].
Rutitzky e colegas (2006) relata células T CD4 pró-inflamatórias produzindo IL-17,
estimuladas pela citocina heterodimérica IL-23, já Smith (2007) fala sobre o mecanismo
dependente de macrófagos, que diverge da modulação das respostas Th2 ou indução por CD4 +,
CD25 +, IL-10 e TGF-β, células imunoreguladoras, os macrófagos detectados neste mecanismo
foram F4/80 + CD11b + CD11c -. Osada (2010) observou uma diminuição da atividade
inflamatória por meio da redução de IFN-γ, TNF-α e IL-17 e do aumento de IL-4 e IL-10 [45,
43, 46].
A infecção por Schistosoma mansoni levou ao aumento da expressão de Resistin-like
alpha (RELMα) no tecido infectado, incluindo celulas inumes inatas, macrófagos e eosinófilos,
que atuaram para suprimir a imunidade Th2, como observado por Chen e Jang (2016, 2015).
Além disso, a formação de granuloma pulmonar induzido pelos ovos do parasito S.
16
mansoni depende da IL-4 e IL-13, que está associado a aumentos acentuados na expressão de
RELMα [32, 23, 24].
O estudo de Pesce (2006), mostra o receptor da IL-21 (IL-21R) significativamente
homologado com o receptor IL-4R, e as células CD4+ e Th2. Mostra-se que a resposta
granulomatosa e a fibrose hepática foram reduzidas em camundongos deficientes desde a
citocina, assim como os que também fazem uso/tratamento com ela, a redução acentuada na
expressão e função das citocinas Th2, como evidenciado pelas respostas atenuadas de IL-4, IL-
13, enzimas clivadoras de quitina (AMCase), quitinase 3-like 3 (Ym1) e FIZZ1 (também
conhecidas como RELMα) nos tecidos, também contribuiram para este resultado clínico. IL-21
apesenta-se como um importate amplificador de ativação alternativa de macrófagos [47], ainda,
Hebert (2004), corrobora com a ideia da importância de macrófagos alternativos para proteção
contra lesão de órgãos através da regulação negativa da inflamação induzida por macrófagos /
neutrófilos ativados por IL-4 / IL-13 durante T H2 respostas. Em estudos in vivo, a IL-10 não é
capaz de compensar a ausência de macrófagos alternativos ativados por IL-4 / IL-13, levando
os camundongos a óbito. Coletivamente, em estudos humanos, os níveis de IFN-γ, NO e TNF-
α mostraram-se altamente elevados, enquanto pacientes com esquistossomose humana
assintomática obtiveram produção elevada de IgE e IL-5 [48].
3.7 Teníase e inflamação
Obteve-se 165 artigos de acordo com a temática, onde 7 foram desiganados para esta
revisão.
No estudo de Nash (2017), foi encontrado fator de necrose tumoral alfa (TNF-α) [49].
Resposta das células T auxiliares Th1 e Th2; IL-2 e interferon-γ sendo produzidas por Th1;
altos níveis de citocinas Th2, como IL-4 (induzindo a produção de IgE) , IL-5 (quimiocina para
recrutamento de eosinófilos) e as metaloproteinases (MMP) em quantidades aumentadas foram
encontradas na resposta inflamatória do hospedeiro para este parasito, segundo Mahanty (2017)
[50]. Além disto, Johnston (2010) observou a ativação de macrófagos: interleucina-1β (IL-1β),
IL-6 e fator de necrose tumoral alfa que são induzidos por lipopolissacarídeo (LPS) TNF-α, e
TNF-α e IL-6 induzidos por poli (I: C) [51].
Adalid-Peralta (2012), analisou a frequência das células T reguladoras (Tregs) e sua
relação com o nível de resposta proliferativa, o nível de linfócitos ativados e as citocinas
expressas em pacientes. Tregs periféricos significativamente aumentados (CD4, CD25, FoxP3,
CTLA4 e IL10 ) e uma diminuição significativa nas células T ativadas (CD38 e CD69 ) foram
17
observadas [52], Arce-Sillas (2016), também estudou os mecanismos de ação das células T
reguladoras no controle da resposta imune. Curiosamente, as células T reguladoras
expressaram níveis mais altos de antígeno linfocitário T citotóxico 4 (CTLA‐ 4), morte
programada 1 (PD‐ 1) e receptor de fator de necrose tumoral induzido por glicocorticóide
(GITR), sugerindo um mecanismo de contato célula a célula com células dendríticas. Além
disso, níveis mais altos de IL‐ 10 e de células T reguladoras tipo 1 (Tr1) foram encontrados no
sangue periférico de pacientes, sugerindo que o mecanismo de ação das células T reguladoras
envolve a liberação de citocinas imunomoduladoras. As células T reguladoras supressivas
correlacionaram-se negativamente com linfócitos ativados tardiamente (CD4 +CD38 + ) [53].
Arce-Sillas e Adalid-Peralta (2018, 2012), reafirmam o trabalho anterior em relação a
maiores porcentagens de Tr1, CD4+, CD25+, FOXP3+, e acrecenta CD127–e, CD4+,
CD45RO+, CTLA4+, FOXP3HI, IL-10 e o papel crítico das células Tregs no equilibrio da
inflamação [54, 52].
18
Quadro 1: Perfil Inflamatório nas parasitoses intestinais.
Parasitose Intestinal Perfil Inflamatório Referências
Ascaridíase Citocinas aumentadas: IL-4, IL-5, IL-13, IL-10, IL-6, IL-33,
eosinófilos, macrófagos e TNF-α redução de IFN-γ. Predomínio de
Th2 e Th17 para a resposta pulmonar.
[11]; [12]; [13]; [14]; [15]; [16]; [17]
Ancilostomíase Aumento de IL-4, IL-5, IL-13, IL-33, IL-10, IL-17, IgE, eosinófilos,
células caliciformes e células dendríticas.
[18]; [19]; [20]; [21]; [22]; [23];
[24]; [25]; [26]; [27]
Tricuríase Aumento de IL-4, TGF -β, IL-35 e IL-10, IL-13, IgE, macrófagos e
redução de IFN-γ. Resposta Th1 incialmente, com predomínio de Th2.
[23]; [28]; [29]; [30]; [31]; [32]; [33]
Enterobiose Aumento de leucócitos e neutrófilos, IL-4, IL-13 e ausência das
citocinas do tipo 1 IFN-γ e IL-12. Predomínio da resposta Th2.
[34]; [35]; [36]
Estrogiloidíase Aumento das citocinas IL-4, IL-5, IL-9, IL-10, IL-13, TGFβ, IgA e
IgE, acompanhada de mastócitos intestinais, eosinófilos, células
caliciformes, proliferação de enterócitos e contratilidade intestinal.
Predomínio da resposta Th2, redução de Th1 e Th17.
[37]; [38]; [39]; [40]; [41]; [32]
Esquistossomose Aumento das citocinas IL-4, IL-5, IL-13, IL-12, IL-10, IL-17,
macrófagos, eosinófilos e redução de IFN-γ, TNF-α e óxido nítrico
(NO). Predomínio de Th2.
[32]; [23]; [24]; [6]; [44]; [36]; [42];
[43]; [45]; [46]; [47]; [48]
Teníase Aumento de TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-1β, IL-6, IL-10, IgE,
eosinófilos e as metaloproteinases. Resposta Th1 e Th2, com
predomínio de Th2.
[50]; [51]; [52]; [53]; [54]
Fonte: Elaborado pelo autor.
19
4 DISCUSSÃO
Nesta revisão foi realizado um apanhado das citocinas e células pró-inflamatórias e anti-
inflamatórias produzidos durante a infecção por helmintos intestinais. Alguns parasitos,
dependendo do tipo e localização, apresentaram células inovadoras ou diferentes em todos os
perfis, o que comprova a diversidade de moléculas que eles produzem e os vários mecanismos
ainda desconhecidos [55]. O fato é que todos os perfis mostraram moléculas em comum,
provando que o mecanismo imunológico para os helmintos é bem semelhante (Figura 2):
ocorreu elevação das citocinas Th2 (IL-4, IL-5, IL-13 e, mais recentemente, IL-21 e IL-25 (IL-
17E)), que podem realmente ser produzidas por uma população Th25. Bloqueio nas citocinas
Th1 (IL-12, IL-17, IFN-γ), eosinofilia, basofilia, mastocitose, elevações na IgE e IgG1,
hiperplasia de células da mucosa, aumento da expressão de células caliciformes e a consequente
inclusão da polarização das células T auxiliares às células Th2 como os macrófagos
alternativamente ativados (AAMΦs) [56].
Figura 2: Resposta imune do hospedeiro a ação de helmintos. Polarização da resposta Th2
e síntese de interleucinas.
Fonte: Elaborado pelo autor.
Recentemente descobriu-se que a IL-17 também faz parte da resposta aos helmintos,
vista para vários perfis, mas principalmente em ancilostomídeos e Ascaris lumbricoides, e
sendo uma citocina bem comum na asma [57]. A IL-17A é uma citocina pró-inflamatória e é o
principal membro de uma família com mais cinco membros adicionais, incluindo IL-17B, IL-
20
17C, IL-17D, IL-17E e IL-17F. Células T produtoras de IL-17 são uma população Th distinta
das células Th1 e Th2. Tanto a IL-17A quanto a F poderiam induzir células epiteliais das vias
aéreas para produzir mediadores pró-inflamatórios, como quimiocinas (CXCL1 e CXCL8), que
podem atrair células inflamatórias (neutrófilos) e citocinas (IL-6), que promovem a ativação
das células Th17. A IL-25 (IL-17E), uma citocina recém-identificada, também aparece no perfil
e é necessária uma elucidação. Ela é produzida principalmente por células Th2, MCs e células
epiteliais. A IL-25 induz a expressão de IL-4, IL-5, IL-9 e IL-13, resultando em inflamação
mediada por eosinófilos e aumento da produção de IgE. A diferenciação aumentada de Th2
mediada por IL-25 requer sinais induzidos por um complexo receptor heterodimérico composto
por IL-17RB e IL-17RA [57, 61].
Outro ponto a ser salientado, é o mecanismo de imunoregulação/imunomodulação, que
é onde ocorre elevação de muitas citocinas como a IL-10 e TGF-β, por exemplo, como visto
nos resultados para vários parasitos. A IL-10 e TGF-β, chamadas células Th3, produzidas por
T CD4+, podem se tornar células T polarizadas e são citocinas imunossupressoras [58].
Os helmintos induzem o sistema imunológico do hospedeiro a produzir citocinas IL-4 e
IL-5, que ativam macrófagos de maneiras distintas dos macrófagos expostos às citocinas
Th1. Esses macrófagos chamados alternativamente ativados exibem um receptor de manose e
de IL-4Ra em suas membranas externas e produzem algumas moléculas únicas como arginase-
1, RELMα, Ym11 e algumas quitinases, mostrando que RELMα e Ym11 caminham junto com
a resposta Th2 e atuam para reduzir a carga parasitária. Embora produzam pouco IL-12, os
macrófagos alternativamente ativados podem tornar a IL-10, TGF-β e outros fatores
imunomoduladores notáveis por limitar a inflamação do tipo Th1 [59].
Os Helmintos são mestres na manipulação das respostas imunes do hospedeiro, usando
uma variedade de mecanismos sofisticados. Um dos principais mecanismos que permitem aos
helmintos estabelecer infecções crônicas é o direcionamento de receptores de reconhecimento
de padrões (PRRs), incluindo receptores Toll-like, receptores de lectina do tipo C e o
inflamassoma, visto, por exemplo, no Ascaris lumbricoides. Dado o papel crítico desses
receptores e suas vias intracelulares na regulação das respostas inflamatórias inatas e também
direcionando a imunidade adaptativa às respostas Th1 e Th2, o reconhecimento das vias
desencadeadas e/ou moduladas pelos helmintos e seus produtos fornecerá informações
detalhadas sobre como os helmintos são capazes de estabelecer um ambiente
imunorregulatório. Contudo, os helmintos também visam mecanismos independentes de PRRs
21
e provavelmente outros mecanismos e vias ainda desconhecidos que sustentam a bateria de
moléculas diferentes que os helmintos produzem [55].
O ciclo celular, revestimento com cutícula espessa, produção de mediadores, produção
de Tregs, variação antigênica e o fato de se alojarem em lugares inacessíveis, aumentam a
susceptibilidade de permanência desses seres [60].
Então, devido ao mecanismo de imunomodulação, acredita-se que produtos secretados
pelos parasitos modulam diretamente as funções imunológicas do hospedeiro e a resposta imune
inata gerada pela infecção poderia amenizar as reações imunopatológicas que conduzem
doenças autoimunes e inflamatórias, como: esclerose múltipla, artrite reumatóide, asma,
diabetes tipo 1, doenças inflamatórias do intestino (doença de Crohn e colite ulcerosa) e outras
doenças. A hipótese ainda levanta a possibilidade de que, pessoas infectadas com helmintos
poderiam ser menos susceptíveis a estas doenças, assim surgindo a possibilidade de uma fonte
inexplorada de medicamentos imunomoduladores ou moléculas que podem servir de modelo
para novos medicamentos [59, 11, 13,14].
5 CONCLUSÃO
Esta revisão abordou uma série de vias moleculares de respostas inflamatórias desenvolvidas a
partir do contato com estes parasitos. O que colabora para melhor entendimento da patogenia
desenvolvida pelos helmintos, bem como, a forma que nosso organismo encontra para
responder às agressões causadas por eles. Além disso, os diversos mecanismos imunológicos e
imurregulatórios envolvidos com os helmintos nos sugerem abordagens alternativas no
desenvolvimento de novos medicamentos, com ênfase em doenças crônicas e inflamatórias,
como por exemplo artrite reumatóide, esclerose múltipla, asma, entre outras.
AGRADECIMENTOS
Agradecemos a Universidade Federal do Rio Grande do Norte e as professoras Ana Claúdia
Galvão Freire Gouveia e Marcela Abbot Galvão Ururahy pelas colaborações.
CONFLITOS DE INTERESSE
Os autores declaram não ter conflitos de interesse.
22
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APÊNDICE – VERSÃO EM INGLÊS
1 INTRODUCTION
Parasitic infections are common events in our country and occur in all age groups and socioeconomic
levels [1]. It has a high prevalence in disadvantaged socioeconomic communities, especially in tropical and
subtropical countries [2], with alterations according to the environment and the parasite species used [3]. Parasitic
diseases, mainly caused by helminths, trigger hundreds of preventable deaths each year and are among the most
recurrent infectious diseases in the world. This is a public health problem with about 3.5 billion people infected
worldwide [2], where Ascaris lumbricoides, cilostomidae and tricuris trichiura infect about 1.450 million, 1.300
and 1.050 million people respectively, while schistosomiasis. intestinal disease affects more than 200 million
people, according to an estimate by who [4].
In Brazil, in 2014, data from the Department of Informatics of the Unified Health System (DATASUS)
show that infectious and parasitic diseases represent a sixth cause of morbidity in the country, totaling 776,358
hospitalizations, which corresponds to 7.28% of morbidity. hospital in the period [5].
Helminths comprise a diverse group of metazoan organisms that infect billions of people and domestic
animals worldwide. Largely as helminthiasis are caused by members of the phylum Nematoda (cylindrical) and
Platyhelminthes (flattened). Species belonging to both phyla occupy numerous niches within their mammalian
hosts, ranging from the small intestine to intravascular and even intracellular sites [6].
Host infection with the parasite generates an inflammatory process, with recruitment of phagocytes,
peripheral blood leukocytes, and plasma proteins at the site of infection. Blood flow and vascular permeability
increase, mainly in the endothelium to allow leukocyte transmigration and the entry of plasma proteins,
complement system, coagulation factors and antibodies [7]. During infection, the immune mechanisms are also
activated as the adaptive or specific immune response, which occurs against microorganisms or antigens
previously recognized by the innate response, with the predominant adaptive response to intestinal parasites. The
innate or nonspecific immune response, which is the host's first line of defense, has pre-existing protection
methods, including natural barriers (skin and mucosa), secretions, neutrophils, macrophages, mast cells and natural
killer cells (NK). Macrophages participate as both antigen presenting cells and effector cells via release of so-
called proinflammatory cytokines (eg, beta transforming growth factor [TGF-β] and Interleukins IL-1, IL-10, IL -
12 and IL-23), chemokines, reactive oxygen species, prostanoid production and extracellular matrix
metalloproteinases [8].
Parasites, particularly helminths, can modulate the immune response and provide an anti-inflammatory
environment that favors their survival within the host organism, that is, suppressing proinflammatory immune
responses to maintain their life cycle. In these infections, although complement and other innate immune response
factors may act in defense, the adaptive or specific immune response predominates with the production of
antibodies and cytokines. Type 2 CD4 + and TCD8 + T cells are cytokine producers such as IL-4, IL-5 and IL-13
which, among other functions, induce B cell production IgE and activation of eosinophils, mast cells and basophils,
respectively. Key components in defense against parasites, regulatory cytokines such as IL-10 and TGF-β are also
present in the response. IgE immunoglobulin class antibodies bind to circulating basophils or tissue mast cells,
inducing the release of histamine and other mediators of the immediate hypersensitivity reaction, which leads to
29
helminth destruction. They also inhibit interferon-gamma (IFN-γ), IL-1 and IL-17 and suppress the inflammatory
immune response of Th1 and Th17 cells [7, 8, 9, 10].
Helminths secrete excretory-secretory (ES) products (Figure 1), such as ES-62, which are glycosylated
and induce Th2 cytokines and regulatory T cell expansion. In addition, the amount of regulatory T cells (CD4 +
CD25 + FOXP3 +) that produce IL-10 and TGF-β increases after helminth infection, contributing to their
permanence within the host organism. Homeostasis generated by these immune responses prevents an exaggerated
reaction against parasites that would also harm the host, ensuring helminth survival [7].
The main objective of this review is to discuss the inflammatory profile in the main intestinal parasites
and the mechanisms that are triggered. This will contribute to the perspective of elucidating pathogenesis
mechanisms and research into new therapeutic alternatives.
Figure 1: Effect of helminth excretory / secretory (ES) products on host immune cells.
Source: (Smallwood et al., 2017).
2 METHODOLOGY
2.1. Election criteria
The selection of studies to be included in this study was based on the following: (1) the study should be
on inflammation due to intestinal parasites; (2) the study must be published in English and Portuguese; (3) studies
should present the inflammatory profile in intestinal parasites; (4) Studies should be published between 1999 and
2019; (5) Studies should not address research with treatments. Exclusion criteria for the purpose of this review
were studies unrelated to inflammation due to intestinal parasites.
30
2.2. Search strategy
The search was electronic, aiming at studies that discussed inflammation due to intestinal parasites. This
produced 1087 references, but only 6 were included in the review using the inclusion / exclusion criteria. Articles
were extracted by electronic search from PubMed, NCBI, LILACS and other relevant journals. Several keywords
used in the search strategy included the following: inflammation, intestinal parasites, inflammatory profile,
intestinal helminths, ascariasis, hookworm, thricuriasis, enterobiasis, stroloidiasis, schistosomiasis and teniasis.
Various keyword combinations were made using “AND” and “OR” as Boolean operators. A practical approach to
inflammation in intestinal parasites arising from this review and the authors' experience is presented here.
3 RESULTS
This review found 1087 articles related to the researched theme, of which 53 were selected according to
the criteria established for our analysis and comparison. At the end of this session, Table 1 summarizes these
findings.
3.1 Ascariasis and inflammation
The review found 43 articles related to the researched theme, where 7 were rejected according to the
election criteria. Weatherhead and co-workers (2018) found increased IL-4, IL-5, IL-13 and slightly elevated IL-
10, resulting in an increase in Type 2 cytokines in contrast to the Th1 response, TNF-α was not noted. or IFN-γ,
meaning a reduction or absence [11]. Zavala et al. (2018) noted IL-10 regulating TNF-α and IL-6 in inflammation
[12]. Gazzinelli-Guimaraes et al. (2019) demonstrated significant increases in IL-4, IL-13, IL-13Rα2, IL-1β and
TNF-α levels, in contrast, levels of IL-5 and IL-6 showed a fairly high pattern. IL-4, IL-13, IL-33, in addition to
marked increases in CCL-11 (eotaxin or eosinophil chemotactic protein), CCL-2 (monocyte chemoattractant
protein 1 or MCP-1) and CXCL-10 ( Interferon gamma-induced protein 10 or IP-10), a small but measurable
accumulation of CD4 + effector Th2 cells, activated eosinophils and alternatively activated macrophages (M2) has
also been found [13]. In a previous study Gazzinelli-Guimaraes (2013) had observed only the increase of IL-5, IL-
6 and TNF-α [14]. Nogueira et al. (2016), in addition to noting the increase in IL-4, IL-5, IL-6, IL-10 and TNF-α
as seen in other studies, also noted the increase in IL-17A and the intense pulmonary inflammation associated with
a polarized systemic Th2 / Th17 immune response during multiple exposures to Ascaris lumbricoides, as this worm
may also develop its pathogenesis in the pulmonary system [15].
Also, Aceved et al. (2013) compared and demonstrated the strong induction of IgE by these parasites in
relation to allergens [16], which was also confirmed by Pitrez and his collaborators (2015) in relation to
eosinophils, as well as production. of IL-10 and the reduction of IL-5 in already sensitized individuals [17].
3.2 Hookworm and inflammation
We found 88 articles, of which 10 were assigned to this review, taking into account the established
criteria. In addition to the innate immune response, interleukins such as IL-33, IL-25, antigen presenting cells
(dendritic cells), and innate lymphoid cells (ILC2) have led to increased release of IL-4, IL-5, and type 2 cytokines.
IL-13, signaled via the IL-4Rα / Stat6 pathway [18, 19]. Damle (2016) highlights IgE production as well as
31
increased mucus production, goblet cell hyperplasia, eosinophilia, and enteric nerve stimulation to facilitate
expulsion of the intestinal worm [20].
Navarro and colleagues (2016) identified a hookworm-secreted protein, anti-inflammatory protein-2
(AIP-2), which suppressed inflammation as well as reduced expression of costimulatory markers in human
dendritic cells (DCs) and suppressed cells. T [21].
Ferreira and colleagues (2017) analyzed the recombinant anti-inflammatory protein (AIP-1), secreted in
abundance by hookworms in the intestinal mucosa and noted that with the presence of the protein local infiltration
of inflammatory cells decreased, showing minimal loss of goblet cells and the mucosal architecture being
preserved. Furthermore, treatment with AIP - 1 promoted the production of interleukins in the IL-10 colon, TGF-
β and thymus stromal lymphopoietin (TSLP), resulting in the suppression of tumor necrosis factor (TNF) -α, IL-
13 and IL-17 A, featuring an accumulation of regulatory T cells in the colon [22].
Jang (2015) also states that Th2 cytokine suppression by RELMα, further adds that resin expression is
an innate response to multiple helminths where it promotes monocyte recruitment and a pro-inflammatory cytokine
type 1 environment decreased helminth clearance and exacerbated inflammation associated with infection [23].
Pesce, Fitzsimmons and colleagues (2009, 2014) suggest that Th2 immunity is increased during helminth
infection [24, 25], just as IL-17 initially contributed to inflammation, while subsequent IL-1 receptor signaling. 4
(IL-4R) reduced elevations in IL-17 mRNA levels, although other studies show that IL-17 mediates the course of
inflammation. IL-10 increased its expression and stimulated the development of M2 macrophages, which
contributed to the rapid resolution of tissue damage [26].
Chenery and colleagues (2019) address an alternative activation marker, alveolar macrophage-derived
Ym1 (Mφs), which may lead to IL-1R receptor-dependent innate neutrophil recruitment during nematode
infection, also discuss increased eosinophilia and inflammasome proteins such as NLRP3, which have an important
pro-inflammatory function [27].
3.3 Trichuriasis and inflammation
In the review, 65 articles were found, of which 7 were elected according to the criteria determined for
our analysis and comparison.
Like Yang (2017), Duque-Correa (2019) initially observed the Th1 response, followed by transforming
growth factor TGF-β, IL-35 and IL-10, macrophages and T cells in response to excretory-secretory parasitic
antigens (ES) [28, 29]. Jang (2015) reaffirms this response by enhancing the balance between Th2 cytokines and
type 1 proinflammatory cytokines such as IFNγ and TNFα, considering the counter-regulation between them. For
example, IFNγ inhibition promotes the expulsion of Trichuris muris, allowing the development of a protective Th2
immune response [23].
Urban et al. (2000), in studies with Trichuris muris-infected mice, blocking B7 ligand interactions,
inhibited protective immunity, suppressed IL-4 production and increased IFN-γ production, but unexpectedly did
not inhibit production. of Th2 cytokine, IL-13. Blocking IFN-γ and B7 restored protective immunity, which
32
depended on IL-13, but did not restore IL-4 or associated IgE responses. Although IL-13 was required for the
expulsion of worms in mice in which IFN-γ and B7 were blocked, IL-4 could mediate expulsion in the absence of
IL-13 and IFN-γ [30].
Nair and colleagues (2008), using a natural model of intestinal inflammation induced by chronic infection
with Trichuris muris gastrointestinal helminth, identified dual functions for RELMβ in enhancing CD4 + Th1 cell
responses and promoting production-associated intestinal inflammation. Robust IFN-γ [31]. It was confirmed by
Chen (2016) that RELMβ promotes macrophage and T-cell activation, leading to increased intestinal inflammation
and decreased Th2 immune response [32]. On the other hand, RELMβ function during helminth infection may be
parasite dependent [33].
3.4 Enterobiosis and inflammation
For this term, 38 articles were found, of which 3 were selected according to the criteria established for
our analysis and comparison.
In the study by Panidis et al. (2011), a marked number of leukocytes and neutrophils can be observed
[34]. Th2 as the predominant immune response and the elevation of IL-4 and IL-13, noting that IL-13 plays a more
dominant role than IL-4, the absence of IFN-γ and IL-12 type 1 cytokines and decrease in secretory IgA-S (SigA)
levels in the intestine [35, 36].
3.5 Estrogiloidiasis and inflammation
90 articles related to the researched topic were found, 6 were selected according to the specified criteria.
Bleay (2007) explains the vertebrate immune response to this helminth, showing that the response is typically a T-
helper type 2 (Th2) response rather than a Th1-type inflammatory response that is generated in response to
microparasites. A Th2-type immune response is characterized by the production of IL-4, IL-5, IL-13, IgA and IgE
[37], accompanied by intestinal mast cells, eosinophils, goblet cells, enterocyte proliferation and intestinal
contractility, as well as IL-9 secretion by Th2 cytokines, according to Sipahi (2017). Other accessory pathways
are activated, including increased expression of regulatory T-cells and IL-10 and / or transformation of growth
factor beta levels, leading to a predominantly anti-inflammatory response [38]. Furthermore, Anuradha (2015)
confirmed the role of CD4 + T cells in the expression of Th1, Th2 and Th17 cytokines in human infection with S.
stercoralis, which demonstrated a decrease in Th1 and Th17 functional cells and an increase in Th2 functional
cells. compared to uninfected individuals. Th1, Th2 and Th17 cell regulation were predominantly IL-10 dependent,
while Th2 cell regulation, but not Th1 or Th17, was also TGFβ dependent. Significantly lower circulating levels
of pro-inflammatory cytokines (interferon gamma, tumor necrosis factor alpha and IL-1) and significantly higher
levels of anti-inflammatory cytokines (IL-4, IL-5, IL-9, IL) were found. -10, IL-13, IL-27, IL-37 and TGF-β) [39].
Rajamanickam (2016) also adds inflammatory markers (matrix metalloproteinase 1 [MMP-1] and heme oxygenase
1 [HO-1]), and proinflammatory cytokines (IL-6, IL-8, monocyte chemoattractant protein 1 [MCP -1] and IL-1β
[40].
Pace (2018) states the increased production of Th2 and interleukins, highlighting IL-4 as responsible for
activating the transcription factor STAT6 and its clinical importance [39]. In a study, Reitz (2018), uses
33
Strongyloides ratti-infected IL-9 receptor deficient mice and proves that IL-9 receptor deficient animals exhibited
increased intestinal parasite burden and prolonged infection. Increased parasitic load was correlated with
reciprocally reduced early degranulation of mucosal mast cells, reduced intestinal IL-13 expression caused by IL-
9 receptor deficiency in hematopoietic cells [41].
3.6 Schistosomiasis and inflammation
According to criteria, this search found 598 articles, of which 13 were used for the results. Studies show
that infection produces higher Th2 responses, followed by an early Th1 response that may be associated with a
Th17 response. The acute phase of infection is characterized by the production of regulatory cytokines such as
interleukin (IL) -10, which is capable of inhibiting proinflammatory cytokines such as interferon (IFN) -γ, tumor
necrosis factor (TNF) -α and nitric oxide (NO) [36, 42, 43]. Previous studies by MacDonald et al. (2002) have
addressed IL-13 and IL-12 immunoregulation, and Weinstock (2014) has studied suppression of IL12p40
splenocytes and central nervous system (CNS) production, IFNγ and TNFα while increasing TGFβ, IL10 and IL4
[6, 44].
Rutitzky and colleagues (2006) report pro-inflammatory CD4 T-cells producing IL-17 stimulated by IL-
23 heterodimeric cytokine. Smith (2007) talks about the macrophage-dependent mechanism that diverges from
modulation of Th2 responses or CD4 induction. +, CD25 +, IL-10 and TGF-β, immunoregulatory cells, the
macrophages detected in this mechanism were F4 / 80 + CD11b + CD11c -. Osada (2010) observed a decrease in
inflammatory activity by reducing IFN-γ, TNF-α and IL-17 and increasing IL-4 and IL-10 [45, 43, 46].
Schistosoma mansoni infection led to increased expression of Resistin-like alpha (RELMα) in infected
tissue, including innate innate cells, macrophages and eosinophils, which acted to suppress Th2 immunity, as noted
by Chen and Jang (2016, 2015) and the formation of pulmonary granuloma induced by S. parasite eggs mansoni
depends on IL-4 and IL-13, which is associated with marked increases in expression RELMα [32, 23, 24].
In the study by Pesce (2006), it shows the IL-21 receptor (IL-21R) significantly homologated with the
IL-4R receptor, and CD4 + and Th2 cells. It is shown that the answer granulomatosa and liver fibrosis have been
reduced in deficient mice since cytokine, as well as those who also use / treat it, the marked reduction in expression
and function of Th2 cytokines, as evidenced by attenuated IL-4 responses, IL-13, chitin-cleaving enzymes
(AMCase), 3-like chitinase 3 (Ym1) and FIZZ1 (also RELMα) in tissues also contributed to this clinical outcome.
IL- 21 appears as an importate alternative macrophage activation amplifier [47], Hebert (2004) also corroborates
the idea of the importance of alternative macrophages for protection against organ damage by down-regulating
inflammation induced by IL-4 / IL-13 activated macrophages / neutrophils during T H2 responses. In studies in
IL-10 is not able to compensate for the absence of alternative macrophages activated by IL-4 / IL-13, leading the
mice to death. Collectively, in human studies, the levels of IFN-γ, NO and TNF-α were highly elevated, while
patients with Asymptomatic human schistosomiasis obtained high IgE and IL-5 production [48].
3.7 Teniasis and inflammation
We obtained 165 articles according to the theme, where 7 were displaced for this review.
34
The study by Nash (2017) found tumor necrosis factor alpha (TNF-α) [49]. Helper T cell response Th1
and Th2; IL-2 and interferon-γ being produced by Th1; high levels of Th2 cytokines, such as IL-4 (inducing IgE
production), IL-5 (chemokine eosinophil recruitment) and metalloproteinases (MMP) in increased amounts were
found in the host inflammatory response to this parasite, according to 18 Mahanty (2017) [50]. In addition,
Johnston (2010) observed macrophage activation: interleukin-1β (IL-1β), IL-6 and tumor necrosis factor alpha
which are induced by lipopolysaccharide (LPS) TNF-α, and poly (I: C) induced TNF-α and IL-6 [51].
Adalid-Peralta (2012) analyzed the frequency of regulatory T cells (Tregs) and their relation to
proliferative response level, activated lymphocyte level and cytokines expressed in patients. Significantly
increased peripheral tregs (CD4, CD25, FoxP3, CTLA4 and IL10) and a significant decrease in activated T cells
(CD38 and CD69) were observed [52], Arce-Sillas (2016), also studied the mechanisms of action of regulatory T
cells in controlling the immune response. Interestingly, the regulatory T cells expressed higher levels of cytotoxic
T lymphocyte antigen 4 (CTLA-4), death 1 (PD-1) and glucocorticoid-induced tumor necrosis factor receptor
(GITR), suggesting a cell-to-cell contact mechanism with dendritic cells. Beyond In addition, higher levels of IL-
10 and type 1 regulatory T cells (Tr1) were found. peripheral blood of patients, suggesting that the mechanism of
action of T cells regulatory processes involves the release of immunomodulatory cytokines. Regulatory T cells
suppressive correlates negatively with late-activated lymphocytes (CD4 + CD38 +) [53].
Arce-Sillas and Adalid-Peralta (2018, 2012), reaffirm previous work in relation to higher percentages of
Tr1, CD4 +, CD25 +, FOXP3 +, and adds CD127 – e, CD4 +, CD45RO +, CTLA4 +, FOXP3HI, IL-10 and the
critical role of Tregs cells in the balance of inflammation [54, 52].
4 DISCUSSION
In this review a survey of cytokines and proinflammatory and antiinflammatory cells for intestinal
helminths was performed. Some parasites, depending on the type and location, presented innovative or different
cells in all profiles, which proves the diversity of molecules they produce and the various mechanisms still
unknown [55]. The fact is that all profiles showed molecules in common, proving that the immune mechanism for
helminths is quite similar (Figure 2): elevation of Th2 cytokines (IL-4, IL-5, IL-13 and, more recently, IL -21 and
IL-25 (IL-17E)), which can actually be produced by a Th25 population. Th1 cytokine blockade (IL-12, IL-17,
IFN-γ), eosinophilia, basophilia, mastocytosis, IgE and IgG1 elevations, mucosal cell hyperplasia, increased goblet
cell expression and the consequent inclusion of cell polarization T helper T cells such as alternatively activated
macrophages (AAMΦs) [56].
35
Figure 2: Host immune response to helminth action. Th2 response polarization and interleukin synthesis.
Source: Prepared by the author.
It has recently been found that IL-17 is also part of the helminth response, various profiles, but mainly hookworms
and Ascaris lumbricoides, and being a very common cytokine in asthma [57]. IL-17A is a proinflammatory
cytokine and is the main member of a family with five additional members, including IL-17B, IL-17C, IL-17D,
IL-17E and IL-17F. IL-17 producing T cells are a Th population distinct from Th1 and Th2 cells. Both IL-17A
and F could induce epithelial cells airways to produce pro-inflammatory mediators such as chemokines (CXCL1
and CXCL8), which can attract inflammatory cells (neutrophils) and cytokines (IL-6), which promote activation
of Th17 cells. IL-25 (IL-17E), a newly identified cytokine, also appears on the profile and clarification is required.
It is mainly produced by Th2 cells, MCs and epithelial cells. IL-25 induces the expression of IL-4, IL-5, IL-9 and
IL-13, resulting in eosinophil-mediated inflammation and increased IgE production. THE IL-25-mediated
enhanced Th2 differentiation requires complex-induced signals heterodimeric receptor composed of IL-17RB and
IL-17RA [57, 61]. Another point to note is the immunoregulation / immunomodulation mechanism, which is where
elevation of many cytokines such as IL-10 and TGF-β occurs, for example as seen in the results for various
parasites. IL-10 and TGF-β, called Th3 cells, produced by CD4 + T, can become polarized T cells and are cytokines
immunosuppressive drugs [58].
Helminths induce host immune system to produce IL-4 cytokines and IL-5, which activate macrophages
in different ways than cytokine-exposed macrophages Th1. These so-called alternatively activated macrophages
exhibit a mannose receptor and IL-4Ra in their outer membranes and produce some unique molecules like
arginase-1, RELMα, Ym11 and some chitinases, showing that RELMα and Ym11 walk together with the Th2
response and act to reduce the parasitic load. Although they produce little IL-12, alternatively activated
macrophages can render IL-10, TGF-β and other factors immunomodulators notable for limiting Th1-type
inflammation [59].
Helminths are masters at manipulating host immune responses using a variety of sophisticated
mechanisms. One of the main mechanisms enabling helminths establish chronic infections is the targeting of
recognition receptors (PRRs) including Toll-like receptors, C-type lectin receptors and inflammasome, seen, for
36
example, in Ascaris lumbricoides. Given the critical role of these receptors and their intracellular pathways in
regulating innate inflammatory responses and also directing adaptive immunity to Th1 and Th2 responses,
recognition of the pathways triggered and / or modulated by the helminths and their products will provide how
helminths are able to establish an environment immunoregulatory. However, helminths also target independent
mechanisms of PRRs and probably other yet unknown mechanisms and pathways that support the battery of
different molecules that helminths produce [55].
Cell cycle, thick cuticle coating, mediator production, Tregs, antigenic variation and staying in
inaccessible places susceptibility of permanence of these beings [60].
So, due to the immunomodulation mechanism, it is believed that secreted products by parasites directly
modulate host immune functions and host response innate immune system generated by the infection could
alleviate the immunopathological reactions that lead autoimmune and inflammatory diseases such as multiple
sclerosis, rheumatoid arthritis, asthma, type 1 diabetes, inflammatory bowel disease (Crohn's disease and ulcerative
colitis) and other diseases. The hypothesis further raises the possibility that people infected with 23 helminths
could be less susceptible to these diseases, thus giving rise to the possibility of an untapped source of
immunomodulatory drugs or molecules that may serve of model for new drugs [59, 11, 13,14].
5 CONCLUSION
Helminths infect billions of people worldwide, developing infections with complex inflammatory responses. This
review addressed a number of molecular pathways of inflammatory responses developed from contact with these
parasites. This approach discussed here contributes to a better understanding of the pathogenesis developed by
helminths, as well as the way our bodies find to respond to the aggressions caused by them. In addition, the various
immunological and immunoregulatory mechanisms involved with helminths suggest alternative approaches to the
development of new drugs, with emphasis on chronic and inflammatory diseases, such as rheumatoid arthritis,
multiple sclerosis, asthma, among others.
ACKNOWLEDGMENT
Credit to the Federal University of Rio Grande do Norte and professors Ana Claudia Galvao Freire Gouveia and
Marcela Abbot Galvao Ururahy for their contributions.
INTEREST CONFLICTS
The authors declare no conflicts of interest.
37
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