4. SISTEMA IMUNE 1 Generalidades
4.6. Linfócitos T
Os linfócitos T subdividem-se em diferentes populações, de entre as quais os linfócitos T citotóxicos (Tc), os linfócitos T auxiliares/helper (Th), os linfócitos T γδ e os linfócitos T Natural Killer (NKT)178.
Os linfócitos Tc favorecem a necrose dos hepatócitos, por intermédio de citocinas pró-inflamatórias, entre as quais, o TNF-α, a perforina e a granzima179
(Figura 12).
O grupo dos linfócitos Th pode ser subdividido em Th1 e Th2. Os linfócitos Th1 caracterizam-se por um perfil de citocinas pró-inflamatórias, tendo como exemplo o interferão-γ (IFN- γ). No outro espetro, temos os linfócitos Th2 que
segregam citocinas anti-inflamatórias, como as interleucinas (IL) 4, 5 e 13178. A
sobrevida é superior quando favorecida laboratorialmente a resposta Th2, em relação à resposta Th1180.
As células de Kupffer ativam a população de linfócitos T γδ, com recurso à libertação da interleucina-23 (IL-23). Por sua vez, os linfócitos T γδ têm a
capacidade de chamar neutrófilos para o local de necrose, servindo-se da interleucina-17 (IL-17)181.
Wang X et al observaram um efeito hepatotóxico, em que a depleção farmacológica de linfócitos T γδ levou à atenuação da lesão hepática182.
As células de Kupffer são capazes de chamar os NKT por quimiotaxia, através da secreção de chemokine C-X-C motif ligand 16 (CXCL16)183. A ativação dos
NKT despoleta a secreção de interleucina-4 (IL-4) e de IFN-γ. A IL-4 tem o poder de conseguir ativar os neutrófilos, enquanto o IFN-γ tem o poder de os inibir184.
Ainda assim, o IFN-γ é uma citocina pró-inflamatória que contribui para a necrose
dos hepatócitos185.Neste caso, os NKT são o tipo de linfócitos T mais frequente
que existem em volta dos sinusóides hepáticos186.
Martin-Murphy BV et al constataram o efeito protetor das NKT, utilizando o knockout destas células que se associou a um aumento dos níveis das transaminases hepáticas e da mortalidade187.
No entanto, Liu ZX et al verificaram o efeito oposto, utilizando anticorpos anti- NKT, registou-se uma diminuição das transaminases hepáticas, da necrose dos hepatócitos, enquanto a mortalidade foi superior à do grupo controlo188. Todavia,
Masson MJ et al replicaram a mesma experiência, utilizando um solvente diferente nas preparações, e não conseguiram observar estas diferenças189.
À imagem dos NKT, as células Natural Killer (NK) também libertam IFN-γ, para além de outras citocinas pró-inflamatórias, como o TNF-ɑ, a perforina e
granzima. Apesar disso, as NK segregam igualmente citocinas anti-inflamatórias, tal como a IL-10190.
O estudo de Liu ZX et al que revelou a hepatotoxicidade das NKT188 e o estudo
de Masson et al que não observou diferenças significativas alterando o solvente utilizado revelaram os mesmos resultados para as NK189.
5. CONCLUSÕES
Em suma, a toxicidade hepática provocada pela intoxicação pelo paracetamol assenta na disfunção das mitocôndrias dos hepatócitos, que combinada com a destruição subsequente do material genético nuclear, origina a necrose hepatocitária. Em paralelo, a disfunção mitocondrial é capaz de ativar diversas vias de sinalização complementares que interagem, positiva ou negativamente, em diferentes passos deste mecanismo.
Após a necrose dos hepatócitos, são chamados distintos tipos de células efetoras do sistema imune, cujo papel na proteção ou potenciação do dano hepático permanece controverso.
Nesta revisão, possíveis alvos farmacológicos foram explorados e, com o aumento dos estudos nesta matéria, espera-se que surjam cada vez mais e melhores estratégias terapêuticas para lidar com uma etiologia de insuficiência hepática tão prevalente no Mundo desenvolvido.
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