流感病毒免疫學

Immunity to Influenza Viruses

流感病毒是最常感染人類的病毒之一，它主要造成急性呼吸道症狀，雖然通常相當輕微，但也有少數例外，如1918 年西班牙流感，以及近年來高致病性的H5N1 禽流感，會造成嚴重的肺部傷害，甚至導致死亡。預防流感首推疫苗，目前的去活性流感疫苗雖能有效地誘發中和抗體對抗流感病毒，但由於流感病毒易於突變，所以常會造成抗體失效，這也是為何疫苗常需要每年施打，以及宿主常會反覆感染不同種或不同亞型流感病毒的主要原因。本篇文章，在介紹流感病毒的免疫反應，包括先天與後天的免疫反應，以及免疫反應如何清除病毒。此外，過度的免疫反應也會造成宿主肺部組織的傷害。宿主的先天免疫系統，位居第一線控制病毒感染，包括發炎細胞（如肺部巨噬細胞與樹突細胞）與一些誘發發炎反應的分子或細胞素。先天免疫系統透過不同能辨識病原體特殊分子標記的受器，如Toll-like receptor（TLR）、RIG-I-like receptor （RLR）、以及Nod-like receptor（NLR）去偵測流感病毒的感染，誘發先天免疫反應，並產生細胞素，其中最重要的是第一型干擾素。先天免疫反應並不只單純在初期控制病毒的複製，它也會影響後天免疫反應的品質與強度。流感病毒的後天免疫反應，包括了B 細胞分泌中和抗體，阻絕病毒表面蛋白與宿主受器的結合，以阻止病毒進入宿主細胞內；以及T 細胞免疫力，尤其是CD8 T 細胞免疫力，能清除受感染的細胞。T細胞免疫力能辨識流感病毒內部蛋白的抗原部位，這些內部蛋白基因於不同種或亞型的流感病毒間變異較小，所以T 細胞免疫力往往能對不同種甚至是不同亞型的流感病毒具有交叉保護作用，也因此T細胞疫苗被認為有潛力發展成為廣效性疫苗。了解病毒的免疫反應與致病機轉，能幫助我們發展更好的疫苗，以應付未來可能再發生的流感病毒大流行。理想的疫苗必須能誘發有效的免疫記憶反應，尤其是記憶T 細胞的建立，但要避免造成宿主組織的免疫傷害。

Influenza virus is one of the most common viruses infecting human beings. Although it often causes acute and mild respiratory symptoms, it sometimes can induce severe lung injury. For instance, 1918 Spanish flu and high pathogenic avian influenza virus (H5N1) are two examples that influenza infection can cause severe morbidity and even death. Vaccination is the best strategy for prevention of influenza virus infection. Current inactivated vaccine can induce robust neutralizing antibody against specific influenza strains. However, because of its mutation-prone nature, influenza virus can easily escape from antibody attack. This review introduces the immune responses stimulated by infection of influenza virus, including innate and adaptive immunity, and how host immunity can eradicate virus. We also discuss the immunopathology caused by over-reactive immune responses. The innate immunity is the first-line host defense against influenza infection, including certain inflammatory cells, like macrophages and dendritic cells, cytokines and cellular receptors that recognize specific molecular signatures of pathogens. Influenza virus can trigger three classes of innate receptors, the Toll-like receptor(TLR), RIG-I-like receptor(RLR) and Nod-like receptor(NLR) that result in production of proinflammatory cytokines and activation of innate immune responses. Among the induced cytokines, type I interferon is the most important. The innate immunity not only controls early viral replication, but also determines the quality and strength of the adaptive immunity. The adaptive immunity against influenza infection includes B cell-secreted neutralizing antibodies and T cell immunity, particularly, CD8 T cell immunity which is responsible for viral clearance. T cells recognize the epitopes of conserved viral internal proteins, hence exhibit the potential for inducton of immune responses against different strains or subtypes of influenza virus. Understanding the immune responses and immunopathology caused by influenza infection can help develop ideal vaccine that can stimulate robust immune responses but avoid causing host damage in order to cope with the potential threat of future influenza pandemics.