Stevens David A
Department of Medicine, Santa Clara Valley Medical Center and Stanford University Medical School, San Jose and Stanford, California, USA.
Med Mycol. 2006 Sep 1;44(Supplement_1):S229-S235. doi: 10.1080/13693780600760773.
The outcome of the Th1/Th2 balance is a critical determinant of the outcome in invasive aspergillosis. The innate immune system encounters the pathogen first. Dendritic cells (DC) appear to be the critical fulcrum at the intersection of the innate immune system, and which receptors are engaged, particularly which Toll-like receptors are triggered by the pathogen, likely determines which co-stimulatory molecules are expressed during the DC maturation process, and thus which cytokine pathway will eventually dominate. Some proinflammatory cytokines initially produced by naïve phagocytes may also direct dendritic cell direction. Thus DC are the main connections of the innate and adaptive immune systems. The cytokine pathway may be affected by the antigen load, whether and what type of immunosuppressive drug or immunosuppressive co-morbidity is present, the pathogen's success in converting from conidia to hyphae, the pathogen's production of toxins, and later whether appropriate antimicrobial chemotherapy is given. Chemokines triggered by cellular interaction with the pathogen call different host cell populations to the site of infection, collectins affect the phagocyte-fungus interaction, and the cytokines produced by the adaptive immune system then regulate the antifungal power of mononuclear phagocytes and polymorphonuclear neutrophils. In these ways the innate and adaptive immune systems work together in host defense. The key cytokines associated with a successful outcome of Aspergillus infection are upregulation of Th1 and proinflammatory cytokines IFNγ, TNFα, IL-12, GM-CSF, IL-1, IL-6 and IL-18, and down-regulation of IL-4 and IL-10. The converse is associated with progressive disease. The most data about favorable cytokine effects on phagocytes vs. Aspergillus concerns IFNγ, GM-CSF and G-CSF, and for unfavorable effects, IL-10 and IL-4. GM-CSF and IFNγ have also been shown to possess the ability to reverse the down-regulating effects of immunosuppressants on anti-Aspergillus phagocyte function. Neutralization of several Th1 cytokines in vivo has been shown directly to result in a bad outcome of infection, whereas administering Th1 or proinflammatory cytokines or neutralizing Th2 cytokines has been shown to produce a favorable outcome. Antifungal chemotherapy is associated with a switch to a Th1 profile, and antifungal chemotherapy combined with Th1 cytokine immunotherapy acts synergistically. Thus improved definition of the Th1/Th2 balance is essential for future prospects for immunotherapy, antimicrobial chemotherapy, and vaccination.
Th1/Th2平衡的结果是侵袭性曲霉病预后的关键决定因素。固有免疫系统首先接触病原体。树突状细胞（DC）似乎是固有免疫系统交叉点上的关键支点，所涉及的受体，特别是病原体触发的哪些Toll样受体，可能决定了DC成熟过程中表达哪些共刺激分子，进而决定最终哪种细胞因子途径将占主导地位。初始吞噬细胞最初产生的一些促炎细胞因子也可能指导树突状细胞的走向。因此，DC是固有免疫系统和适应性免疫系统的主要连接点。细胞因子途径可能受到抗原负荷、是否存在以及何种类型的免疫抑制药物或免疫抑制合并症、病原体从分生孢子转化为菌丝的成功情况、病原体毒素的产生，以及后期是否给予适当的抗微生物化疗的影响。细胞与病原体相互作用触发的趋化因子将不同的宿主细胞群体召集到感染部位，凝集素影响吞噬细胞与真菌的相互作用，然后适应性免疫系统产生的细胞因子调节单核吞噬细胞和多形核中性粒细胞的抗真菌能力。通过这些方式，固有免疫系统和适应性免疫系统在宿主防御中协同工作。与曲霉感染成功预后相关的关键细胞因子是Th1和促炎细胞因子IFNγ、TNFα、IL-12、GM-CSF、IL-1、IL-6和IL-18的上调，以及IL-4和IL-10的下调。相反的情况则与疾病进展相关。关于细胞因子对吞噬细胞与曲霉的有利影响，数据最多的是IFNγ、GM-CSF和G-CSF，而关于不利影响的数据最多的是IL-10和IL-4。GM-CSF和IFNγ也已被证明具有逆转免疫抑制剂对抗曲霉吞噬细胞功能的下调作用的能力。体内几种Th1细胞因子的中和已被直接证明会导致感染预后不良，而给予Th1或促炎细胞因子或中和Th2细胞因子已被证明会产生有利的结果。抗真菌化疗与向Th1型转变相关，抗真菌化疗与Th1细胞因子免疫疗法联合使用具有协同作用。因此，更明确地界定Th1/Th2平衡对于免疫疗法、抗微生物化疗和疫苗接种的未来前景至关重要。
