Hematianlarki Marjan, Nimmerjahn Falk
Division of Genetics, Department of Biology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Immunol Rev. 2024 Nov;328(1):372-386. doi: 10.1111/imr.13404. Epub 2024 Sep 27.
Antibodies provide an essential layer of protection from infection and reinfection with microbial pathogens. An impaired ability to produce antibodies results in immunodeficiency and necessitates the constant substitution with pooled serum antibodies from healthy donors. Among the five antibody isotypes in humans and mice, immunoglobulin G (IgG) antibodies are the most potent anti-microbial antibody isotype due to their long half-life, their ability to penetrate almost all tissues and due to their ability to trigger a wide variety of effector functions. Of note, individuals suffering from IgG deficiency frequently produce self-reactive antibodies, suggesting that a normal serum IgG level also may contribute to maintaining self-tolerance. Indeed, the substitution of immunodeficient patients with pooled serum IgG fractions from healthy donors, also referred to as intravenous immunoglobulin G (IVIg) therapy, not only protects the patient from infection but also diminishes autoantibody induced pathology, providing more direct evidence that IgG antibodies play an active role in maintaining tolerance during the steady state and during resolution of inflammation. The aim of this review is to discuss different conceptual models that may explain how serum IgG or IVIg can contribute to maintaining a balanced immune response. We will focus on pathways depending on the IgG fragment crystallizable (Fc) as pre-clinical data in various mouse model systems as well as human clinical data have demonstrated that the IgG Fc-domain recapitulates the ability of intact IVIg with respect to its ability to trigger resolution of inflammation. We will further discuss how the findings already have or are in the process of being translated to novel therapeutic approaches to substitute IVIg in treating autoimmune inflammation.
抗体为抵御微生物病原体感染和再感染提供了至关重要的保护层面。产生抗体的能力受损会导致免疫缺陷，因此需要持续用健康供体的混合血清抗体进行替代治疗。在人类和小鼠的五种抗体同种型中，免疫球蛋白G（IgG）抗体是最有效的抗微生物抗体同种型，这归因于其较长的半衰期、几乎能穿透所有组织的能力以及触发多种效应功能的能力。值得注意的是，患有IgG缺乏症的个体经常产生自身反应性抗体，这表明正常的血清IgG水平也可能有助于维持自身耐受性。事实上，用来自健康供体的混合血清IgG组分替代免疫缺陷患者，即静脉注射免疫球蛋白G（IVIg）治疗，不仅能保护患者免受感染，还能减轻自身抗体诱导的病理变化，这提供了更直接的证据，表明IgG抗体在稳态和炎症消退过程中维持耐受性方面发挥着积极作用。本综述的目的是讨论不同的概念模型，这些模型可能解释血清IgG或IVIg如何有助于维持平衡的免疫反应。我们将重点关注依赖于IgG可结晶片段（Fc）的途径，因为各种小鼠模型系统中的临床前数据以及人类临床数据都表明，IgG Fc结构域在触发炎症消退的能力方面重现了完整IVIg的能力。我们还将进一步讨论这些发现已经如何或正在如何转化为替代IVIg治疗自身免疫性炎症的新治疗方法。
