Molecular Immunity Unit, Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge, UK.
The Francis Crick Institute, London, UK.
Scand J Immunol. 2022 Feb;95(2):e13139. doi: 10.1111/sji.13139. Epub 2022 Jan 12.
The gastrointestinal tract is colonized by trillions of commensal microorganisms that collectively form the microbiome and make essential contributions to organism homeostasis. The intestinal immune system must tolerate these beneficial commensals, whilst preventing pathogenic organisms from systemic spread. Humoral immunity plays a key role in this process, with large quantities of immunoglobulin (Ig)A secreted into the lumen on a daily basis, regulating the microbiome and preventing bacteria from encroaching on the epithelium. However, there is an increasing appreciation of the role of IgG antibodies in intestinal immunity, including beneficial effects in neonatal immune development, pathogen and tumour resistance, but also of pathological effects in driving chronic inflammation in inflammatory bowel disease (IBD). These antibody isotypes differ in effector function, with IgG exhibiting more proinflammatory capabilities compared with IgA. Therefore, the process that leads to the generation of different antibody isotypes, class-switch recombination (CSR), requires careful regulation and is orchestrated by the immunological cues generated by the prevalent local challenge. In general, an initiating signal such as CD40 ligation on B cells leads to the induction of activation-induced cytidine deaminase (AID), but a second cytokine-mediated signal determines which Ig heavy chain is expressed. Whilst the cytokines driving intestinal IgA responses are well-studied, there is less clarity on how IgG responses are generated in the intestine, and how these cues might become dysfunctional in IBD. Here, we review the key mechanisms regulating class switching to IgA vs IgG in the intestine, processes that could be therapeutically manipulated in infection and IBD.
胃肠道定植着数万亿种共生微生物，这些微生物共同构成了微生物组，对机体稳态起着至关重要的作用。肠道免疫系统必须耐受这些有益的共生微生物，同时防止病原体向全身扩散。体液免疫在这个过程中起着关键作用，大量免疫球蛋白（Ig）A 每天分泌到腔中，调节微生物组，防止细菌侵袭上皮细胞。然而，人们越来越认识到 IgG 抗体在肠道免疫中的作用，包括在新生儿免疫发育、病原体和肿瘤抵抗中的有益作用，但也包括在炎症性肠病（IBD）中驱动慢性炎症的病理作用。这些抗体同型在效应功能上有所不同，与 IgA 相比，IgG 具有更强的促炎能力。因此，导致不同抗体同型（类别转换重组（CSR））产生的过程需要仔细调节，并由流行的局部挑战产生的免疫信号来协调。一般来说，B 细胞上的 CD40 配体等起始信号会诱导激活诱导胞苷脱氨酶（AID），但第二个细胞因子介导的信号决定了哪种 Ig 重链表达。虽然驱动肠道 IgA 反应的细胞因子已经得到了很好的研究，但对于 IgG 反应在肠道中的产生方式以及这些信号在 IBD 中如何变得失调的了解较少。在这里，我们综述了调节肠道中 IgA 与 IgG 类别转换的关键机制，这些机制可能在感染和 IBD 中进行治疗性干预。
