总结：强调了本文是从时间（病程，不同疾病阶段）、空间（不同组织器官）角度去分析PSC的发病机制。从时间角度来看，大部分的研究主要集中在PSC诊断后及进展期（终末期），而关于PSC临床前阶段或者移植后复发的研究较少。从空间角度来讲，则包括PSC患者在肝、胆管、肠、血液中的疾病特点。另外，男女均可患PSC，儿童、成年均可见，但是具有遗传异质性，且主要好发于30岁以上的男性，是否能够从免疫学机制来解释这一现象还有待探讨。不同组织结构中免疫系统的组成和功能各异，免疫系统在各组织结构中的相互作用促进了PSC的发生发展。最后，疾病的严重程度、复发性细菌性胆管炎、血清IgG4增高、大胆管或小胆管的累积、自身免疫性肝炎存在等都体现了遗传异质性，从免疫学角度来解释PSC遗传异质性也是一个值得探讨的问题。
We propose that the current immunobiological knowledge of PSC, to a greater extent, is placed into the context of time, space, and clinical presentation of the disease for improved interpretation (Figure 2). The time of study/sampling regarding the clinical course of the disease is an important aspect as PSC progression is observed over the course of several decades and can lead to a variable degree of fibrosis and multifocal biliary strictures.
To date, most of the immunobiological knowledge, out of necessity, is from the time window of “post-diagnosis" to “end-stage disease”(Figure 2). Studying preclinical onset as well as posttransplant recurrent disease will likely provide additional key insights to better understand disease etiology and progression. While posttransplant recurrent disease will be easier to target in translational study designs, identifying cohorts of patients before the disease presents poses a challenge. However, clever usage of historical biobanks (serum and biopsies), patients with lBD who later present with PSC-lBD, as well as ongoing(or future) large population-based studies (UK Biobankand similar efforts), should likely yield translational opportunities, especially since novel technologies (proteomics, scRNAseq, and spatial methods)now permit detailed and broad analysis on for instance formal-fixed tissue.
Furthermore, although PSC is mostly studied and managed as a single disease entity, its clinical presentation and progression are heterogeneous, which should be looked upon when placing immunobiological knowledge into context.Indeed, PSC can affect both sexes, and the age at disease onset can span from childhood to late adulthood. These aspects might be of importance as both age and sex are associated with differences in the composition and function of the immune system.[158,159] To date, limited immunological knowledge is available on these aspects to understand the predominance of PSC diagnosis in males in their 30s.
Regarding the spatial component of the disease, a large proportion of patients also have lBD with specific characteristics, as well as a high risk of developing cancer both in the biliary tract and the colon. As we know it today, the composition and function of the immune system vary in each tissue and evolve with age.[160] Knowledge provided from the liver and the gut has revealed complementary immunological views of PSC. This highlights the need for looking at various tissue niches to better understand the complex interplay between tissues driving PSC pathogenesis. Beyond space at the organ level, technological development now also allows for spatial assessment of RNA, proteins, and metabolites at the single-cell level in situ.[5] As discussed above, such efforts have already yielded novel insights into PSC pathogenesis, and it is clear that the biliary niche is distinct from that of the liver parenchyma.[5,9] Future work will likely benefit from an even greater consideration of events occurring within micro-niches.
Finally, the heterogeneity of PSC is driven by additional features such as the levels of severity of disease, secondary effects of the presence of high-grade strictures, recurrent bacterial cholangitis, circulating lgG4, the involvement of small or large bile duct, or the presence of autoimmune hepatitis features. Immunological investigations are needed to better dissect these PSC subtypes. Specifically, as the portfolio of immunotherapeutic agents is expanding, immunobiological knowledge placed in the context of time, space, and heterogeneity of PSC might provide future options for precision medicine.
