Gill Tejpal, Rosenbaum James T
Division of Arthritis and Rheumatic Diseases, Department of Medicine, Oregon Health & Science University, Portland, OR, United States.
Departments of Ophthalmology, Medicine, and Cell Biology, Oregon Health & Science University, Portland, OR, United States.
Front Immunol. 2021 Jan 18;11:586494. doi: 10.3389/fimmu.2020.586494. eCollection 2020.
Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.
脊柱关节炎（SpA）是一组免疫介导的炎症性疾病，与主要组织相容性（MHC）I类分子HLA - B27密切相关。尽管HLA - B27与强直性脊柱炎（AS）之间的关联已为人所知近50年，但疾病发病机制背后的原因仍不清楚。多年来，人们提出了三种假说来解释HLA - B27与疾病的关联：1）HLA - B27呈递致关节炎肽，从而引发病理性免疫反应；2）HLA - B27错误折叠导致内质网（ER）应激，进而激活未折叠蛋白反应（UPR）；3）HLA - B27在细胞表面二聚化，并作为自然杀伤（NK）细胞的靶标。这些假说均不能完全解释SpA的发病机制。有证据支持HLA - B27相关疾病具有微生物发病机制这一假说。在各种SpA的动物模型中，无菌环境可消除疾病发展，而用肠道共生微生物定殖这些动物可恢复疾病表现。由于我们能够使用下一代测序方法对肠道中的微生物群落进行表征，因此已经认识到微生物对SpA发展的影响程度。在这篇综述中，我们将讨论HLA - B27相关疾病发病机制中各种假定的致病共生菌。我们探究单一的致病共生菌或微生物群落及功能的破坏是否与HLA - B27相关疾病有关。此外，各种疾病相关微生物的代谢功能可能是关键，而不是特定的致病共生菌。虽然使用SpA的无菌模型有助于理解微生物在疾病发展中的作用，但未来使用模拟多种微生物群落而非单一定殖的动物模型进行研究是必不可少的。我们讨论疾病发病机制背后的因果机制，包括这些致病共生菌在粘蛋白降解、粘膜粘附以及肠道上皮屏障破坏和炎症中的作用。最后，我们综述微生物作为治疗手段的各种用途，包括益生元/益生菌、饮食、微生物代谢产物和粪便微生物群移植。揭示这些复杂的宿主 - 微生物相互作用将有助于开发新的靶点/疗法，以缓解SpA和其他HLA - B27相关疾病。
