Refractory celiac disease (RCD) encompasses biologically heterogeneous disorders that develop in a small proportion (0.3%) of individuals with celiac disease that are associated with high morbidity. Two broad categories are currently recognized, type I (RCD I) and type II (RCD II), based on immunophenotypic and molecular features of the intraepithelial lymphocytes (IELs). RCD I is characterized by a polyclonal expansion of IELs displaying a normal immunophenotype, while RCD II represents a clonal proliferation of immunophenotypically “aberrant” IELs, and is considered a low-grade lymphoproliferative disorder. The pathogenesis of RCD I has not been clarified, but limited studies suggest multifactorial etiology. On the other hand, recent immunologic, molecular and immunophenotypic analyses have proposed lineage-negative innate IELs to be the cell of origin of a proportion of RCD II cases. Furthermore, sequencing studies have identified frequent, recurrent, activating mutations in members of the JAK-STAT pathway in RCD II. This finding, in conjunction with prior in vitro experimental observations, suggests roles of deregulated cytokine signaling in disease pathogenesis. In this review, we describe current understanding of environmental, immune and genetic factors associated with the development of RCD and briefly discuss diagnostic and therapeutic considerations.

难治性乳糜泻 (RCD) 包括在与高发病率相关的一小部分 (0.3%) 患有乳糜泻的个体中发生的生物学异质性疾病。根据上皮内淋巴细胞 (IEL) 的免疫表型和分子特征，目前公认的两大类是 I 型 (RCD I) 和 II 型 (RCD II)。RCD I 的特征是显示正常免疫表型的 IEL 的多克隆扩增，而 RCD II 代表免疫表型“异常” IEL 的克隆增殖，被认为是一种低度淋巴增殖性疾病。RCD I 的发病机制尚未阐明，但有限的研究表明多因素病因。另一方面，最近的免疫学，分子和免疫表型分析表明，谱系阴性的先天 IEL 是部分 RCD II 病例的起源细胞。此外，测序研究已经确定了 RCD II 中 JAK-STAT 通路成员中频繁、反复、激活的突变。这一发现与之前的体外实验观察结果相结合，表明失调的细胞因子信号传导在疾病发病机制中的作用。在这篇综述中，我们描述了当前对与 RCD 发展相关的环境、免疫和遗传因素的理解，并简要讨论了诊断和治疗方面的考虑。结合先前的体外实验观察，表明失调的细胞因子信号传导在疾病发病机制中的作用。在这篇综述中，我们描述了当前对与 RCD 发展相关的环境、免疫和遗传因素的理解，并简要讨论了诊断和治疗方面的考虑。结合先前的体外实验观察，表明失调的细胞因子信号传导在疾病发病机制中的作用。在这篇综述中，我们描述了当前对与 RCD 发展相关的环境、免疫和遗传因素的理解，并简要讨论了诊断和治疗方面的考虑。