Pôle de Pathologies Rhumatismales Systémiques et Inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
INSERM U1227, UFR Médecine, Brest, France.
Clin Rev Allergy Immunol. 2017 Oct;53(2):181-197. doi: 10.1007/s12016-017-8605-8.
Biases in the distribution and phenotype of T, B, and antigen-presenting cell populations are strongly connected to mechanisms of disease development in mouse models of systemic lupus erythematosus (SLE). Here, we describe longitudinal changes in lymphoid and antigen-presenting cell subsets in bone marrow, blood and spleen from two lupus-prone strains (MRL/lpr and B6.Sle1.Sle2.Sle3 tri-congenic mice), and how they integrate in our present understanding of the pathogenesis of the disease. In particular, we focus on (autoreactive) T cell activation patterns in lupus-prone mice. Break of T cell tolerance to chromatin constituents (histone peptides) is key to the development of the disease and is related to T cell intrinsic defects, contributed by genetic susceptibility factors and by extrinsic amplificatory mechanisms, in particular over-stimulation by antigen-presenting cells. We also describe shifts in B cell sub-populations, going from skewed immature B cell populations as an indication of disturbed central and peripheral tolerance checkpoints, to enriched long-lived plasma cells, which are key to persistent autoantibody production in the disease. B cell activation mechanisms in SLE are both T cell-dependent (break of tolerance and production of specific autoantibodies) and -independent (polyclonal B cell activation, production of autoantibodies by long-lived plasma cells). By providing a comprehensive evaluation of B and T cell surface markers in two major mouse models of SLE and a description of their changes before and after disease onset, this review illustrates how the study of lymphoid cell phenotype delivers key information regarding pathogenic pathways and supplies tools to assess the beneficial effects of novel therapeutic interventions.
T、B 和抗原呈递细胞群体在分布和表型上的偏倚与系统性红斑狼疮（SLE）小鼠模型中疾病发展的机制密切相关。在这里，我们描述了两种狼疮易感株（MRL/lpr 和 B6.Sle1.Sle2.Sle3 三基因敲入小鼠）骨髓、血液和脾脏中淋巴样和抗原呈递细胞亚群的纵向变化，以及它们如何整合到我们目前对疾病发病机制的理解中。特别是，我们关注狼疮易感小鼠中（自身反应性）T 细胞激活模式。T 细胞对染色质成分（组蛋白肽）的耐受性破坏是疾病发展的关键，与 T 细胞内在缺陷有关，这些缺陷由遗传易感性因素和外在扩增机制贡献，特别是抗原呈递细胞的过度刺激。我们还描述了 B 细胞亚群的变化，从作为中央和外周耐受检查点紊乱的指示的偏向未成熟 B 细胞群体，到富含长寿浆细胞，这是疾病中持续产生自身抗体的关键。SLE 中的 B 细胞激活机制既有 T 细胞依赖性（耐受破坏和产生特异性自身抗体），也有 T 细胞独立性（多克隆 B 细胞激活，长寿浆细胞产生自身抗体）。通过对两种主要 SLE 小鼠模型中的 B 和 T 细胞表面标志物进行全面评估，并描述疾病发生前后的变化，本综述说明了淋巴样细胞表型的研究如何提供有关致病途径的关键信息，并提供工具来评估新型治疗干预措施的有益效果。
