Spontaneous regression of primary autoreactivity during chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis
Spontaneous regression of primary autoreactivity during chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis
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DOI：
10.1084/jem.189.7.1033
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发表时间：
1999-04-05
影响因子：
15.3
通讯作者：
Kinkel, RP
中科院分区：
文献类型：
--
作者：
Tuohy, VK;Yu, M;Kinkel, RP
实验性自身免疫性脑脊髓炎（EAE）是一种广泛用于多发性硬化症（MS）的动物模型。 EAE 通常由针对单一引发免疫显性髓磷脂肽决定簇的 CD+ T 辅助细胞 1 型 (Th1) 自身反应引发。最近的研究表明，EAE 的临床进展涉及新自身反应性的积累，通常称为表位扩散，针对不参与 dir 打印过程的肽决定簇。这项研究直接探讨了初级自身反应性和次级表位扩散在 EAE 和 MS 进展中的相对作用。为此，我们连续评估了印有明显不同的髓磷脂蛋白脂质蛋白致脑炎决定簇的 SWXJ 小鼠中几种表位扩散级联的发展。在一系列类似的实验中，我们研究了孤立性单症状脱髓鞘综合征患者随着疾病进展为临床明确的多发性硬化症而表位扩散的发展。我们的结果表明，在EAE和多发性硬化症中，与临床疾病发作相关的原发性增殖自身反应性总是随着时间的推移而消退，并且在疾病进展期间通常无法检测到。相比之下，对传播决定因素的持续继发自身反应的出现始终与 EAE 和 MS 的疾病进展相关。我们的结果表明，EAE 和 MS 的慢性进展涉及自身反应性前沿主要起始自我决定因素向确定的次级决定因素级联的转变，这些次级决定因素在疾病进展期间维持自我识别过程。
Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for multiple: sclerosis (MS). EAE is typically initiated by CD+ T helper cell type 1 (Th1) autoreactivity directed against a single priming immunodominant myelin peptide determinant. Recent studies have shown that clinical progression of EAE involves the accumulation of neo-autoreactivity, commonly referred to as epitope spreading, directed against peptide determinants not involved in dir printing process. This study directly addresses the relative roles of primary autoreactivity and secondary epitope spreading in the progression of both EAE and MS. To this end we serially evaluated the development of several epitope-spreading cascades ill SWXJ mice printed with distinctly different encephalitogenic determinants of myelin proteolipid protein. Tn a series of analogous experiments, we examined the development of epitope spreading in patients with isolated monosymptomatic demyelinating syndrome as their disease progressed to clinically definite MS, Our results indicate that in both EAE and MS, primary proliferative autoreactivity associated with onset of clinical disease invariably regresses with time and is often undetectable during periods of disease progression. In contrast, the emergence of sustained secondary autoreactivity to spreading determinants is consistently associated with disease progression in both EAE and MS. Our results indicate that chronic progression of EAE and MS involves a shifting of autoreactivity front primary initiating self-determinants to defined cascades of secondary determinants that sustain the self-recognition process during disease progression.