Lymphoid Aggregates in the CNS of Progressive Multiple Sclerosis Patients Lack Regulatory T Cells
Lymphoid Aggregates in the CNS of Progressive Multiple Sclerosis Patients Lack Regulatory T Cells
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DOI：
10.3389/fimmu.2019.03090
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发表时间：
2020-01-15
影响因子：
7.3
通讯作者：
Berberich-Siebelt, Friederike
中科院分区：
文献类型：
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作者：
Bell, Luisa;Lenhart, Alexander;Berberich-Siebelt, Friederike
在多发性硬化的灰质病理学中，神经变性与高度的脑膜炎性活动相关。重要的是，在进行性多发性硬化患者的炎症脑膜处发现了异位淋巴滤泡（eLF）。除T淋巴细胞外，它们还包括B细胞，并可能引起生发中心（GC）样反应。GC反应由FOXP 3（+）T-滤泡调节细胞（T-FR）控制，但尚不清楚它们是否参与eLF中自身抗体的产生。从进行性多发性硬化症患者的尸检中收集的人类尸检材料，确实可以在血管周围区域和深沟中检测到富含B细胞的明显炎性浸润。CD 35（+）细胞、滤泡旁CD 138（+）浆细胞和淋巴细胞上GC归巢受体CXCR 5的大量表达将其中一些定义为eLF。然而，它们仅在不同程度上类似GC，因为T细胞不表达PD-1，只有少数细胞对关键转录调节因子BCL-6和持续增殖呈阳性，而大量T细胞表达高NFATc 1样GC滤泡T细胞。此外，主要的细胞质NFATc 1和富含CD 3（+）CD 27（+）记忆和CD 4（+）CD 69（+）组织驻留细胞暗示了慢性状态，与PD-1和BCL-6下调非常一致。有趣的是，FOXP 3（+）细胞在整个脑切片中几乎不存在，并且在淋巴聚集体中从未发现CD 3（+）FOXP 3（+）T（FR）。这也表明，在这些淋巴聚集体中，体液免疫反应的控制程度较低，可能使多发性硬化症患者发生CNS特异性自身抗体。
In gray matter pathology of multiple sclerosis, neurodegeneration associates with a high degree of meningeal inflammatory activity. Importantly, ectopic lymphoid follicles (eLFs) were identified at the inflamed meninges of patients with progressive multiple sclerosis. Besides T lymphocytes, they comprise B cells and might elicit germinal center (GC)-like reactions. GC reactions are controlled by FOXP3(+) T-follicular regulatory cells (T-FR), but it is unknown if they participate in autoantibody production in eLFs. Receiving human post-mortem material, gathered from autopsies of progressive multiple sclerosis patients, indeed, distinct inflammatory infiltrates enriched with B cells could be detected in perivascular areas and deep sulci. CD35(+) cells, parafollicular CD138(+) plasma cells, and abundant expression of the homing receptor for GCs, CXCR5, on lymphocytes defined some of them as eLFs. However, they resembled GCs only in varying extent, as T cells did not express PD-1, only few cells were positive for the key transcriptional regulator BCL-6 and ongoing proliferation, whereas a substantial number of T cells expressed high NFATc1 like GC-follicular T cells. Then again, predominant cytoplasmic NFATc1 and an enrichment with CD3(+)CD27(+) memory and CD4(+)CD69(+) tissue-resident cells implied a chronic state, very much in line with PD-1 and BCL-6 downregulation. Intriguingly, FOXP3(+) cells were almost absent in the whole brain sections and CD3(+)FOXP3(+) T(FR)s were never found in the lymphoid aggregates. This also points to less controlled humoral immune responses in those lymphoid aggregates possibly enabling the occurrence of CNS-specific autoantibodies in multiple sclerosis patients.