Inclusion Body Myositis Laser Microdissection Reveals Differential Up-Regulation of IFN-γ Signaling Cascade in Attacked versus Nonattacked Myofibers
Inclusion Body Myositis Laser Microdissection Reveals Differential Up-Regulation of IFN-γ Signaling Cascade in Attacked versus Nonattacked Myofibers
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DOI：
10.1016/j.ajpath.2011.05.055
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发表时间：
2011-09-01
影响因子：
6
通讯作者：
Dornmair, Klaus
中科院分区：
文献类型：
--
作者：
Ivanidze, Jana;Hoffmann, Reinhard;Dornmair, Klaus
散发性包涵体肌炎（IBM）是一种肌肉疾病，有两个独立的致病成分，变性和炎症。通常，非坏死肌纤维被CD 8（+）T细胞和巨噬细胞局灶性包围和侵入。受攻击和未受攻击的肌纤维都表达高水平的人类白细胞抗原I类（HLA-I）分子，这是抗原呈递给CD 8（+）T细胞的先决条件。然而，只有HLA-I+肌纤维的一个亚组被免疫细胞攻击。通过使用IHC，我们分类肌纤维从5例散发性IBM攻击（A（IBM））或非攻击（N-IBM）和分离的肌纤维细胞内内容物分别由激光显微切割。为了比较，我们从对照组（H-CTRL）中分离肌纤维。采用微阵列杂交和定量PCR技术对样本进行分析。在A（IBM）和N-IBM中观察到HIA-I上调，而H-CTRL对HLA-I呈阴性。相反，与N-IBM和H-CTRL纤维相比，A（IBM）中干扰素（IFN）γ受体（IFNGR 2）和几个IFN-γ诱导基因的诱导链上调。共聚焦显微镜证实了A（IBM）细胞膜上IFNGR 2的节段性上调，这与相邻CD 8（+）T细胞的数量呈正相关。因此，在受攻击的纤维中观察到的IFN-γ信号级联的差异上调与局部炎症有关，而IBM肌纤维上普遍存在的HLA-I表达不需要IFNGR表达。(Am J Pathol 2011，179：1347-1359; DOI：10.1016/j.ajpath.2011.05.055）
Sporadic inclusion body myositis (IBM) is a muscle disease with two separate pathogenic components, degeneration and inflammation. Typically, nonnecrotic myofibers are focally surrounded and invaded by CD8(+) T cells and macrophages. Both attacked and nonattacked myofibers express high levels of human leukocyte antigen class I (HLA-I) molecules, a prerequisite for antigen presentation to CD8(+) T cells. However, only a subgroup of HLA-I+ myofibers is attacked by immune cells. By using IHC, we classified myofibers from five patients with sporadic IBM as attacked (A(IBM)) or nonattacked (N-IBM) and isolated the intracellular contents of myofibers separately by laser microdissection. For comparison, we isolated myofibers from control persons (H-CTRL). The samples were analyzed by microarray hybridization and quantitative PCR. HIA-I up-regulation was observed in A(IBM) and N-IBM, whereas H-CTRL were negative for HLA-I. In contrast, the inducible chain of the interferon (IFN) gamma receptor (IFNGR2) and several IFN-gamma-induced genes were up-regulated in A(IBM) compared with N-IBM and H-CTRL fibers. Confocal microscopy confirmed segmental IFNGR2 up-regulation on the membranes of A(IBM), which positively correlated with the number of adjacent CD8(+) T cells. Thus, the differential up-regulation of the IFN-gamma signaling cascade observed in the attacked fibers is related to local inflammation, whereas the ubiquitous HLA-I expression on IBM muscle fibers does not require IFNGR expression. (Am J Pathol 2011, 179:1347-1359; DOI:10.1016/j.ajpath.2011.05.055)