FcγRIIIA-mediated activation of NK cells by IgG heavy chain complexed with MHC class II molecules
FcγRIIIA-mediated activation of NK cells by IgG heavy chain complexed with MHC class II molecules
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DOI：
10.1093/intimm/dxz010
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发表时间：
2019-05-01
影响因子：
4.4
通讯作者：
Arase, Hisashi
中科院分区：
文献类型：
--
作者：
Shimizu, Yuta;Kohyama, Masako;Arase, Hisashi
自然杀伤（NK）细胞是一种主要的表达Fc γ riia的淋巴细胞群，介导抗体依赖性细胞毒性。尽管NK细胞对病毒和肿瘤的免疫至关重要，但它们在类风湿关节炎（RA）患者的关节中也被激活，并可能参与疾病进展。我们之前发现，人类白细胞抗原（HLA） II类分子通过与其肽结合凹槽的关联，将错误折叠的细胞蛋白（如IgG重链（IgGH））转运到细胞表面。此外，我们还发现，与RA易感等位基因编码的HLA II类分子结合的IgGHs是类风湿因子（一种与RA相关的自身抗体）的特异性靶点。在这里，我们报告了与HLA II类分子结合的IgGHs优先刺激表达Fc γ riia的细胞，而不是表达Fc γ ri的细胞。我们观察到表达Fc γ riiia的细胞对特定HLA-DR等位基因的IgGH复合物的反应性与HLA-DR等位基因与RA相关的比值比之间存在显著的相关性。此外，表达Fc γ RIIIA的原代人NK细胞对表达IgGH与HLA II类分子复合物的细胞表现出ifn - γ产生和细胞毒性。我们的研究结果表明，IgGH与HLA II类分子的复合物参与了在关节炎关节内观察到的表达Fc γ riia的NK细胞的激活。
Natural killer (NK) cells are a major Fc gamma RIIIA-expressing lymphocyte population that mediate antibody-dependent cellular cytotoxicity. Although NK cells are critical for immunity against viruses and tumors, they are also activated in the joints of patients with rheumatoid arthritis (RA) and may be involved in disease progression. We previously found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins, such as IgG heavy chain (IgGH), to the cell surface via association with their peptide-binding grooves. Furthermore, we found that IgGHs bound to HLA class II molecules encoded by RA susceptibility alleles are specific targets for rheumatoid factor, an auto-antibody involved in RA. Here, we report that IgGHs bound to HLA class II molecules preferentially stimulate Fc gamma RIIIA-expressing but not Fc gamma RI-expressing cells. A significant correlation was observed between the reactivity of Fc gamma RIIIA-expressing cells to IgGH complexed with a specific HLA-DR allele and the odds ratio for HLA-DR allele's association with RA. Moreover, primary human NK cells expressing Fc gamma RIIIA demonstrated IFN-gamma production and cytotoxicity against cells expressing IgGH complexed with HLA class II molecules. Our findings suggest that IgGH complexed with HLA class II molecules are involved in the activation of Fc gamma RIIIA-expressing NK cells observed within arthritic joints.