Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity.
Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity.
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DOI：
10.4049/jimmunol.2200212
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发表时间：
2023-03-01
期刊：
影响因子：
--
通讯作者：
Bull KR
中科院分区：
文献类型：
--
作者：
Hodgson R;Crockford TL;Bhandari A;Kepple JD;Back J;Cawthorne E;Abeler-Dörner L;Laing AG;Clare S;Speak A;Adams DJ;Dougan G;Hayday AC;Deobagkar-Lele M;Cornall RJ;Bull KR
我们证明了氨酰基脯氨酸二肽酶缺乏症和自身免疫之间的因果关系。PEPD的丧失导致效应CD 8 T细胞的Ag非依赖性增加。KLRG 1 + CD 8效应子的细胞外源性扩增与PEPD自身免疫相关。脯氨酰二肽酶缺乏症（PD）是由PEPD基因突变引起的多系统疾病，PEPD基因编码一种广泛表达的金属肽酶，对水解含有C-末端脯氨酸或羟脯氨酸的二肽至关重要。PD通常在儿童期表现为发育迟缓、皮肤溃疡、复发性感染，在某些患者中，还表现为类似系统性红斑狼疮的自身免疫性特征。自身免疫相关性的基础尚不确定，但可能是由于自身抗原暴露伴组织损伤，或由慢性感染和微生物负荷间接驱动。在这项研究中，我们解决了因果关系的问题，并表明Pepd基因敲除小鼠的抗核自身抗体增加，血清伊加升高，伴有肾脏免疫复合物沉积，与系统性狼疮样疾病一致。这些特征与脾脏和肝脏中CD 4和CD 8效应T细胞的积累有关。Pepd缺陷导致自发T细胞活化和增殖成效应子亚群，其是细胞固有的并且不依赖于Ag受体特异性或抗原刺激。然而，在混合嵌合体中未观察到KLRG 1+效应CD 8细胞的增加，其中也不存在自身免疫表型。我们的研究结果将PD的自身免疫易感性与自发性T细胞功能障碍联系起来，可能与造血系统外的免疫激活剂联合作用，但这是由于非酶促脯氨酰二肽酶功能异常或丧失所致。这一知识提供了深入了解氨酰基脯氨酸二肽酶在维持自身耐受性中的作用，并强调了治疗控制T细胞活化的重要性。
We demonstrate a causal link between prolidase deficiency and autoimmunity. Loss of PEPD leads to an Ag-independent increase in effector CD8 T cells. Cell-extrinsic expansion of KLRG1+ CD8 effectors is associated with PEPD autoimmunity. Prolidase deficiency (PD) is a multisystem disorder caused by mutations in the PEPD gene, which encodes a ubiquitously expressed metallopeptidase essential for the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. PD typically presents in childhood with developmental delay, skin ulcers, recurrent infections, and, in some patients, autoimmune features that can mimic systemic lupus erythematosus. The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden. In this study, we address the question of causation and show that Pepd-null mice have increased antinuclear autoantibodies and raised serum IgA, accompanied by kidney immune complex deposition, consistent with a systemic lupus erythematosus–like disease. These features are associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver. Pepd deficiency leads to spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of Ag receptor specificity or antigenic stimulation. However, an increase in KLRG1+ effector CD8 cells is not observed in mixed chimeras, in which the autoimmune phenotype is also absent. Our findings link autoimmune susceptibility in PD to spontaneous T cell dysfunction, likely to be acting in combination with immune activators that lie outside the hemopoietic system but result from the abnormal metabolism or loss of nonenzymatic prolidase function. This knowledge provides insight into the role of prolidase in the maintenance of self-tolerance and highlights the importance of treatment to control T cell activation.
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影响因子：
5.4
作者：
Lambe, Teresa;Crawford, Greg;Johnson, Andy L.;Crockford, Tanya L.;Bouriez-Jones, Tiphaine;Smyth, Aisling M.;Pham, Trung H. M.;Zhang, Qian;Freeman, Alexandra F.;Cyster, Jason G.;Su, Helen C.;Cornall, Richard J.
通讯作者：
Cornall, Richard J.
DOI：
10.1186/1546-0096-10-18
发表时间：
2012-06-22
期刊：
Pediatric rheumatology online journal
影响因子：
--
作者：
Butbul Aviel Y;Mandel H;Avitan Hersh E;Bergman R;Adiv OE;Luder A;Brik R
通讯作者：
Brik R
影响因子：
3.5
作者：
Lupi, A.;Tenni, R.;Forlino, A.
通讯作者：
Forlino, A.
影响因子：
2.8
作者：
Uhrin, P.;Perkmann, T.;Binder, B.;Schabbauer, G.
通讯作者：
Schabbauer, G.
DOI：
10.1002/ajmg.b.30945
发表时间：
2010-01-01
影响因子：
2.8
作者：
Falik-Zaccai, Tzipora C.;Khayat, Morad;Mandel, Hanna
通讯作者：
Mandel, Hanna