Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.
Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.
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DOI：
10.3109/08916934.2013.819855
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发表时间：
2013-12
期刊：
影响因子：
3.5
通讯作者：
Amalfitano A
中科院分区：
文献类型：
--
作者：
Seregin SS;Rastall DP;Evnouchidou I;Aylsworth CF;Quiroga D;Kamal RP;Godbehere-Roosa S;Blum CF;York IA;Stratikos E;Amalfitano A
强直性脊柱炎（AS）是一种慢性全身性关节炎，在全世界约0.5%的人口中导致严重的残疾和生活质量下降。目前还没有治愈AS的方法，其发病机制也不清楚。AS具有高度遗传性，超过70%的遗传风险与HLA-B27和内质网氨基肽酶-1 （ERAP1）等位基因的存在有关。此外，HLA-B27和ERAP1 AS风险等位基因之间的基因-基因相互作用最近已被证实。在这里，我们证明了不同的ERAP1等位基因可以不同地介导HLA-B27呈递抗原在人细胞上的表面表达。具体来说，对于所有测试的肽，我们发现，相对于低AS风险的ERAP1变体，含有高AS风险snp的ERAP1变体减少了HLA-B27呈现的肽的数量。这些结果通过体外肽催化实验得到进一步验证，表明高AS风险等位基因具有增强的催化活性，可以更快地破坏许多HLA-B27靶向肽，这一结果与相同肽的HLA-B27呈现减少相关。这些发现表明，AS发病机制可能与同时携带HLA-B27和高风险ERAP1等位基因的AS患者向免疫系统适应性臂正确显示多种肽的能力改变有关，由于适应性免疫系统异常显示病原体或自身衍生肽，可能使这些个体暴露于更高的AS风险。
Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ~0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed. Here, we demonstrate that various ERAP1 alleles can differentially mediate surface expression of antigens presented by HLA-B27 on human cells. Specifically, for all peptides tested, we found that an ERAP1 variant containing high AS risk SNPs reduced the amount of the peptide presented by HLA-B27, relative to low AS risk ERAP1 variants. These results were further validated using peptide catalysis assays in vitro, suggesting that high AS risk alleles have an enhanced catalytic activity that more rapidly destroys many HLA-B27-destined peptides, a result that correlated with decreased HLA-B27 presentation of the same peptides. These findings suggest that one mechanism underlying AS pathogenesis may involve an altered ability for AS patients harboring both HLA-B27 and high AS risk ERAP1 alleles to correctly display a variety of peptides to the adaptive arm of the immune system, potentially exposing such individuals to higher AS risk due to abnormal display of pathogen or self derived peptides by the adaptive immune system.
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影响因子：
--
作者：
de Castro, JAL;Alvarez, I;Vázquez, M
通讯作者：
Vázquez, M
DOI：
10.4049/jimmunol.1002653
发表时间：
2011-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bowness P;Ridley A;Shaw J;Chan AT;Wong-Baeza I;Fleming M;Cummings F;McMichael A;Kollnberger S
通讯作者：
Kollnberger S
影响因子：
15.9
作者：
Fiorillo, MT;Maragno, M;Sorrentino, R
通讯作者：
Sorrentino, R
DOI：
10.1073/pnas.1101262108
发表时间：
2011-05-10
影响因子：
11.1
作者：
Kochan, Grazyna;Krojer, Tobias;Oppermann, Udo
通讯作者：
Oppermann, Udo
影响因子：
4.9
作者：
Appel, H;Kuon, W;Sieper, J
通讯作者：
Sieper, J