β2-microglobulin-free HLA class I heavy chain epitope mimicry by monoclonal antibody HC-10-specific peptide
β2-microglobulin-free HLA class I heavy chain epitope mimicry by monoclonal antibody HC-10-specific peptide
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DOI：
10.4049/jimmunol.171.4.1918
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发表时间：
2003-08-15
影响因子：
4.4
通讯作者：
Dammacco, F
中科院分区：
文献类型：
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作者：
Perosa, F;Luccarelli, G;Dammacco, F
mAb HC-10在与β（2）-微球蛋白（β（2）m）结合后失去与HLA I类（HLA-I）H链（HC）的反应性。此外，HC-10定义的表位似乎参与脊柱关节病的发病机制，因为HC-10降低了HLA-B27（+）β（2）m度/MHC II类基因敲除小鼠的发病率。本研究对HC-10识别的决定簇进行了表征。用HC-10淘选噬菌体展示肽文库导致基序PxxWDR的分离，其可以与与HC-10反应的HLA-I HC同种特异性的第一结构域的P57、W 60、D 61和R62比对。（55）EGPEY WDR（N/E）T-64（p-1）是最短的带有基序的肽，与HC-10反应并抑制其与可溶性HLA-B7 HC的结合，无论N（p-1a）或E（p-1b）是否存在于63位。相比之下，HC-10不与另外六种肽反应，每种肽具有HC-10非反应性HLA-I同种特异性中存在的基序氨基酸取代。p-1衍生的Qp-1，与额外的保守Q54合成，其显示出与HC-10的最高体外反应性，是唯一一种在小鼠中诱导IgG的Qp-1，其特异性与HC-10相似。HC-10定义的决定簇的图谱表明，mAb与β 2 m相关HLA-I HC反应性的缺乏是由β 2 m相关HLA-I HC沟中的肽阻断引起的，尽管不能排除HC与13 m结合后构象变化的作用。这些信息有助于我们理解β 2 m-游离和β 2 m-相关HLA-I HC抗原谱的分子基础，并可能有助于开发脊柱关节病的主动特异性免疫治疗。
mAb HC-10 loses its reactivity with HLA class I (HLA-I) H chain (HC) following its association with beta(2)-microglobulin (beta(2)m). Furthermore, the HC-10 defined epitope appears to be involved in the pathogenesis of spondyloarthropathies, because HC-10 reduced their incidence in HLA-B27(+)beta(2)mdegrees/MHC class II knockout mice. This study has characterized the determinant recognized by HC-10. Panning of a phage display peptide library with HC-10 resulted in isolation of the motif PxxWDR, which could be aligned with P57, W60, D61, and R62 of the first domain of the HLA-I HC allospecificities reactive with HC-10. The (55)EGPEY WDR(N/E)T-64 (p-1) is the shortest motif-bearing peptide that reacts with HC-10 and inhibits its binding to soluble HLA-B7 HC, irrespective of whether N (p-1a) or E (p-1b) is present at position 63. By contrast, HC-10 did not react with six additional peptides, each bearing motif amino acid substitutions present in HC-10-not-reactive HLA-I allospecificities. The p-1-derived Qp-1, synthesized with the additional conserved Q54, which displays the highest in vitro reactivity with HC-10, was the only one to induce in mice IgG resembling HC-10 in their fine specificity. Mapping of the HC-10-defined determinant suggests that the lack of mAb reactivity with beta(2)m-associated HLA-I HC is caused by blocking by the peptide in the groove of beta(2)m-associated HLA-I HC, though a role of HC conformational changes following its association with 13,m cannot be excluded. This information contributes to our understanding of the molecular basis of the antigenic profiles of beta(2)m-free and beta(2)m-associated HLA-I HC and may serve to develop active specific immunotherapy of spondyloarthropathies.