Implications of structural and thermodynamic studies of HLA-B27 subtypes exhibiting differential association with ankylosing spondylitis.
Implications of structural and thermodynamic studies of HLA-B27 subtypes exhibiting differential association with ankylosing spondylitis.
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HLA-B27 亚型的结构和热力学研究与强直性脊柱炎存在差异相关性。
DOI：
10.1007/978-1-4419-0298-6_13
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发表时间：
2009
影响因子：
--
通讯作者：
B. Uchánska‐Ziegler
中科院分区：
文献类型：
--
作者：
A. Ziegler;B. Loll;R. Misselwitz;B. Uchánska‐Ziegler
HLA-B27分子的结构和热力学性质为其在免疫系统中的功能提供了基础，也可能是理解HLA-B27相关疾病（如分析性脊柱炎（as））病理的核心。一些HLA-B27等位基因与as相关，而另一些则不是，尽管前者编码的蛋白质可能与后者指定的蛋白质只有一个氨基酸交换不同。这表明，亚型特异性多态性残基在确定HLA-B27亚型是否与as相关中起关键作用，并开启了将特定亚型的结构、热力学和功能特征与疾病关联联系起来的可能性。我们的研究涉及x射线晶体学和各种其他生物物理技术，以检查几种不同的肽是如何在分子的结合槽内被容纳的。这些分析主要选择HLA-B*2705和HLA-B*2709亚型，它们的产物彼此之间只有一个氨基酸残基不同，但我们的研究最近也扩展到密切相关的HLA-B*2703， HLA-B*2704和HLA-B*2706亚型。分析表明HLA-B27复合物之间可能存在结构和热力学差异，这取决于所显示的肽。此外，研究还发现，aviralpeptide和两种自肽表现出HLA-B27亚型依赖的分子模仿，从而为解释自身反应性t细胞亚型依赖的存在提供了分子基础。尽管这些结果并不排除其他关于AS发病机制的理论，但它们支持了关节炎肽假说，该假说设想HLA-B*2705阳性个体（特别是当他们患有AS时）中发现的自身反应性t细胞的交叉反应性在HLA-B*2705呈现的外源肽和自身肽之间存在分子模仿。
Structural and thermodynamic properties of HLA-B27 molecules provide the basis for their function within the immune system and are probably also central for the understanding of the pathology of HLA-B27-associated diseases such as ankolysing spondylitis (AS). Several HLA-B27 alleles are AS-associated, whereas some are not, although the protein encoded by the former may differ in only a single amino acid exchange from those specified by the latter. This indicates that subtype-specific polymorphic residues play a key role in determining whether an HLA-B27 subtype is AS-associated or not and open the possibility to correlate structural, thermodynamic and functional characteristics ofa given subtype with the disease association. Our studies involved X-ray crystallography and various other biophysical techniques to examine how several different peptides are accommodated within the binding groove of the molecules. The HLA-B*2705 and HLA-B*2709 subtypes, whose products differ in only a single amino acid residue of their heavy chains from each other, were primarily chosen for these analyses, but our studies have recently also been extended to the closely related subtypes HLA-B*2703, HLA-B*2704 and HLA-B*2706. The analyses reveal that structural and thermodynamic differences between HLA-B27 complexes may exist, depending on the peptide that is displayed. Furthermore, aviralpeptide and two self-peptides were found that exhibit HLA-B27 subtype-dependent molecular mimicry, thereby providing a molecular basis to account for the subtype-dependent presence of autoreactive T-cells. Although these results do not exclude other theories for the pathogenesis of AS, they support the arthritogenic peptide hypothesis which envisages molecular mimicry between HLA-B27-presented foreign and self-peptides to explain the cross-reactivity of autoreactive T-cells that are found in HLA-B*2705-positive individuals, in particular when they suffer from AS.
影响因子：
2.9
作者：
R. F. Tilton;John C. Dewan;G. Petsko
通讯作者：
R. F. Tilton;John C. Dewan;G. Petsko
MHC I 类分子、结构和功能。
DOI：
--
发表时间：
1999
期刊：
Reviews in immunogenetics
影响因子：
--
作者：
Natarajan,K;Li,H;Mariuzza,RA;Margulies,DH
通讯作者：
Margulies,DH
DOI：
10.1073/pnas.89.8.3429
发表时间：
1992-04-15
影响因子：
11.1
作者：
GARBOCZI, DN;HUNG, DT;WILEY, DC
通讯作者：
WILEY, DC