Khan M A, Kellner H
Case Western Reserve University, Cleveland, Ohio.
Rheum Dis Clin North Am. 1992 Nov;18(4):837-64.
The association of HLA-B27 with ankylosing spondylitis and related spondyloarthropathies has been known for two decades and has provided a great impetus to the epidemiologic studies and also helped broaden the clinical spectrum of these diseases. The etiology of these diseases is likely to be multifactorial and include genetic, immunologic, and environmental mechanisms. The detailed three-dimensional x-ray crystallographic structure of B27 has now been reported. It has revealed electron density compatible with oligopeptides that are nine amino acid-long (nonamers) bound in the antigen-binding cleft of the molecule. Microsequence analysis of 11 peptides eluted from the antigen-binding cleft has confirmed that all are nonamers. The most restricted position in the bound peptide is the second position, where all the 11 peptides contain arginine. The side chain of arginine extends into the B pocket ("45 pocket"), which seems to act as a specificity side pocket in the antigen-binding cleft of the B27 molecule. It is very likely that an understanding of the detailed structure of B27, including the peptide-binding motif and the structural domains recognized by cytotoxic T cells, along with the recent development of the B27 transgenic rat model for spondyloarthropathies, will further enhance our understanding of the immunogenetics of these diseases. It is hoped that this will lead to the source of the arthritogenic triggers and possibly disease prevention by antigen-specific immunomodulation. Because T-cell activation is initiated by the formation of antigen-MHC complexes that are the ligands that are recognized by the antigen-specific T-cell receptor (TCR), it might be possible to inhibit this activation by blocking the antigen-binding cleft of MHC molecules by using high-affinity MHC-binding peptides (MHC blockade) or by a novel, new, and more efficient method of TCR antagonism.
HLA - B27与强直性脊柱炎及相关脊柱关节病的关联已为人所知达二十年之久，这为流行病学研究提供了巨大推动力，也有助于拓宽这些疾病的临床谱。这些疾病的病因可能是多因素的，包括遗传、免疫和环境机制。现在已报道了B27详细的三维X射线晶体结构。该结构揭示了与结合在分子抗原结合裂隙中的九氨基酸长（九聚体）寡肽相匹配的电子密度。从抗原结合裂隙洗脱的11种肽的微序列分析证实，所有肽均为九聚体。结合肽中最具限制性的位置是第二位，所有11种肽在该位置均含有精氨酸。精氨酸的侧链延伸至B口袋（“45口袋”），该口袋似乎在B27分子的抗原结合裂隙中充当特异性侧口袋。很有可能，对B27详细结构的了解，包括肽结合基序和细胞毒性T细胞识别的结构域，以及最近针对脊柱关节病的B27转基因大鼠模型的开发，将进一步增进我们对这些疾病免疫遗传学的理解。希望这将揭示致关节炎触发因素的来源，并有可能通过抗原特异性免疫调节实现疾病预防。由于T细胞活化是由抗原 - MHC复合物的形成引发的，而抗原 - MHC复合物是抗原特异性T细胞受体（TCR）识别的配体，因此有可能通过使用高亲和力MHC结合肽阻断MHC分子的抗原结合裂隙（MHC阻断）或通过一种新颖、高效的TCR拮抗方法来抑制这种活化。
