Tissue Typing Laboratory, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, England.
Transplantation. 2011 Jan 27;91(2):183-90. doi: 10.1097/TP.0b013e3181ffff99.
We have shown previously that human leukocyte antigen (HLA) class I immunogenicity can be predicted by the number, position, and physiochemical differences of polymorphic amino acids (AAs). We have now modeled the structural and physiochemical polymorphisms of HLA class II alloantigens and correlated these with humoral alloimmunity in sensitized patients awaiting kidney transplantation.
Sera obtained from 30 patients with high levels of IgG HLA-specific antibodies were screened using single-antigen HLA antibody detection beads. A computer program was developed to determine the number of AA mismatches (after interlocus and intralocus subtraction) and their hydrophobicity and electrostatic mismatch score for each mismatched HLA-DR and -DQ specificity. Regression methods were used to compare these variables with the occurrence and magnitude of alloantibody responses.
HLA-specific antibody was detected against 879 (55%) of 1604 mismatched HLA specificities evaluated. There was a strong correlation between increasing number of AA mismatches and the occurrence (P<0.001, odds ratio 3.85 per AA) and magnitude of alloantibody responses (P<0.001); only 6% of alloantigens with 0 to 2 mismatched AA-induced alloantibody (median fluorescence intensity 37) compared with 82% of alloantigens with more than or equal to 20 mismatched AAs (median fluorescence intensity 9969). Hydrophobicity and electrostatic mismatch scores also correlated closely with alloantibody response (P<0.001), but neither variable had independent predictive value over the number of AA mismatches alone.
Differences in the number of polymorphic AA mismatches and their physiochemical properties for a given recipient HLA type are strong predictors of class II alloantigen immunogenicity and alloantibody response before kidney transplantation.
我们之前已经证明，人类白细胞抗原 (HLA) Ⅰ类免疫原性可以通过多态氨基酸 (AA) 的数量、位置和物理化学差异来预测。我们现在已经对 HLA Ⅱ类同种异体抗原的结构和物理化学多态性进行了建模，并将其与致敏患者等待肾移植时的体液同种异体免疫进行了相关性分析。
使用单抗原 HLA 抗体检测珠对来自 30 名 IgG 特异性 HLA 抗体水平较高的患者的血清进行筛选。开发了一个计算机程序，用于确定每个错配 HLA-DR 和-DQ 特异性的 AA 错配数量（在基因间和基因内相减后）及其疏水性和静电错配评分。使用回归方法比较这些变量与同种异体抗体反应的发生和程度。
在评估的 1604 个错配 HLA 特异性中，检测到针对 879 个（55%）的 HLA 特异性抗体。AA 错配数量的增加与同种异体抗体反应的发生（P<0.001，每增加一个 AA 的优势比为 3.85）和程度（P<0.001）之间存在很强的相关性；仅 6%的具有 0 到 2 个错配 AA 的同种异体抗原诱导同种异体抗体（中位荧光强度 37），而 82%的具有多于或等于 20 个错配 AA 的同种异体抗原诱导同种异体抗体（中位荧光强度 9969）。疏水性和静电错配评分也与同种异体抗体反应密切相关（P<0.001），但这两个变量都没有单独的 AA 错配数量具有独立的预测价值。
对于给定的受者 HLA 类型，多态性 AA 错配的数量及其物理化学特性差异是预测 II 类同种异体抗原免疫原性和肾移植前同种异体抗体反应的强有力指标。
