Amicosante Massimo, Berretta Floriana, Rossman Milton, Butler Richard H, Rogliani Paola, van den Berg-Loonen Ella, Saltini Cesare
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Respir Res. 2005 Aug 14;6(1):94. doi: 10.1186/1465-9921-6-94.
Susceptibility to beryllium (Be)-hypersensitivity (BH) has been associated with HLA-DP alleles carrying a glutamate at position 69 of the HLA-DP beta-chain (HLA-DPGlu69) and with several HLA-DP, -DQ and -DR alleles and polymorphisms. However, no genetic associations have been found between BH affected subjects not carrying the HLA-DPGlu69 susceptibility marker.
In this report, we re-evaluated an already described patient populations after 7 years of follow-up including new 29 identified BH subjects. An overall population 36 berylliosis patients and 38 Be-sensitization without lung granulomas and 86 Be-exposed controls was analysed to assess the role of the individual HLA-class II polymorphisms associated with BH-susceptibility in HLA-DPGlu69 negative subjects by univariate and multivariate analysis.
As previously observed in this population the HLA-DPGlu69 markers was present in higher frequency in berylliosis patients (31 out of 36, 86%) than in Be-sensitized (21 out of 38, 55%, p = 0.008 vs berylliosis) and 41 out of 86 (48%, p < 0.0001 vs berylliosis, p = 0.55 vs Be-sensitized) Be-exposed controls.However, 22 subjects presenting BH did not carry the HLA-DPGlu69 marker. We thus evaluated the contribution of all the HLA-DR, -DP and -DQ polymorphisms in determining BH susceptibility in this subgroup of HLA-Glu69 subjects. In HLA-DPGlu69-negatives a significant association with BH was found for the HLA-DQLeu26, for the HLA-DRB1 locus residues Ser13, Tyr26, His32, Asn37, Phe47 and Arg74 and for the HLA-DRB3 locus clusterized residues Arg11, Tyr26, Asp28, Leu38, Ser60 and Arg74. HLA-DRPhe47 (OR 2.956, p < 0.05) resulting independently associated with BH. Further, Be-stimulated T-cell proliferation in the HLA-DPGlu69-negative subjects (all carrying HLA-DRPhe47) was inhibited by the anti-HLA-DR antibody (range 70-92% inhibition) significantly more than by the anti-HLA-DP antibody (range: 6-29%; p < 0.02 compared to anti-HLA-DR) while it was not affected by the anti-HLA-DQ antibody.
We conclude that HLA-DPGlu69 is the primary marker of Be-hypersensitivity and HLA-DRPhe47 is associated with BH in Glu69-negative subjects, likely playing a role in Be-presentation and sensitization.
铍（Be）超敏反应（BH）易感性与 HLA - DP 等位基因相关，这些等位基因在 HLA - DPβ链第 69 位携带谷氨酸（HLA - DPGlu69），也与多个 HLA - DP、- DQ 和 - DR 等位基因及多态性有关。然而，在未携带 HLA - DPGlu69 易感性标记的 BH 患者中未发现遗传关联。
在本报告中，我们对已描述的患者群体进行了 7 年随访后的重新评估，包括新确定的 29 名 BH 患者。分析了一个总体人群，其中包括 36 例铍中毒患者、38 例无肺部肉芽肿的 Be 致敏者和 86 例 Be 暴露对照者，通过单因素和多因素分析评估个体 HLA - II 类多态性在 HLA - DPGlu69 阴性受试者中与 BH 易感性的关联作用。
如先前在此群体中观察到的，HLA - DPGlu69 标记在铍中毒患者中的频率更高（36 例中的 31 例，86%），高于 Be 致敏者（38 例中的 21 例，55%，与铍中毒相比 p = 0.008）和 86 例 Be 暴露对照者中的 41 例（占 48%，与铍中毒相比 p < 0.0001，与 Be 致敏者相比 p = 0.55）。然而，22 名表现出 BH 的受试者未携带 HLA - DPGlu69 标记。因此，我们评估了所有 HLA - DR、- DP 和 - DQ 多态性在该 HLA - Glu69 阴性受试者亚组中确定 BH 易感性的作用。在 HLA - DPGlu69 阴性者中，发现 HLA - DQLeu26、HLA - DRB1 基因座的 Ser13、Tyr26、His32、Asn37、Phe47 和 Arg74 位点以及 HLA - DRB3 基因座的 Arg11、Tyr26、Asp28、Leu（原文此处有误，应为 38）、Ser60 和 Arg74 位点与 BH 有显著关联。HLA - DRPhe47（比值比 2.956，p < 0.05）独立地与 BH 相关。此外，在 HLA - DPGlu69 阴性受试者（均携带 HLA - DRPhe47）中，抗 HLA - DR 抗体对 Be 刺激的 T 细胞增殖的抑制作用（抑制范围 70 - 92%）明显大于抗 HLA - DP 抗体（抑制范围：6 - 29%；与抗 HLA - DR 相比 p < 0.02），而抗 HLA - DQ 抗体对其无影响。
我们得出结论，HLA - DPGlu69 是 Be 超敏反应的主要标记，而 HLA - DRPhe47 在 Glu69 阴性受试者中与 BH 相关，可能在 Be 提呈和致敏过程中起作用。
