Chauhan B, Santiago L, Hutcheson P S, Schwartz H J, Spitznagel E, Castro M, Slavin R G, Bellone C J
Department of Internal Medicine, St Louis University School of Medicine, St Louis, MO 63104, USA.
J Allergy Clin Immunol. 2000 Oct;106(4):723-9. doi: 10.1067/mai.2000.109913.
Allergic bronchopulmonary aspergillosis (ABPA) is a disease with uncertain pathology. Studies have suggested a pathogenic role for T(H)2 cells. Previously, we demonstrated, in a small group of patients, that T(H)2 reactivity to a major Aspergillus fumigatus antigen was restricted by HLA-DR2 or HLA-DR5 alleles.
We sought to confirm whether susceptibility to ABPA is exclusively associated with HLA-DR locus and to investigate the involvement of HLA-DQ genes in the development of ABPA.
Genomic DNA was extracted from patients with ABPA, patients without ABPA but with positive A fumigatus skin test responses and asthma or cystic fibrosis, and healthy control subjects. HLA-DR and HLA-DQ genes were detected by using low-resolution typing; high-resolution typing was done only on HLA-DR2- and HLA-DR5-positive individuals by using sequence-specific primers (PCR-SSP).
A significantly higher frequency of HLA-DR2 was observed in patients with ABPA versus those without ABPA (corrected P <.01) or healthy control subjects (corrected P <.01). Genotype analysis revealed that susceptibility to ABPA is associated with HLA-DR2 alleles DRB11503 and DRB11501 and, to a lesser extent, with the HLA-DR5 allele DRB1*1104. The presence of DR4 or DR7 alleles in non-DR2/5 patients with ABPA suggests that these alleles may also be contributing factors in this disease. Another striking observation was the significantly high frequency of HLA-DQ2 in patients without ABPA (67. 4%) compared with patients with ABPA (20.5%) and normal control subjects (37.7%), suggesting that these alleles may confer protection in the population without ABPA.
These genetic studies suggest that HLA-DR molecules DR2, DR5, and possibly DR4 or DR7 contribute to susceptibility while HLA-DQ2 contributes to resistance and that a combination of these genetic elements determines the outcome of ABPA in patients with cystic fibrosis and asthma.
变应性支气管肺曲霉病（ABPA）是一种病理尚不明确的疾病。研究提示辅助性T细胞2（TH2）具有致病作用。此前，我们在一小部分患者中证实，TH2对烟曲霉主要抗原的反应性受人类白细胞抗原（HLA）-DR2或HLA-DR5等位基因限制。
我们试图确认ABPA易感性是否仅与HLA-DR基因座相关，并研究HLA-DQ基因在ABPA发病中的作用。
从ABPA患者、无ABPA但烟曲霉皮肤试验反应阳性且患有哮喘或囊性纤维化的患者以及健康对照者中提取基因组DNA。采用低分辨分型法检测HLA-DR和HLA-DQ基因；仅对HLA-DR2和HLA-DR5阳性个体使用序列特异性引物（PCR-SSP）进行高分辨分型。
与无ABPA患者（校正P<.01）或健康对照者（校正P<.01）相比，ABPA患者中HLA-DR2的频率显著更高。基因型分析显示，ABPA易感性与HLA-DR2等位基因DRB11503和DRB11501相关，在较小程度上与HLA-DR5等位基因DRB1*1104相关。非DR2/5的ABPA患者中存在DR4或DR7等位基因，提示这些等位基因可能也是该疾病的促成因素。另一个显著发现是，无ABPA患者中HLA-DQ2的频率（67.4%）显著高于ABPA患者（20.5%）和正常对照者（37.7%），提示这些等位基因可能在无ABPA人群中具有保护作用。
这些遗传学研究表明，HLA-DR分子DR2、DR5以及可能的DR4或DR7与易感性相关，而HLA-DQ2与抗性相关，这些遗传因素的组合决定了囊性纤维化和哮喘患者中ABPA的发病情况。
