Williams A J K, Aitken R J, Chandler M A-M, Gillespie K M, Lampasona V, Bingley P J
Diabetes and Metabolism, Clinical Science at North Bristol, University of Bristol Medical School Unit, Southmead Hospital, Bristol, BS10 5NB, UK.
Diabetologia. 2008 Aug;51(8):1444-8. doi: 10.1007/s00125-008-1047-3. Epub 2008 May 27.
AIMS/HYPOTHESIS: To further our understanding of antigen presentation by HLA class II molecules, we have examined the influence of HLA class II genotype on expression of autoantibodies to islet antigen-2 (IA-2A).
HLA class II genotype and IA-2A were determined within 3 months of diagnosis in 618 patients with type 1 diabetes (median age 11 years [range 0.7-20.9]). Antibodies to the juxtamembrane region of IA-2 were measured by a radiobinding assay in 481 of 484 IA-2A-positive patients.
IA-2A prevalence was highest in patients carrying at least one HLA-DRB104-DQA10301 (385 of 450; 86%), DRB107-DQA1(0201 or 0301) (58 of 64; 91%) or DRB109-DQA10301 haplotype (18 of 19; 95%). Multiple regression showed that IA-2A were strongly associated with the number of these haplotypes carried; only 69 of 132 (52%) patients carrying none of these haplotypes had IA-2A, compared with 322 of 391 (82%) patients with one and 93 of 95 (98%) with two of these haplotypes (p < 0.001). IA-2 juxtamembrane antibodies were less frequent in IA-2A-positive patients with one (35%) or two (36%) DRB103-DQB102 or DRB107-DQB102 haplotypes than in those negative for these haplotypes (52%) (p = 0.002), but showed an independent positive association with IA-2A level (p < 0.001).
CONCLUSIONS/INTERPRETATION: HLA class II alleles strongly influence the prevalence of IA-2A. The high IA-2A prevalence in patients carrying DRB104, DRB107 and DRB109 alleles in linkage disequilibrium with DQA10301 or the closely related DQA1*0201 suggests the humoral response to IA-2 may be driven by HLA-DQA1 genes.
目的/假设：为了进一步了解 HLA Ⅱ类分子的抗原呈递，我们研究了 HLA Ⅱ类基因型对胰岛抗原 2 自身抗体（IA-2A）表达的影响。
在 618 例 1 型糖尿病患者（中位年龄 11 岁[范围 0.7 - 20.9]）诊断后的 3 个月内确定 HLA Ⅱ类基因型和 IA-2A。在 484 例 IA-2A 阳性患者中的 481 例中，通过放射结合试验检测针对 IA-2 跨膜区的抗体。
携带至少一种 HLA-DRB104-DQA10301（450 例中的 385 例；86%）、DRB107-DQA1（0201 或 0301）（64 例中的 58 例；91%）或 DRB109-DQA10301 单倍型（19 例中的 18 例；95%）的患者中，IA-2A 患病率最高。多元回归显示，IA-2A 与携带的这些单倍型数量密切相关；在 132 例未携带任何这些单倍型的患者中，只有 69 例（52%）有 IA-2A，而在携带一种这些单倍型的 391 例患者中有 322 例（82%），携带两种这些单倍型的 95 例患者中有 93 例（98%）（p < 0.001）。在携带一种（35%）或两种（36%）DRB103-DQB102 或 DRB107-DQB102 单倍型的 IA-2A 阳性患者中，IA-2 跨膜抗体的频率低于不携带这些单倍型的患者（52%）（p = 0.002），但与 IA-2A 水平呈独立正相关（p < 0.001）。
结论/解读：HLA Ⅱ类等位基因强烈影响 IA-2A 的患病率。与 DQA10301 或密切相关的 DQA10201 处于连锁不平衡状态的携带 DRB104、DRB107 和 DRB1*09 等位基因的患者中 IA-2A 患病率较高，这表明对 IA-2 的体液反应可能由 HLA-DQA1 基因驱动。
