Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQB1 chain genes promote the Ro (SS-A)/La (SS-B) autoantibody responses.
Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQB1 chain genes promote the Ro (SS-A)/La (SS-B) autoantibody responses.
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DOI：
10.4049/jimmunol.146.11.3871
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发表时间：
1991-06
影响因子：
4.4
通讯作者：
J. Reveille;Miriam J. Macleod;K. Whittington;F. Arnett
中科院分区：
文献类型：
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作者：
J. Reveille;Miriam J. Macleod;K. Whittington;F. Arnett
为了明确HLA-DR和DQ等位基因以及参与抗Ro/La自身抗体应答的特异性DQA 1和DQB 1链基因，对58例白人和48例美国黑人SLE和Sjögren综合征患者进行了限制性片段长度多态性分析和序列特异性寡核苷酸分型。在白人和黑人患者中，与269名正常种族匹配的对照组或80名抗Ro阴性的SLE/Sjögren综合征患者相比，DQw2.1（与HLA-DR 3连锁不平衡）和DQw 6（DQw 1的一种亚型）等位基因的杂合性导致抗Ro反应（伴或不伴抗La）的相对风险最高。个体DQA 1和DQB 1链等位基因的分析显示，DQA 1 *0501和DQB 1 *0201是最常见的，其次是包含DQw 6的DQA 1和DQB 1等位基因。在不具有DQw2.1和/或DQw 6等位基因的患者中，HLA-DQB 1 *0302和HLA-DQA 1 *0401（尤其是黑人）显著增加。这些相关等位基因的核苷酸序列分析显示，100%的抗Ro患者在DQA 1链最外结构域的第34位具有谷氨酰胺残基和/或在DQB 1链最外结构域的第26位具有亮氨酸。与抗Ro阴性SLE患者或对照组相比，抗Ro + La患者更可能具有所有四个含有这些氨基酸残基的DQA 1/DQB 1链。这些数据暗示了位于HLA-DQA 1：B1异源二聚体的Ag结合裂缝底部的DQA 1和DQB 1链上的特定氨基酸残基，并进一步表明了“基因剂量”在抗Ro（+/- La）自身抗体应答中的作用。
In order to define the HLA-DR and DQ alleles, as well as the specific DQA1 and DQB1 chain genes involved in the anti-Ro/La autoantibody responses, RFLP analysis and sequence-specific oligonucleotide typing was carried out on 58 Caucasians and 48 American blacks with SLE or Sjögren's syndrome and anti-Ro antibodies. Among both Caucasian and black patients, the highest relative risk for the anti-Ro response (both with and without accompanying anti-La) was conferred by heterozygosity for the DQw2.1 (in linkage disequilibrium with HLA-DR3) and DQw6 (a subtype of DQw1) alleles compared with either 269 normal race-matched controls or 80 anti-Ro negative SLE/Sjögren's syndrome patients. Analysis of individual DQA1 and DQB1 chain alleles revealed that DQA1*0501 and DQB1*0201 were most frequent, followed by DQA1 and DQB1 alleles comprising DQw6. In patients not possessing DQw2.1 and/or DQw6 alleles, HLA-DQB1*0302 and HLA-DQA1*0401 (especially in blacks) were significantly increased. Nucleotide sequence analysis of these associated alleles showed that 100% of patients with anti-Ro had a glutamine residue at position 34 of the outermost domain of the DQA1 chain and/or a leucine at position 26 of the outermost domain of the DQB1 chain. Patients with anti-Ro plus La were more likely to have all four of their DQA1/DQB1 chains containing these amino acid residues than either anti-Ro-negative SLE patients or controls. These data implicate specific amino acid residues on both DQA1 and DQB1 chains located in the floor of the Ag binding cleft of the HLA-DQA1:B1 heterodimer and further suggest a role for "gene dosage" in the anti-Ro (+/- La) autoantibody response.