Association between protein tyrosine phosphatase 22 variant R620W in conjunction with the HLA-DRB1 shared epitope and humoral autoimmunity to an immunodominant epitope of cartilage-specific type II collagen in early rheumatoid arthritis
Association between protein tyrosine phosphatase 22 variant R620W in conjunction with the HLA-DRB1 shared epitope and humoral autoimmunity to an immunodominant epitope of cartilage-specific type II collagen in early rheumatoid arthritis
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DOI：
10.1002/art.21498
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发表时间：
2006-01-01
影响因子：
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通讯作者：
Reis, A
中科院分区：
文献类型：
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作者：
Burkhardt, H;Hüffmeier, U;Reis, A
目标。目的分析蛋白酪氨酸磷酸酶N22(PTPN22)和人类白细胞抗原DRB1(HLADRB1)等位基因变异对早期类风湿关节炎(RA)11型胶原(CII)免疫优势构象表位(C1(III)；氨基酸残基359~369)的免疫球蛋白抗体形成的影响。从一开始的RA患者队列(n=221；平均症状持续时间为6个月)纳入研究时获得的血清进行了循环抗C1(III)分析。免疫球蛋白自身抗体。一种基于固相偶联合成的三螺旋胶原肽的酶联免疫吸附试验被用来定量不道德的自身免疫反应。采用等位基因特异性聚合酶链式反应、基因组DNA扩增和序列特异性杂交等方法确定HLA-DRB1基因分型。采用等位基因识别TaqMan法进行PTPN22*620W基因分型。早期RA患者抗C_1(III)自身抗体滴度明显高于正常对照组(n=70)。含有RA相关的人类白细胞抗原-DRB1共同表位(SE)等位基因的RA患者的滴度升高比那些没有SE的患者更明显。此外，PTPN22*620W变异与软骨特异性CII决定簇C1(III)的强烈不道德自身免疫反应密切相关。编码T细胞多肽呈递结合口袋(SE)和T细胞受体信号负调节功能域(PTPN22*620W)的等位基因变体分别在早期RA中协同作用，打破对C1(III)的自身耐受，C1(III)是一种进化上保守的软骨决定基因，也经常被作为小鼠关节炎体液自身免疫的靶点。
Objective. To analyze the genetic impact of allelic variants of the protein tyrosine phosphatase N22 (PTPN22) and HLA-DRB1 alleles on IgG autoantibody formation directed toward an immunodominant conformational epitope (C1(III); amino acid residues 359-369) of type 11 collagen (CII) in early rheumatoid arthritis (RA).Methods. Sera obtained at study inclusion from an inception cohort of RA patients (n = 221; mean symptom duration 6 months) were analyzed for circulating anti-C1(III). IgG autoantibodies. An enzyme-linked immunosorbent assay based on solid-phase-coupled synthetic triple-helical collagen peptides was used to quantify Immoral autoimmune responses. HLA-DRB1 genotypes were determined by allele-specific polymerase chain reaction amplification of genomic DNA and sequence-specific hybridization. PTPN22*620W genotyping was performed using an allelic discrimination TaqMan assay.Results. Anti-C1(III) IgG autoantibody titers were significantly elevated in patients with early RA as compared with those in healthy controls (n = 70). The increased titers were more pronounced in RA patients harboring alleles of the RA-associated HLA-DRB1 shared epitope (SE) consensus sequence than in those lacking the SE. In addition, the PTPN22*620W variant was strongly associated with a vigorous Immoral autoimmune response to the cartilage-specific CII determinant C1(III).Conclusion. Allelic variants encoding the binding pocket for peptide presentation (SE) to T cells and a functional domain of a negative regulator of T cell receptor signaling (PTPN22*620W), respectively, synergize in early RA to break self tolerance toward C1(III), an evolutionarily conserved cartilage determinant that is also frequently targeted in arthritogenic humoral autoimmunity in mice.