Snijders A, Elferink D G, Geluk A, van Der Zanden A L, Vos K, Schreuder G M, Breedveld F C, de Vries R R, Zanelli E H
Immunohematology and Blood Transfusion and Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
J Immunol. 2001 Apr 15;166(8):4987-93. doi: 10.4049/jimmunol.166.8.4987.
Predisposition to rheumatoid arthritis (RA) is thought to be associated with HLA-DR1, -DR4, and -DR10. However, many epidemiological observations are better explained by a model in which the DQ alleles that are linked to these DR alleles, i.e., DQ5, DQ7, and DQ8, predispose to RA, while certain DR alleles have a dominant protective effect. All protective DRB1 alleles, e.g., *0402, *1301, and 1302, encode a unique motif, (70)DERAA(74). The protection may be explained by the presentation of DRB1-derived peptides by DQ to immunoregulatory T cells, because it was demonstrated in various autoimmune disease models that T cell responses to certain self-Ags can be involved in disease suppression. The aim of this study was to analyze whether peptides carrying the DERAA motif are naturally processed by human APC and presented in the context of the RA-predisposing DQ. Using a synthetic peptide carrying the DRB10402-derived sequence (65)KDILEDERAAVDTYC(79), we generated DERAA peptide-specific DQ-restricted T cell clones (TCC) from a DQ8 homozygous individual carrying DERAA-negative DR4 alleles. By analyzing the proliferation of these TCC, we demonstrated natural processing and presentation of the DERAA sequence by the APC of all the individuals (n = 12) carrying a DERAA-positive DRB1 allele and either DQ8 or the DQ8-related DQ7. Using a panel of truncated synthetic peptides, we identified the sequence (67)(I)LEDERAAVD(TY)(78) as the minimal determinant for binding to DQ8 and for recognition by the TCC. These findings support a model in which self-MHC-derived peptide can modulate predisposition to autoimmune disease in humans.
类风湿关节炎（RA）的易感性被认为与HLA - DR1、- DR4和 - DR10相关。然而，许多流行病学观察结果用一种模型能更好地解释，在该模型中，与这些DR等位基因连锁的DQ等位基因，即DQ5、DQ7和DQ8，易患RA，而某些DR等位基因具有显性保护作用。所有保护性DRB1等位基因，例如*0402、1301和1302，都编码一个独特的基序（70）DERAA（74）。这种保护作用可能是由于DQ将DRB1衍生的肽呈递给免疫调节性T细胞来解释，因为在各种自身免疫性疾病模型中已证明，T细胞对某些自身抗原的反应可能参与疾病抑制。本研究的目的是分析携带DERAA基序的肽是否由人抗原呈递细胞（APC）自然加工并在易患RA的DQ背景下呈递。使用携带DRB1 * 0402衍生序列（65）KDILEDERAAVDTYC（79）的合成肽，我们从携带DERAA阴性DR4等位基因的DQ8纯合个体中产生了DERAA肽特异性的DQ限制性T细胞克隆（TCC）。通过分析这些TCC的增殖，我们证明了所有携带DERAA阳性DRB1等位基因以及DQ8或与DQ8相关的DQ7的个体（n = 12）的APC对DERAA序列进行了自然加工和呈递。使用一组截短的合成肽，我们确定序列（67）（I）LEDERAAVD（TY）（78）是与DQ8结合以及被TCC识别的最小决定簇。这些发现支持了一种模型，即自身MHC衍生的肽可以调节人类自身免疫性疾病的易感性。
