HLA-DR4-Associated T and B Cell Responses to Specific Determinants on the IA-2 Autoantigen in Type 1 Diabetes
HLA-DR4-Associated T and B Cell Responses to Specific Determinants on the IA-2 Autoantigen in Type 1 Diabetes
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DOI：
10.4049/jimmunol.1301902
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发表时间：
2014-11-01
影响因子：
4.4
通讯作者：
Christie, Michael R.
中科院分区：
文献类型：
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作者：
McLaughlin, Kerry A.;Gulati, Kavita;Christie, Michael R.
1型糖尿病患者IA-2自身抗体与HLA-DR4相关，提示HLA-DR4限制性T细胞对IA-2特异性B细胞反应的影响。本研究的目的是通过确定IA-2表位的自身抗体是否与T细胞对DR4呈递的IA-2肽的反应相关，来研究可能的T- b细胞协同作用。通过细胞因子ELISPOT对hla型糖尿病患者体内分泌ifn - γ和IL-10细胞因子以响应7种已知的引起1型糖尿病患者T细胞应答的肽进行定量。T细胞对所有测试的肽均有反应，但只有IL-10对841-860和853-872肽的反应与DR4相关。facs分类的CD45RO(hi) T细胞分泌IL-10响应这两种肽，通过RT-PCR进行表型分析表明，这些细胞表达gta3或T-bet，但不表达FOXP3，这与它们是Th2或Th1记忆T细胞而不是调节性表型一致。T细胞对这两种肽的反应也与特异性抗体相关：对841-860肽的反应与抗体对近膜表位的反应有关，这些表位出现在糖尿病前期早期，而对853-872肽的反应与抗体对位于IA-2酪氨酸磷酸酶域831-862中心区域的表位的反应与抗体有关。抗体对膜旁和中央区域的构建均与DR4相关。本研究确定了HLA- dr4糖尿病患者B细胞和T细胞对IA-2反应的焦点区域，这可能解释了IA-2自身抗体与HLA的关联，并且该区域可能为未来免疫干预提供靶点以预防疾病。
Autoantibodies to IA-2 in type 1 diabetes are associated with HLA-DR4, suggesting influences of HLA-DR4-restricted T cells on IA-2-specific B cell responses. The aim of this study was to investigate possible T-B cell collaboration by determining whether autoantibodies to IA-2 epitopes are associated with T cell responses to IA-2 peptides presented by DR4. T cells secreting the cytokines IFN-gamma and IL-10 in response to seven peptides known to elicit T cell responses in type 1 diabetes were quantified by cytokine ELISPOT in HLA-typed patients characterized for Abs to IA-2 epitopes. T cell responses were detected to all peptides tested, but only IL-10 responses to 841-860 and 853-872 peptides were associated with DR4. Phenotyping by RT-PCR of FACS-sorted CD45RO(hi) T cells secreting IL-10 in response to these two peptides indicated that these expressed GATA-3 or T-bet, but not FOXP3, consistent with these being Th2 or Th1 memory T cells rather than of regulatory phenotype. T cell responses to the same two peptides were also associated with specific Abs: those to 841-860 peptide with Abs to juxtamembrane epitopes, which appear early in prediabetes, and those to peptide 853-872 with Abs to an epitope located in the 831-862 central region of the IA-2 tyrosine phosphatase domain. Abs to juxtamembrane and central region constructs were both DR4 associated. This study identifies a region of focus for B and T cell responses to IA-2 in HLA-DR4 diabetic patients that may explain HLA associations of IA-2 autoantibodies, and this region may provide a target for future immune intervention to prevent disease.