T Cell Responses to Steroid Cytochrome P450 21-Hydroxylase in Patients with Autoimmune Primary Adrenal Insufficiency
T Cell Responses to Steroid Cytochrome P450 21-Hydroxylase in Patients with Autoimmune Primary Adrenal Insufficiency
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DOI：
10.1210/jc.2009-1115
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发表时间：
2009-12-01
影响因子：
5.8
通讯作者：
Husebye, Eystein S.
中科院分区：
文献类型：
--
作者：
Bratland, Eirik;Skinningsrud, Beate;Husebye, Eystein S.
背景：自身免疫性Addison病被认为是由T细胞介导的自身免疫引起的。在大多数患者中发现了针对甾体源性细胞色素P450酶21-羟化酶（21OH）的自身抗体，因此21OH可能是抗原特异性T细胞的靶标。目的：研究自身免疫性艾迪生病21OH的细胞免疫及其与21OH自身抗体和人白细胞抗原等位基因的关系。设计/患者：收集了33例自身免疫性阿狄森氏病患者和21例对照组的外周血单个核细胞。我们测试了21OH或21OH衍生肽刺激下细胞增殖和细胞因子的产生。结果：与健康对照组相比，患者对21OH反应的细胞增殖（P = 0.0009）和干扰素γ分泌（P < 0.0001）显著增加，并与21OH自身抗体的存在相关（P = 0.0052）。此外，21OH特异性干扰素γ的产生在21OH自身抗体的存在下得到增强。这种作用部分被抗Fc受体IgG、CD32的抗体抑制。此外，成熟树突状细胞比其他抗原呈递细胞更能唤起细胞对21OH的反应。细胞免疫21OH与Addison病高危HLA基因型DRB1*0301-DQ2/DRB1*0404-DQ8之间存在相关性（P = 0.0089）。最后，检测到DRB1*0404- dq8单倍型与预测与DRB1*0404结合的21oh衍生肽的细胞应答之间存在显著关联（P = 0.0055）。结论：自身免疫性Addison病患者存在循环的21OH特异性T细胞，21OH的342-361氨基酸可能构成HLA-DRB1*0404呈递的疾病特异性表位。[J] .中华内分泌杂志，2009:517 - 524。
Context: Autoimmune Addison's disease is thought to result from T cell mediated autoimmunity. Autoantibodies against the steroidogenic cytochrome P450 enzyme 21-hydroxylase (21OH) are found in most patients, and 21OH is therefore a likely target for antigen-specific T cells.Objective: The aim was to study cellular immunity to 21OH and its associations with 21OH auto-antibodies and human leukocyte antigen alleles in autoimmune Addison's disease.Design/Patients: Peripheral blood mononuclear cells were collected from 33 patients with autoimmune Addison's disease and 21 controls. Cellular proliferation and production of cytokines in response to stimulation with 21OH or 21OH-derived peptides were tested.Results: Cellular proliferation (P = 0.0009) and secretion of interferon-gamma (P < 0.0001) in response to 21OH was significantly higher in patients compared to healthy controls and associated with the presence of 21OH autoantibodies (P = 0.0052). Furthermore, the 21OH-specific production of interferon-gamma was enhanced in the presence of 21OH autoantibodies. This effect was partially inhibited by antibodies against the Fc receptor for IgG, CD32. Moreover, mature dendritic cells proved superior to the other antigen-presenting cells in invoking cellular responses to 21OH. An association between cellular immunity to 21OH and the high-risk HLA genotype for Addison's disease, DRB1*0301-DQ2/DRB1*0404-DQ8, was observed (P = 0.0089). Finally, a significant association between the DRB1*0404-DQ8 haplotype and cellular responses to a 21OH-derived peptide predicted to bind to DRB1*0404 was detected (P = 0.0055).Conclusion: Patients with autoimmune Addison's disease have circulating 21OH-specific T cells, with amino acids 342-361 of 21OH possibly constituting a disease-specific epitope presented by HLA-DRB1*0404. (J Clin Endocrinol Metab 94: 5117-5124, 2009)