Glutamine deamidation does not increase the immunogenicity of C-peptide in people with type 1 diabetes

IF 4.7 Q2 IMMUNOLOGY Journal of Translational Autoimmunity Pub Date : 2023-01-01 DOI:10.1016/j.jtauto.2022.100180
Abby Foster , Pushpak Bhattacharjee , Eleonora Tresoldi , Miha Pakusch , Fergus J. Cameron , Stuart I. Mannering
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引用次数: 1

Abstract

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease in which the insulin-producing beta cells are destroyed. While it is clear that full-length C-peptide, derived from proinsulin, is a major antigen in human T1D it is not clear how and why C-peptide becomes a target of the autoimmune CD4+ T-cell responses in T1D. Neoepitopes formed by the conversion of glutamine (Q) residues to glutamic acid (E) by deamidation are central to the immune pathogenesis of coeliac disease and have been implicated in autoimmune responses in T1D. Here, we asked if the immunogenicity of full-length C-peptide, which comprises four glutamine residues, was enhanced by deamidation, which we mimicked by substituting glutamic acid for glutamine residue. First, we used a panel of 18 well characterized CD4+ T-cell lines specific for epitopes derived from human C-peptide. In all cases, when the substitution fell within the cognate epitope the response was diminished, or in a few cases unchanged. In contrast, when the substitution fell outside the epitope recognized by the TCR responses were unchanged or slightly augmented. Second, we compared CD4+ T-cell proliferation responses, against deamidated and unmodified C-peptide, in the peripheral blood of people with or without T1D using the CFSE-based proliferation assay. While, as reported previously, responses were detected to unmodified C-peptide, no deamidated C-peptide was consistently more stimulatory than native C-peptide. Overall responses were weaker to deamidated C-peptide compared to unmodified C-peptide. Hence, we conclude that deamidated C-peptide does not play a role in beta-cell autoimmunity in people with T1D.

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谷氨酰胺脱酰胺不会增加1型糖尿病患者c肽的免疫原性
1型糖尿病(T1D)是一种t细胞介导的自身免疫性疾病,其中产生胰岛素的β细胞被破坏。虽然很明显,来自胰岛素原的全长c肽是人类T1D的主要抗原,但尚不清楚c肽如何以及为什么成为T1D自身免疫CD4+ t细胞反应的靶标。由谷氨酰胺(Q)残基通过脱酰胺转化为谷氨酸(E)形成的新表位是乳糜泻免疫发病机制的核心,并与T1D的自身免疫反应有关。在这里,我们询问包含四个谷氨酰胺残基的全长c肽的免疫原性是否通过用谷氨酸代替谷氨酰胺残基来模拟脱酰胺而增强。首先,我们使用了一组18个表征良好的CD4+ t细胞系,这些细胞系对源自人c肽的表位具有特异性。在所有情况下,当替换落在同源表位内时,反应减弱,或在少数情况下不变。相比之下,当取代位落在被TCR识别的表位之外时,反应没有变化或略有增强。其次,我们使用基于cfse的增殖试验比较了T1D患者或非T1D患者外周血中CD4+ t细胞对脱酰胺和未修饰c肽的增殖反应。然而,正如之前报道的那样,检测到未修饰的c肽的反应,没有脱酰胺c肽始终比天然c肽更具刺激性。与未修饰的c肽相比,脱酰胺c肽的总体反应较弱。因此,我们得出结论,脱酰胺c肽在T1D患者的β细胞自身免疫中不起作用。
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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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