Pathomechanisms Inducing and Perpetuating an Autoimmune Response in Psoriasis vulgaris

寻常型银屑病诱导和维持自身免疫反应的病理机制

• 批准号: 317045689
• 负责人: Professor Dr. Jörg Christoph Prinz
• 金额: --
• 依托单位: Klinik und Poliklinik für Dermatologie und Allergologie und Städtisches Krankenhaus Thalkirchener-Straße
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/317045689?language=en
• 关键词: Pathomechanisms; Inducing; Perpetuating; Autoimmune; Response

Psoriasis is a complex T-cell mediated autoimmune disease involving genetic predisposition and environmental risk factors. The HLA-class I-allele HLA-C*06:02 is the main psoriasis risk gene. Psoriasis risk is modulated by epistasis between HLA-C*06:02 and certain variants of endoplasmic reticulum aminopeptidase I (ERAP1) which trims precursor peptides to the appropriate length for binding to the peptide-binding groove of HLA class I molecules. Because HLA-class I-molecules present peptide antigens from intracellular proteins to CD8+ T cells, an HLA-class I restricted immune response must be directed against a particular target cell. Psoriasis lesions develop upon epidermal infiltration and activation of CD8+ T cells. Using a pathogenic T-cell receptor (TCR) from a lesional epidermal CD8+ T cell clone of an HLA-C*06:02-positive psoriasis patient we had shown that HLA-C*06:02 mediates an autoimmune response against melanocytes, and we had identified a peptide autoantigen from ADAMTS-like protein 5 (ADAMTSL5) as melanocytic autoantigen. These data established direct experimental evidence for the autoimmune nature of psoriatic inflammation and they provide the basis for the ongoing and the projected research project. For this, the pathogenic psoriatic V Alpha 3S1 / V Beta 13S1-TCR represents a unique opportunity for elucidating the immunopathogenesis of psoriasis. In no other human autoimmune disease a similar approach has been successfully conducted yet. In the ongoing project we could demonstrate that proinflammatory signals cooperate with predisposing HLA-class alleles in promoting the T-cell mediated psoriatic autoimmune response, and we provided data showing that systemic inflammation in psoriasis at least partially results from skin inflammation. We characterized particular structural features of the autoantigenic psoriatic ADAMTLS5 peptide. We showed that protective and risk variants of ERAP1 affect the HLA-C*06:02-restricted autoimmune response against ADAMTSL5 through differential supply of antigenic peptides from NH2-terminal elongated peptide precursors for HLA binding. We identified several environmental antigens from pathogens, microbiota and food that might induce an ADAMTSL5-specific autoimmune response through cross-reactivity of the Vα3S1/Vβ13S1-TCR.In the renewal proposal we plan to finalize the analysis of the specific role of ERAP1 in the HLA-C*06:02-restricted autoimmune response against ADAMTSL5 and melanocytes; we intend to analyze the potential relevance of environmental trigger antigens for inducing a cross-reactive autoimmune response against ADAMTSL5; and we plan to identify B-cell autoantigen(s) which may activate the ADAMTSL5-specific Vα3S1/Vβ13S1-TCR and maintain a continuous supply of autoreactive melanocyte-specific psoriatic T cells. Overall, the insights obtained from these approaches may complete understanding of psoriatic autoimmune pathogenesis and provide a general concept for T-cell mediated autoimmunity.

银屑病是一种复杂的T细胞介导的自身免疫性疾病，涉及遗传易感性和环境危险因素。HLA I类等位基因HLA-C*06：02是银屑病的主要危险基因。银屑病风险由HLA-C*06：02和内质网氨肽酶I（ERAP 1）的某些变体之间的上位性调节，所述ERAP 1将前体肽修剪至适当长度以结合HLA I类分子的肽结合沟。因为HLA I类分子将来自细胞内蛋白的肽抗原呈递给CD 8 + T细胞，所以HLA I类限制性免疫应答必须针对特定的靶细胞。银屑病病变在表皮浸润和CD 8 + T细胞活化后发展。使用来自HLA-C*06：02阳性银屑病患者的病变表皮CD 8 + T细胞克隆的致病性T细胞受体（TCR），我们已经表明HLA-C*06：02介导针对黑素细胞的自身免疫应答，并且我们已经鉴定了来自ADAMTS样蛋白5（ADAMTSL 5）的肽自身抗原作为黑素细胞自身抗原。这些数据为银屑病炎症的自身免疫性质建立了直接的实验证据，并为正在进行的和计划的研究项目提供了基础。因此，致病性银屑病V α 3S 1/ V β 13 S1-TCR代表了阐明银屑病免疫发病机制的独特机会。在其他人类自身免疫性疾病中，类似的方法尚未成功实施。在正在进行的项目中，我们可以证明促炎信号与易感的HLA类等位基因合作，促进T细胞介导的银屑病自身免疫反应，我们提供的数据表明，银屑病的全身炎症至少部分是由皮肤炎症引起的。我们表征了自身抗原性银屑病ADAMTLS 5肽的特殊结构特征。我们发现ERAP 1的保护性和风险性变体通过与HLA结合的NH 2-末端延长肽前体不同的抗原肽供应影响针对ADAMTSL 5的HLA-C*06：02限制性自身免疫应答。我们从病原体、微生物群和食物中发现了几种可能通过Vα 3S 1/Vβ 13 S1-TCR的交叉反应性诱导ADAMTSL 5特异性自身免疫反应的环境抗原。在更新提案中，我们计划完成ERAP 1在针对ADAMTSL 5和黑素细胞的HLA-C*06：02限制性自身免疫反应中的特异性作用的分析;我们打算分析环境触发抗原诱导针对ADAMTSL 5的交叉反应性自身免疫应答的潜在相关性;我们计划鉴定B细胞自身抗原，其可能激活ADAMTSL 5特异性Vα 3S 1/Vβ 13 S1-TCR，并维持自身反应性黑素细胞特异性银屑病T细胞的持续供应。总的来说，从这些方法中获得的见解可能会完成银屑病自身免疫发病机制的理解，并提供了一个T细胞介导的自身免疫的一般概念。

项目成果

Genetic analysis of MPO variants in four psoriasis subtypes in patients from Germany.

德国患者四种银屑病亚型 MPO 变异的遗传分析

• DOI: 10.1016/j.jid.2021.01.017
• 发表时间: 2021
• 期刊: The Journal of investigative dermatology
• 作者: Haskamp;J. S. Horowitz;V. Oji;S. Philipp;M. Sticherling;K. Schakel;S. Schuhmann;J. C. Prinz;H. Burkhardt;F. Behrens;B. Bohm;M. Kohm;J. Rech;D. Simon;G. Schett;K. Morrison;S. Gerdes;G. Assmann;A. Nimeh;V. Schuster;A. Jacobi;A. Weye
• 通讯作者: A. Weye

Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma

• DOI: 10.3389/fimmu.2019.01336
• 发表时间: 2019-06-18
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Arakawa, Akiko;Vollmer, Sigrid;Prinz, Joerg C.
• 通讯作者: Prinz, Joerg C.

Antigen Processing, Presentation, and Tolerance: Role in Autoimmune Skin Diseases.

• DOI: 10.1016/j.jid.2021.05.009
• 发表时间: 2021-07
• 期刊: The Journal of investigative dermatology
• 作者: J. Prinz

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases

• DOI: 10.1016/j.ajhg.2020.07.001
• 发表时间: 2020-09-03
• 期刊: AMERICAN JOURNAL OF HUMAN GENETICS
• 影响因子: 9.8
• 作者: Haskamp, Stefan;Bruns, Heiko;Hueffmeier, Ulrike
• 通讯作者: Hueffmeier, Ulrike