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更新于：2025-05-07

PTPN22

更新于：2025-05-07

基本信息

别名

Hematopoietic cell protein-tyrosine phosphatase 70Z-PEP、Lymphoid phosphatase、Lyp

+ [10]

简介

Acts as a negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr-493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro-inflammatory cytokine secretion and autophagy (PubMed:23991106). Acts as an activator of NLRP3 inflammasome assembly by mediating dephosphorylation of 'Tyr-861' of NLRP3 (PubMed:27043286). Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide) (By similarity).

关联

项与 PTPN22 相关的药物

LTV-1

靶点

PTPN22

作用机制

PTPN22 antagonists

在研机构-

原研机构

Sanford Burnham Prebys Medical Discovery Institute

在研适应症-

非在研适应症

自身免疫性疾病

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PTPN22 相关的临床结果

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100 项与 PTPN22 相关的转化医学

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0 项与 PTPN22 相关的专利（医药）

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1,290

项与 PTPN22 相关的文献（医药）

2025-12-01·Immunologic Research

Deciphering autoimmune susceptibility: a meta-analysis of PTPN22 gene variants

Review

作者: Veerabathiran, Ramakrishnan ; Thomas, Sheena Mariam

Autoimmune disorders are intricate conditions where the immune system directs its attack towards the body's tissues. The goal is to perform a thorough meta-analysis focusing on the genetic and epigenetic aspects of autoimmune disorders, specifically examining the role of the PTPN22 gene, particularly the rs2476601 variation, in influencing susceptibility to autoimmune diseases. The study followed PRISMA 2020 guidelines and PROSPERO registration and conducted a comprehensive meta-analysis to explore the association between PTPN22 gene variations and autoimmune disorders. Case-control studies presenting genotype information were included, and quantitative data analysis was performed using MetaGenyo software. The meta-analysis included 43 studies with 20,669 controls and 9,397 cases of autoimmune diseases, focusing on the PTPN22 gene rs2476601 polymorphism. Significant associations were observed between the PTPN22 polymorphisms across multiple genetic models, including allelic, dominant, and recessive models. However, no link was found between the over-dominant model. The obtained p-values were < 0.01 for the allele model (C vs T; OR: 0.63, 95% CI: 0.48-0.81, I² = 92%), 0.03 for the dominant model (CC + CT vs. TT; OR: 0.47, 95% CI: 0.24-0.95, I² = 87%), and < 0.01 for the recessive model (TT vs. CT + CC; OR: 0.61, 95% CI: 0.47-0.79, I² = 89%). However, the over-dominant model (CT vs. CC + TT; OR: 1.68, 95% CI: 1.32-2.15, I² = 86%) did not show a significant p-value (> 0.05). This meta-analysis emphasizes the significant impact of PTPN22 gene variations on autoimmune diseases, suggesting its potential as a biomarker for assessing risk and guiding targeted interventions.

2025-04-01·The Journal of Molecular Diagnostics

Biomimetic Digital Twins and Multiomics

Article

作者: Brough, Dalton ; Du, Luke ; Glick, Joe ; Kearns, William G ; Stamoulis, Georgios ; Germain, Chandra ; Kearns, Laura ; Baisch, Lawrence ; Benner, Andrew

The National Academies of Sciences, Engineering, and Medicine issued a report on December 15, 2023, "Foundational Research Gaps and Future Directions for Digital Twins." This described the importance of using biomimetic digital twins and multiomics in research. These were incorporated in the current analysis of patients with rheumatoid arthritis (RA). Exome sequencing, genotype-phenotype ranking, and biomimetic digital twin analysis were used to identify five pathogenic and one likely pathogenic DNA variants in patient samples analyzed, which were absent from controls. The variants identified in these genes, P2RX7, HTRA2, PTPN22, FLG, CD46, and EIF4G1, play a role in the development of RA. Additionally, 3172 variants of unknown clinical significance (VUSs) were identified in patient samples, which were absent from controls. All VUSs appeared to be associated with RA. Hidden or dark data were identified from six genes. These genes, often found in patient samples, included HIF1A, HLA-DOA, PTGER3, HIPK3, TGFBR3, and HIF1A-AS3. VUSs identified in genes HIF1A, HLA-DOA, PTGER3, and HIPK3 were directly related to the pathogenesis of RA, whereas VUSs identified in genes TGFBR3 and HIF1A-AS3 were indirectly related. The current results suggest that biomimetic digital twins and multiomics can provide further insight into the development of RA. This may also potentially help with the process of reclassifying VUSs. The reclassification of VUSs will play a critical role in complex molecular diagnostics and drug development.

2025-04-01·Biomaterials

LIFU-unlocked endogenous H2S generation for enhancing atherosclerosis-specific gas-enzymatic therapy

Article

作者: Jiang, Weixi ; Li, Pan ; Du, Chier ; Cheng, Chen ; Zhou, Zhiyi ; Ren, Jianli ; Wang, Jingxue ; Xu, Min ; Ran, Haitao ; Wang, Xiaoting ; An, Hongjin ; Guo, Xun ; Hou, Shengzhe ; Wang, Zhigang ; Qiu, Xiaoling

Atherosclerotic plaques, which are characterized by endothelial oxidative stress, lipid metabolism disorders and persistent inflammation, can induce serious cardiovascular diseases. However, the pharmacotherapies currently used to treat atherosclerosis (AS), such as lipid-lowering and antithrombotic drugs, can regulate only a single pathological feature of AS, and there is still a dearth of integrated platforms for the multifaceted regulation of AS progression. Herein, we developed a synergistic combination of endogenous H₂S gas therapy with a multienzyme-like nanozyme (named ^LyP-1Lip@HS) for the treatment of AS. The high affinity of the LyP-1 peptide for macrophages and foam cells within plaques allows ^LyP-1Lip@HS to actively target atherosclerotic lesions. After cavitation was induced by low-intensity focused ultrasound (LIFU), the lipid membrane of ^LyP-1Lip@HS was disrupted, thereby "unlocking" the enzyme-like activity of hollow mesoporous Prussian blue (HMPB) and facilitating the release of the endogenous H₂S donor S-allyl-L-cysteine (SAC). Notably, H₂S endogenously generated by enzymatic catalysis plays multiple roles, upregulating the ATP-binding cassette transporter A1 in foam cells to increase lipid efflux and promote the conversion of M1 macrophages to M2 macrophages. Moreover, the high level of reactive oxygen species in the inflammatory microenvironment of the plaque was mitigated. Overall, ^LyP-1Lip@HS provides a specific and controlled treatment to prevent oxidative stress, inflammation and lipid metabolism disorders, making it a candidate for AS treatment.

项与 PTPN22 相关的新闻（医药）

2025-04-30

·小药说药

炎症性肠病（IBD）的分子机制和免疫治疗

-01-引言炎症性肠病（IBD）由溃疡性结肠炎（UC）和克罗恩病（CD）组成，全球约有600万至800万人受到影响。作为一种慢性、进行性和复发性的肠道疾病，IBD严重影响患者的生活质量和日常生活，增加医疗负担。虽然目前普遍认为IBD是由遗传易感个体对微生物的异常免疫反应引起的，但其确切的发病机制在很大程度上尚不清楚。目前可用的IBD治疗包括非靶向治疗（如氨基水杨酸、糖皮质激素和免疫调节剂）和靶向治疗（如抗TNF、抗IL-12/IL-23和抗α4β7整合素）。虽然生物靶向疗法对许多患者有效，但依然有高达30%的患者对初始治疗没有反应，高达50%的患者随着时间的推移反应消失。因此，深刻理解肠免疫系统的运行机制和IBD的免疫发病机制，将有助于我们开发针对IBD的免疫治疗药物，并为IBD提供了新的免疫治疗手段。-02-一、肠道免疫系统肠道微生物群人类肠道微生物群由数万亿种微生物组成，包括真菌、单细胞动物、病毒、古生菌和占绝大多数的细菌。肠道微生物群通过调节固有免疫系统的激活，影响宿主能量代谢、免疫稳态和成熟，以及维持粘膜完整性，在IBD的发病机制中发挥着至关重要的作用。越来越多的证据表明IBD患者肠道微生物群的组成发生了改变。例如，大肠杆菌作为病原菌在肠道中增加，具有在巨噬细胞中生存和复制的能力，并诱导IBD中TNF-α的分泌和炎症反应。此外，作为益生菌的prausnitzii粪杆菌可以刺激DC分泌抗炎细胞因子IL-10，并抑制肠道中IL-12和INF-γ的产生，而IBD患者的肠道中这些细胞因子显著减少。此外，IBD患者肠道微生物群的代谢产物也会发生改变，例如胆汁酸代谢中断、色氨酸代谢水平降低、SCFA减少以及烟酸、牛磺酸和酰基卡尼汀水平升高。这些代谢物在肠道炎症过程中的丢失可能是IBD发病的驱动力。肠上皮细胞（IECs）肠上皮是人体最大的粘膜表面，充当管腔内容物和潜在免疫系统之间的物理和生化屏障。它由单层不同亚型的特异性内皮细胞组成，主要包括柱状上皮、杯状细胞和Paneth细胞。杯状细胞作为肠上皮的分泌细胞，可以在肠粘膜的管腔表面分泌粘液，粘液层提供了第一道防线。Paneth细胞是一种特殊的含有颗粒的细胞，存在于小肠的上皮隐窝中，在先天性肠道防御和保护附近干细胞中起着至关重要的作用。它们可以产生抗菌肽（AMP），如α-防御素、溶菌酶C、磷脂酶和C型凝集素等，这些抗菌肽可以对抗侵入的管腔病原体。已经证明，AMP在CD患者中存在缺陷。肠上皮的另一个重要组成部分是顶端连接复合体，由紧密连接（TJ）、粘附连接（AJ）和桥粒组成，紧密密封肠上皮细胞，以防止病原体进入，并调节对水、离子和营养素的渗透性。编码TJ的基因突变和TJ功能障碍已被阐明为IBD的关键致病因素。肠道免疫细胞肠道免疫细胞可分为天然免疫细胞和适应性免疫细胞，这两种细胞对IBD的免疫反应都有很大贡献。固有免疫细胞，如巨噬细胞、树突状细胞（DC）、中性粒细胞、自然杀伤（NK）细胞和固有淋巴细胞（ILC），相互作用并产生细胞因子、趋化因子和抗菌素，以触发炎症，导致吞噬、抗原提呈和适应性免疫系统的激活。巨噬细胞、树突状细胞、中性粒细胞、NKT细胞和ILC构成粘膜固有免疫系统的第一道防线。这些固有免疫系统的免疫细胞通过病原体相关分子模式（PAMP），导致多种信号通路的激活，并产生促炎细胞因子、趋化因子和抗菌肽。与天然免疫细胞相比，适应性免疫细胞具有高度的特异性和免疫记忆能力，它们相互补充，消除入侵病原体。适应性免疫反应的关键参与者是T细胞，在肠道相关淋巴组织（GALT）或肠系膜淋巴结中的抗原刺激下，原始T细胞被激活并分化为不同的亚群，在趋化因子受体（如CCR9和CCR10）和整合素等细胞粘附分子作用下迁移到肠道的炎症部位。如今，许多针对这些受体的药物已成功用于临床实践，以阻止T细胞向肠道迁移，以预防IBD患者的炎症。-03- 二、IBD的免疫学发病机制IL-22和IL-6IL-22是一种多效性细胞因子，由Th22、Th17和Th1细胞分泌，激活STAT3以促进肠组织修复并抑制肠道病原体。在IBD中，IL-22受微生物群的信号诱导在小肠中广泛表达。此外，IL-22还促进IBD易感基因如fut2、sec1、bcl2115和PTPN22的表达。IL-6主要由固有层中的巨噬细胞和树突状细胞产生。研究发现，CD患者血清和肠道中IL-6水平升高，并与临床疾病活动、复发频率和炎症严重程度相关。与受体结合后，IL-6激活gp130阳性T细胞，导致STAT-3信号转导和转录激活，随后激活抗凋亡基因Bcl-2和Bcl-xl的转录。目前，人源化抗IL-6R单克隆抗体tocilizumab已经用于治疗IBD。IL-12/IL-23由树突状细胞产生的IL-12和IL-23均属于IL-12家族，在慢性炎症性疾病的发病机制中发挥重要作用。在几种结肠炎模型中，致病性T细胞反应由IL-12和IL-23驱动。IL-12可以促进原始CD4+T细胞分化为产生IFN-γ的Th1细胞，并促进NK细胞、NKT细胞和细胞毒性T细胞的增殖和效应功能。IL-23通过加强和影响Th17细胞反应来发挥其生物学功能，同时它还拮抗抗炎Foxp3+Treg细胞反应从而促进肠道炎症。IL-17IL-17细胞因子，包括IL-17A和IL-17F，也在IBD的发病机制中发挥重要作用。全基因组关联研究（GWAS）已确定了许多与Th17相关的IBD易感基因，包括JAK2、STAT3、IL-23R、IL-12B和CCR6。临床研究发现，与健康对照组相比，IBD患者的肠粘膜和固有层中含有更高水平的Th17细胞、IL-17和IL-23。在小鼠模型中，IL-17A和IL-17F的缺陷显示对结肠炎具有保护作用。Il-10IL-10是抑制免疫系统促炎反应的最重要细胞因子，可由大量不同类型的细胞产生，包括Treg、巨噬细胞、树突状细胞等。在IBD患者的早期发病过程中，IL-10R亚单位基因的突变与肠道炎症免疫反应有关。事实上，IL-10和IL-10R缺陷小鼠都可以发生自发性结肠炎。此外，Treg细胞中c-MAF失活也会导致IL-10产生功能障碍，从而发展为自发性结肠炎。IL-1β家族细胞因子IL-1β是一种由巨噬细胞分泌的促炎细胞因子，与其他促炎细胞因子（如TNF-α和IL-6）协同作用，以诱导IBD炎症。研究发现，IL-10缺陷小鼠在自发性结肠炎发病前IL-1β分泌增加。此外，IL-1β和IL-18信号的遗传缺陷或抑制可缓解实验性结肠炎。TNF和TNF样配体1A（TL1A）TNF被认为是IBD发病机制中的促炎细胞因子，可刺激急性期时的反应，促进IL-1和IL-6的分泌，增加粘附分子的表达。研究发现，活动期IBD患者的血液、上皮组织和粪便中TNF-α显著升高，其水平与CD患者的临床疾病活动性相关。通过抗TNF-α单克隆抗体阻断TNF-α信号已成为中重度难治性IBD患者的重要治疗方法。TNF家族成员TL1A也被发现是肠道炎症的关键介质，在IBD患者中水平也升高。TL1A主要通过结合死亡受体3（DR3）发挥其功能，TL1A还可以协同促进IL-4、IL-12和IL-23的产生，并通过Th1、Th2和Th17细胞增加DR3的表达，以促进炎症。免疫细胞迁移免疫细胞迁移到肠道以启动和维持免疫反应是IBD的关键发病机制，其中T细胞迁移是最重要的一个。免疫细胞迁移的完整过程包括栓系、滚动、激活、粘附和外渗，涉及各种整合素、选择素、趋化因子及其配体或受体，例如促进迁移到小肠的整合素α4β7、α4β1、β2整合素和CCR9。针对免疫细胞迁移不同阶段的多种治疗方法已经应用于临床。-04-三、IBD的免疫治疗目前，7种生物制剂已被美国食品和药物管理局（FDA）正式批准用于治疗IBD，许多治疗IBD的创新候选药物的临床试验也正在进行中。靶向TNF-α抗TNF的抗体已广泛使用约25年。目前，四种TNF-α抑制剂已被批准用于临床，包括infliximab、adalimumab、golimumab和certolizumab pegol。infliximab可诱导粘膜溃疡愈合，这是第一种被批准用于CD肛周瘘的治疗方法，并被证明对CD和UC都有效。Adalimumab被证明可诱导CD的粘膜愈合，它对CD和UC以及对infliximab失去反应的CD患者也有效。此外，golimumab和certolizumab pegol也在美国被批准用于治疗UC。虽然抗肿瘤坏死因子治疗显示出临床疗效，但10-30%的IBD患者没有响应，20-40%的患者随着时间的推移失去响应。靶向IL-12/IL-23Ustekinumab是针对IL-12和IL-23的p40亚单位的单克隆抗体，在治疗IBD中显示出积极作用，它是目前FDA批准的唯一一种抗IL-23疗法。另一个靶点是针对IL-23的p19亚单位，也显示出了临床疗效，包括risankizumab、brazikumab、guselkumab和Mirikizumab。然而，这些抗体仍处于临床试验阶段。靶向JAKJanus激酶（JAK）家族包含四种细胞内酪氨酸激酶：JAK1、JAK2、JAK3和非受体酪氨酸蛋白激酶2，它们激活STAT通路并在IBD的发病机制中发挥关键作用。目前，已经评估了10种JAK抑制剂对IBD的临床疗效，而Tofacitinib是唯一具有临床疗效的抑制剂，并被批准用于UC的临床治疗。靶向细胞粘附分子作为T细胞募集和肠道炎症的重要介质，细胞粘附分子是IBD的潜在靶点。例如，抗α4β7整合素抗体vedolizumab和抗a4整合素单克隆抗体natalizumab在治疗IBD方面显示出了很好的疗效，目前已被批准并广泛应用于临床。此外，Etrolizumab（一种选择性结合β7亚单位的单克隆抗体）、abrilumab（一种阻断α4β7整合素的单克隆抗体）和ontamalimab（一种靶向MAdCAM-1的人源化抗体）在临床前数据中也显示出疗效，目前仍在进行临床试验。靶向NLRP3炎症小体NLRP3炎症小体和促炎细胞因子水平升高是IBD的主要病理机制。已经观察到CD患者具有高水平的NLRP3炎症小体。此外，活化的NLRP3炎性小体可促进过量IL-1β的产生，并改变结肠上皮中TJ的表达，从而加速疾病进展。因此，靶向NLRP3炎症小体为IBD治疗提供了一种有前景的策略。-05-结语在过去的几十年里，IBD的免疫学机制取得了很大进展，为IBD的治疗提供了新的策略和新的思路。在未来，特定基因位点的改变可能是IBD很有希望的治疗方法。此外，新型抗体或抑制剂、联合治疗方案和多因子阻断剂也有望打破IBD治疗的瓶颈，为IBD的患者的疾病改善带来福音。参考资料：1.Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics. J Inflamm Res.2022; 15: 1825–1844.

免疫疗法微生物疗法

2025-04-24

·PRNewswire

TEDCO's Maryland Innovation Initiative Announces FY2025 Technology Assessment Awards

Over $1 million awarded to 7 university projects COLUMBIA, Md., April 24, 2025 /PRNewswire/ -- TEDCO, Maryland's economic engine for technology companies, announced the next round of Maryland Innovation Initiative (MII)'s Technology Assessment awards, marking a significant milestone in promoting the commercialization of groundbreaking research from Maryland's prestigious academic research institutions. The Technology Assessment award is a nine-month project that builds on strong preliminary data that demonstrates the technology's utility for specific commercial applications beyond basic research. TEDCO MII Team Maryland Innovation Initiative (PRNewsfoto/TEDCO) Over $1 million awarded to 7 university projects in Maryland Post this "The Technology Assessment phase of our program provides non-dilutive funding to advance technologies with commercial potential," said Abi Kulshreshtha, MII's executive director. "In this award cycle, the Maryland Innovation Initiative staff and technical reviewers selected seven projects from a competitive pool of applicants, which altogether received grants totaling more than $1 million to advance innovations ranging from new cancer therapeutics to inclusive AI-driven education technology solutions." The seven awardees are below: Heather Ames: Cell-HKer/siRaf, a promising therapeutic for Solid Tumors; University of Maryland, Baltimore Kevin Aroom: The Baby Gro Pro Smartscale: improving early diagnosis of medical problems and rare diseases; University of Maryland, College Park Steven Bernstein: Development of a novel optic nerve-stem cell therapy for glaucoma prevention and treatment; University of Maryland, Baltimore Won Jin Ho: Targeting PTPN22 for cancer immunotherapy; Johns Hopkins University Melanie Killen: Utilizing natural language processing technology for creating inclusive classrooms resubmission; University of Maryland, College Park Yuxing Li: Development and evaluation of a C. difficile-specific endolysin and dual therapy for C. difficile infection; University of Maryland, Baltimore Venkataramana Sidhaye: Development of a novel inhaled gene therapy, based on HAPLN1 transgene expression, for treating COPD; Johns Hopkins University Startup companies joining TEDCO's MII portfolio have access to a variety of TEDCO resources including mentor opportunities. A complete list of funded companies can be found on the MII webpage (here). MII's Funding Opportunities The MII program, administered by TEDCO, was created as a collaboration between the State of Maryland and five leading academic research institutions—Johns Hopkins University, Morgan State University, University of Maryland, Baltimore, University of Maryland, Baltimore County, and University of Maryland, College Park— that aims to leverage each institution's strengths to transition promising technologies into the commercial sector. "MII continues to bring innovation from lab to market," said Renée Winsky, chair of the MII Board of Directors. "Since inception, it has supported the creation of nearly 400 jobs, created or supported more than 190 startups, and invested over $58 million in the Maryland innovation ecosystem and we look forward to continuing this progress." MII has also expanded its reach to include two additional comprehensive universities, Frostburg State University and Bowie State University, along with the creation of the Baltimore Innovation Initiative (BII). All of these pilot programs aim to foster a more equitable innovation and entrepreneurial ecosystem across Maryland. For more information, visit the MII webpage. About TEDCO TEDCO, the Maryland Technology Development Corporation, enhances economic empowerment growth through the fostering of an inclusive entrepreneurial innovation ecosystem. TEDCO identifies, invests in, and helps grow technology and life science-based companies in Maryland. Learn more at . Media Contact Tammi Thomas, Chief Development & Marketing Officer, TEDCO, [email protected] Rachael Kalinyak, Associate Director, Marketing & Communications, TEDCO, [email protected] SOURCE TEDCO WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法

2024-12-07

·生物制药小编

类风湿性关节炎进展三部曲

类风湿性关节炎（rheumatoid arthritis，RA）是一个终身病程，在这个过程中，个体逐渐失去了自我耐受性，开始产生自身抗体，在经历了一个比较长的无症状期之后，进入急性炎症期，最后进入慢性炎症期，导致关节以及其他组织的不可逆的结构性损伤。文献1 现有的抗炎药物治疗，基本上还是针对终末期的慢性炎症，此时关节等组织可能已经遭受了不可逆的损伤，很难进行恢复。本文介绍一篇由斯坦福大学发表在Nature Immunology的文章，他们根据RA的进程，分为三个主要阶段，设置三个检测点，希望能够更多解析和表征早期疾病特征及其机制，寻找诊断及干预治疗的方法。 RA病程中的三个检查点（文献2） 1. 自身耐受的破坏 20世纪90年代初的流行病学研究表明，早在滑膜炎发生之前就存在RFs。RA自身免疫不是针对天然肽序列，而是针对翻译后修饰的蛋白质（包括糖基化的IgG Fc）。由于胸腺选择不清除识别蛋白质修饰的T细胞，发生外周耐受缺陷，被认为是RA的主要原因。 RA的主要遗传危险因素促进了自身抗体的产生。共享表位阳性HLA-DRB1等位基因和PTPN22变异体与RFs和抗瓜氨酸蛋白抗体(ACPA)的产生有关。在HLA-DRB1*04的背景下，T细胞可以识别瓜氨酸化抗原， B细胞包含大量针对瓜氨酸化蛋白自身免疫性B细胞，其递呈抗原给T细胞。控制自身免疫阶段稳定和进展的机制依赖于T细胞。柠檬苦素和羰基化反应是不同的化学反应，既有普遍的反应，也有生理的反应，没有疾病特异性。羰基化是赖氨酸的一种不依赖酶的衍生化，需要活性代谢物氰酸盐，本质上是不可逆的。相比之下，瓜氨酸是一种酶介导的精氨酸残基去亚胺基化。组织炎症和吸烟上调肽基精氨酸去亚胺基酶的表达。自身抗原的丰度对于破坏外周耐受不是很重要。但是翻译后修饰肽详尽的破坏外周耐受的机制尚不清楚，瓜氨酸化、羰基化和糖基化与其他翻译后修饰相比，到底哪些特征对于打破外周耐受是重要的，也还没有清晰的研究。 2. 从无症状过渡到组织炎症在长时间无症状的自身免疫后，RA患者进入急性组织炎症期。自身耐受的破坏在关节外启动，随着先天免疫和适应性免疫细胞进入滑膜，病变位置变换到关节部位。检查点2，临床上以滑膜炎症为标志，与CD4+T细胞内在缺陷密切相关。 T细胞分化缺陷（文献2）造血干细胞，中性粒细胞和幼稚和记忆CD4T细胞DNA修复不足，导致受损DNA在细胞核、端粒末端和线粒体中的积累。下游后果包括细胞周期偏差、过早的端粒丢失和mtDNA的细胞质泄漏，从而触发炎症小体的激活。最终，DNA修复不足会导致T细胞分化缺陷，诱导短寿命效应T细胞，而牺牲长寿命记忆前体细胞。此外，未修复的DNA损伤促进T细胞焦亡、免疫衰竭和过早免疫老化。 RA病人T细胞代谢异常（文献2） mtDNA的断裂影响电子传递链，损害ATP和代谢中间体的产生，并重新编程细胞的能量生产和生物合成程序。 3. 急性滑膜炎转变为慢性持续滑膜炎不是所有在早期滑膜炎临床上出现的患者都进展为慢性滑膜炎和滑膜环境的不可逆结构慢性滑膜炎。从急性滑膜炎向慢性滑膜炎过渡的关键决定因素必须来自局部组织环境，包括成纤维细胞及浸润的各类炎症细胞，当然最主要的致病细胞是T细胞。滑膜成纤维细胞是如何被激活的还不清楚，但发生焦亡的组织浸润性T细胞是炎症和重塑的有力诱导剂。致病T细胞驱动慢性的另一条途径是形成三级淋巴组织，产生持续的慢性炎症。下表为RA病人滑膜组织的主要炎症细胞亚群及标志物：简评在未发生不可逆损伤之前，在未形成三级淋巴组织之前，尽早干预和治疗，对于类风湿性关节炎患者获得更好的预后，改善生活质量是重要的。显然如何维护外周耐受，如减少体内蛋白质非必须的蛋白翻译后修饰，减少T细胞等的DNA损伤或者增强DNA修复，维持T细胞正常分化，减少病理性T细胞等，都是很有意义的研究。而这些或多或少和生活及工作习惯有关联，做好相应的教育和管理，或许也同样重要。参考文献 Myrthe A M van Delft , Tom W J Huizinga，An overview of autoantibodies in rheumatoid arthritis，J Autoimmun . 2020 Jun;110:102392. Cornelia M Weyand, Jörg J Goronzy.The immunology of rheumatoid arthritis,Nat Immunol . 2021 Jan;22(1):10-18.