Immunoregulatory role of saliva polymeric IgA1 in the pathogenesis of primary Sjögren’s Syndrome

唾液聚合 IgA1 在原发性干燥综合征发病机制中的免疫调节作用

• 批准号: 10443885
• 负责人: Samantha Hsin-Yu Chiang
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-02 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443885
• 关键词: Abbreviations; Acetylgalactosamine; Agglutinins; Area; Autoantibodies; Autoimmune; Autoimmunity; Binding; Biological Assay; Biopsy; Blood; Buffers; Cells; Chronology; Classification; Clinical; Clinical Management; Collaborations; Collection; Data; Denmark; Diagnosis; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Erythrina cristagalli; Event; Exhibits; Fabaceae; Fibrosis; Future; Galactose; Goals; Human; IgA receptor; IgA1; IgA2; Immune; Immunity; Immunoassay; Immunoglobulin A; Infiltration; Inflammatory; Interleukin-17; Intestines; Korea; Koreans; Lectin; Lesion; Linear Regressions; Literature; Longitudinal Studies; Lung; Lymphocyte; Measurement; Measures; Minor salivary gland structure; Modeling; Monitor; Mononuclear; Outcome; Pathogenesis; Patients; Peripheral; Polymeric Immunoglobulin Receptors; Polymers; Research; Risk; Role; Saliva; Salivary; Salivary Gland Tissue; Salivary Glands; Serology test; Serum; Sjogren' s Syndrome; Statistical Data Interpretation; Testing; Tissues; base; clinical research site; cohort; cytokine; design; detection limit; electric field; electrical measurement; immunoregulation; improved; mucosa-associated lymphoid tissue lymphoma; novel; polymeric IgA; receptor expression; saliva sample; systemic autoimmune disease

PROJECT SUMMARY/ABSTRACT To date, the pathogenesis of primary Sjögren’s Syndrome (pSS) is not well understood resulting in a 3 to 6 year delayed initial diagnosis. Serum anti-Ro/SSA autoantibodies and biopsy focus score are two key classification criteria of pSS by the 2016 ACR-EULAR1. Literature demonstrated that biopsy focus score is positively associated with the area of minor salivary gland fibrosis, common consequence of tissue damage and inflammation2,3. It is unclear whether tissue-resident lymphocyte infiltration or anti-Ro/SSA autoantibodies initiated autoimmune tissue destruction and orchestrated pSS disease progression. This proposal is to investigate the crosstalk between salivary anti-Ro52/SSA and salivary gland tissue destruction. We have developed a saliva-based electrochemical assay, electric field-induced release and measurement (EFIRM), that can screen, earlier detect, risk assess onset of pSS, alternative to the current ELISA blood-based serology assay. Preliminary data demonstrated: 1) EFIRM can directly detect and quantify salivary anti- Ro52/SSA autoantibodies in pSS patients; 2) Salivary and serum anti-Ro/SSA are correlated in pSS and Sicca patients; 3) Salivary anti-Ro52/SSA IgA1 correlate to salivary gland focus scores. IgA exists in two isotypes, IgA1 and IgA2, and IgA1 can further be subdivided into monomeric (mIgA1) and polymeric (pIgA1) subclasses4,5. Human serum IgA1 mostly exists as monomeric form (85-90%) whereas saliva secretory IgA1 are predominantly polymeric form (90-95%) secreted by polymeric Ig receptor (pIgR). Monomeric and polymeric IgA1 are structurally different due to the presence of galactose in the mIgA1, and absence in the pIgA14,6,7. The presence of galactose in mIgA1 can be detected using the galactose-specific legume lectin, Erythrina cristagalli lectin (ECL)8 whereas pIgA1 can be detected using the N-acetylgalactosamine binding lectin, Helix pomatia agglutinin (HPA)9. In addition to structural differences, mIgA1 and pIgA1 also exhibit differential immunoregulatory roles as immune suppressor5,7 and inducer10 respectively. We hypothesize that salivary pIgA1 anti-Ro52/SSA in pSS patients is associated with salivary gland tissue destruction, measured by biopsy focus score. Two Specific Aims are proposed to test this hypothesis. Aim 1 is to develop saliva-based anti-Ro52 mIgA1 and pIgA1 immunoassays. Aim 2 is to measure anti-Ro52 mIgA1 and pIgA1 in saliva of pSS, Sicca, and control subjects to investigate the correlation of saliva pIgA1 to salivary gland fibrosis and destruction. In future research plan, we will investigate the crosstalk between salivary pIgA1 anti-Ro52/SSA and tissue-resident immune T helper 17 cells12–14. Our studies are intended to determine the role of salivary autoantibody, anti-Ro52/SSA polymeric IgA1, in the context of salivary gland destruction in pSS patients.

项目总结/摘要 迄今为止，原发性干燥综合征（pSS）的发病机制尚不清楚，导致3至6年的随访。 延迟的初步诊断。血清抗Ro/SSA自身抗体和活检病灶评分是两个关键的分类 2016年ACR-EULAR 1的pSS标准。文献表明，活检病灶评分为阳性 与小唾液腺纤维化区域相关，这是组织损伤的常见后果， 炎症2，3.目前尚不清楚是否存在组织驻留淋巴细胞浸润或抗Ro/SSA自身抗体 引发自身免疫性组织破坏并协调pSS疾病进展。这项建议是为了 研究唾液抗Ro 52/SSA和唾液腺组织破坏之间的串扰。 我们已经开发了一种基于唾液的电化学检测，电场诱导释放和测量 （EFIRM），可以筛查，早期检测，风险评估pSS的发作，替代目前的ELISA血液为基础的 血清学测定。初步结果表明：1）EFIRM可直接检测和定量唾液抗-HCV， pSS患者中的Ro 52/SSA自身抗体; 2）pSS和Sicca中唾液和血清抗Ro/SSA相关 3）唾液抗Ro 52/SSA IgA 1与唾液腺病灶评分相关。伊加存在两种同种型， IgA 1和IgA 2以及IgA 1可以进一步细分为单体（mIgA 1）和聚合物（pIgA 1）亚类4，5。 人血清IgA 1主要以单体形式存在（85-90%），而唾液分泌IgA 1主要是 由多聚IG受体（pIgR）分泌的多聚形式（90-95%）。单体和聚合的IgA 1是 由于在mIgA 1中存在半乳糖，而在pIgA中不存在，因此在结构上不同14，6，7。存在 半乳糖特异性的豆科植物凝集素--鸡冠刺桐凝集素（Erythrinacristagalli lectin）可以检测到mIgA 1中的半乳糖 （ECL）8，而pIgA 1可使用N-乙酰半乳糖胺结合凝集素，即H. pomatia凝集素 （HPA）9.除了结构差异外，mIgA 1和pIgA 1还表现出不同的免疫调节作用， 免疫抑制剂5、7和诱导剂10。我们假设pSS患者唾液中的pIgA 1抗Ro 52/SSA 患者与唾液腺组织破坏相关，通过活检病灶评分进行测量。 提出了两个具体目标来检验这一假设。目的1是开发基于唾液的抗Ro 52 mIgA 1， pIgA 1免疫测定。目的2检测pSS、Sicca和正常人唾液中抗Ro 52 mIgA 1和pIgA 1抗体 研究唾液pIgA 1与涎腺纤维化和破坏的相关性。在未来的研究中 计划，我们将研究唾液pIgA 1抗Ro 52/SSA和组织驻留免疫T细胞之间的串扰。 辅助17细胞12 -14.我们的研究旨在确定唾液自身抗体，抗Ro 52/SSA， 聚合的IgA 1，在pSS患者的唾液腺破坏的背景下。

项目成果

Distinctive profile of monomeric and polymeric anti-SSA/Ro52 immunoglobulin A1 isoforms in saliva of patients with primary Sjögren's syndrome and Sicca.

原发性干燥综合征和干燥症患者唾液中单体和聚合抗 SSA/Ro52 免疫球蛋白 A1 亚型的独特特征。

• DOI: 10.1136/rmdopen-2023-003666
• 发表时间: 2024
• 期刊: RMD open
• 影响因子: 6.2
• 作者: Chiang,Samantha;Grogan,Tristan;Kamounah,Sarah;Wei,Fang;Tayob,Nabihah;Kim,JuYeon;KyunPark,Jin;Akin,David;Elashoff,DavidA;Pedersen,AnneMarieLynge;Song,YeongWook;Wong,DavidTW;Chia,David
• 通讯作者: Chia,David

Immunoassay Detects Salivary Anti-SSA/Ro-52 Autoantibodies in Seronegative Patients with Primary Sjögren's Syndrome.

• DOI: 10.4049/immunohorizons.2300043
• 发表时间: 2023-07-01
• 期刊: ImmunoHorizons
• 作者: Kamounah S;Tayob N;Chiang S;Wei F;Park JK;Kwon HM;Feng Z;Chia D;Pedersen AML;Song YW;Wong DTW
• 通讯作者: Wong DTW