Tertiary Lymphoid Neogenesis in Human Lupus Nephritis

人类狼疮性肾炎的三级淋巴新生

• 批准号: 8431406
• 负责人: Marcus Ramsay Clark
• 金额: $ 32.2万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431406
• 关键词: Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigenic Specificity; Antigens; Applications Grants; Arthralgia; Autoantigens; Autoimmune Diseases; Autoimmunity; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Basement membrane; Biopsy; Cell Separation; Cerebritis; Cicatrix; Clinical; Clonal Expansion; Clone Cells; Coupled; Deposition; Development; Diffuse; Disease; Exanthema; Follicular Dendritic Cells; Framework Regions; Glomerulonephritis; Health; Human; Immune response; Immunoglobulin Somatic Hypermutation; Immunoglobulin Variable Region; Immunoglobulins; In Situ; Inflammation; Inflammatory Infiltrate; Kidney; Lasers; Left; Life; Light; Lupus; Lupus Nephritis; Lymphoid; Microscopy; Modeling; Mus; Nephritis; Organ failure; Pathogenesis; Patients; Pattern; Peripheral; Phenotype; Pneumonia; Population; Prevalence; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Tubular formation; Tubulointerstitial Nephritis; interstitial; novel; outcome forecast; response; vector

DESCRIPTION (provided by applicant): The most frequent severe manifestation of SLE is lupus nephritis (LN). Pathologically, lupus nephritis (LN) is characterized by immune complex deposition and inflammation in both glomeruli and tubuluointersitium that, if left untreated, can result in scarring and irreversible organ failure. Of the pathological manifestations of LN, glomerulonephritis (GN) is both the best studied and the feature most often replicated in murine models of autoimmune disease. However, tubulointerstitial inflammation is also a usual feature of LN that contributes to overall disease activity and determines long-term prognosis. Myriad studies indicate that GN results from a systemic break in B cell tolerance and the local deposition of immune complexes containing antibodies reactive with ubiquitous self-antigens. However, the pathogenesis of SLE tubulointerstitial disease is not known. In this grant application, we demonstrate that in over half of patients, the tubulointerstitial inflammatory infiltrate is organized into either well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of in situ expressed immunoglobulins using laser capture microscopy coupled to RT-PCR revealed a restricted repertoire in both histological patterns that likely arose from local clonal expansion. Furthermore, the pattern of somatic hypermutations in GC expressed immunoglobulins was consistent with ongoing antigen-driven selection. The presence of either T:B aggregates or GCs was strongly associated with more severe tubulointerstitial inflammation and the deposition of immune complexes in tubular basement membranes. These observations raise the novel possibility that lupus tubulointerstitial nephritis is not a manifestation of systemic autoimmunity to ubiquitous autoantigens. Rather, it might result from a break in tolerance to locally expressed antigens. In this grant application, we hypothesize that in lupus nephritis, in situ selected B cells secrete autoreactive antibodies which deposit in the tubulointerstitium and contribute to local inflammation. This hypothesis will be tested in the following Specific Aims: Aim 1. To characterize in situ B cell responses in lupus nephritis biopsies manifesting the diffuse, T:B aggregate and GC histological patterns. Aim 2: To determine the origin of the in situ B cell repertoire in lupus nephritis. In Aim 3: To identify the antigenic specificities of in situ expressed antibodies in SLE nephritis. PUBLIC HEALTH RELEVANCE The most prevalent, severe manifestation of systemic lupus erythematosus is nephritis. Recently, we have demonstrated that tertiary lymphoid neogenesis is a common feature of lupus nephritis that is associated with severe tubulointerstitial inflammation. In this application, we will determine if tubulointerstitial nephritis results from a local break in tolerance and the development of in situ immune responses.

描述（由申请人提供）：SLE 最常见的严重表现是狼疮性肾炎 (LN)。在病理学上，狼疮性肾炎 (LN) 的特点是肾小球和肾小管间质中的免疫复合物沉积和炎症，如果不及时治疗，可能会导致疤痕和不可逆的器官衰竭。在 LN 的病理表现中，肾小球肾炎 (GN) 是研究最深入的，也是自身免疫性疾病小鼠模型中最常复制的特征。然而，肾小管间质炎症也是 LN 的一个常见特征，它有助于整体疾病活动并决定长期预后。大量研究表明，GN 是由于 B 细胞耐受性的系统性破坏以及含有与普遍存在的自身抗原发生反应的抗体的免疫复合物局部沉积所致。然而，SLE 肾小管间质疾病的发病机制尚不清楚。在这项拨款申请中，我们证明，在超过一半的患者中，肾小管间质炎症浸润组织成边界良好的 T:B 细胞聚集体或含有滤泡树突状细胞的生发中心 (GC)。使用激光捕获显微镜结合 RT-PCR 对原位表达的免疫球蛋白进行取样，揭示了两种组织学模式中的受限库，这可能是由局部克隆扩张引起的。此外，GC 表达的免疫球蛋白的体细胞超突变模式与正在进行的抗原驱动选择一致。 T:B 聚集体或 GC 的存在与更严重的肾小管间质炎症和肾小管基底膜中免疫复合物的沉积密切相关。这些观察结果提出了一种新的可能性，即狼疮性肾小管间质性肾炎并不是对普遍存在的自身抗原的全身性自身免疫的表现。相反，它可能是由于对局部表达抗原的耐受性中断所致。在本次拨款申请中，我们假设在狼疮性肾炎中，原位选择的 B 细胞会分泌自身反应性抗体，这些抗体沉积在肾小管间质中并导致局部炎症。该假设将在以下具体目标中得到检验： 目标 1. 表征狼疮性肾炎活检中表现出弥漫性、T:B 聚集和 GC 组织学模式的原位 B 细胞反应。目标 2：确定狼疮性肾炎原位 B 细胞库的起源。目标 3：鉴定 SLE 肾炎原位表达抗体的抗原特异性。公共卫生相关性 系统性红斑狼疮最常见、最严重的表现是肾炎。最近，我们证明三级淋巴新生是狼疮性肾炎的一个常见特征，与严重的肾小管间质炎症相关。在此应用中，我们将确定肾小管间质性肾炎是否是由局部耐受性破坏和原位免疫反应的发展引起的。