Identification of in situ immune response target antigens in human lupus nephriti

在小鼠狼疮模型和人类中的大多数研究都将狼疮肾炎(LN)等同于 肾小球肾炎(GN)然而，肾活检上的肾小管间质炎症(TL)与肾小球肾炎无关。 是继发性肾功能衰竭的有力预测指标。机械研究表明，GN结果 由于B细胞耐受性的系统性破坏和含有抗体的免疫复合体的局部沉积 与无处不在的自身抗原发生反应。我们现在提供的证据表明，TL是由根本不同的 致病机制优于GN。在大多数重度TL患者中，炎性浸润物被组织成 T：B细胞聚集体或含有滤泡树突状细胞的生发中心(GC)。 肾活检(三级淋巴新生，TLN)中出现这些淋巴样结构。 与免疫复合体在肾小管基底膜(TBM)的沉积密切相关。 随后对原位表达的免疫球蛋白进行采样，发现GC和T：B都有限制性的谱系 与本地克隆选择一致的聚集体。一种优势基因的表达及功能鉴定 来自肾脏生发中心的原位选择抗体(GC-1)显示与远端小管的特异性反应 上皮细胞和肾小管基底膜免疫复合体。GC-1抗体不与之发生反应 正常肾组织、正常或丙型肝炎肝活检，甚至非狼疮患者的肾活检 间质性肾炎。根据初步结果中描述的这些和其他调查结果，我们建议LINE 是原位自身免疫的一种表现，以及对特定表达于 LIN患者的肾小管间质。 这一模式将在以下具体目标下进行测试： 目的1.对LIN中的原位免疫球蛋白进行功能鉴定。 目的2.鉴定LIN的器官特异性自身抗原。

Most studies in both murine lupus models and humans have equated lupus nephritis (LN) with glomerulonephritis (GN). However, tubulointerstitial inflammation (Tl) on renal biopsy, independently of GN, is a strong predictor of subsequent renal failure. Mechanistic investigations have demonstrated 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. We now provide evidence that Tl results from a fundamentally different pathogenic mechanism than GN. In most patients with severe Tl, the inflammatory infiltrate is organized into either well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. The presence of these lymphoid like structures on renal biopsy (tertiary lymphoid neogenesis, TLN) was strongly associated with deposition of immune complexes in tubular basement membranes (TBM). Subsequent sampling of in situ expressed immunoglobulins revealed a restricted repertoire in both GC and T:B aggregates consistent with local clonal selection. Expression and functional characterization of a predominant in situ selected antibody (GC-1) from a renal germinal center revealed specific reactivity with distal tubular epithelial cells and tubular basement membrane immune complexes. The GC-1 antibody did not react with normal renal tissue, normal or hepatitis C liver biopsies or even renal biopsies from patients with non-lupus interstitial nephritis. Based on these and other findings described in Preliminary Results, we propose that LIN is a manifestation of in situ autoimmunity and a break in tolerance to antigens specifically expressed in the tubulointerstitium of patients with LIN. This model will be tested in the following Specific Aims: Aim 1. To functionally characterize the in situ immunoglobulin in repertoire in LIN. Aim 2. To identify organ-specific autoantigens in LIN.