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

在鼠狼疮模型和人类中的大多数研究都将狼疮性肾炎（LN）等同于 肾小球肾炎（GN）。然而，独立于GN，肾活检中的肾小管间质炎症（TI）是 是肾衰竭的有力预测因素机制研究表明，GN结果 来自B细胞耐受性的系统性破坏和含有抗体的免疫复合物的局部沉积 与普遍存在的自身抗原反应。我们现在提供的证据表明，T1的结果从根本上不同 致病机制比GN。在大多数患有严重TI的患者中，炎性浸润物被组织成 界限清楚的T：B细胞聚集体或含有滤泡树突细胞的生发中心（GC）。 肾活检中出现这些淋巴样结构（三级淋巴样新生，TLN）， 与免疫复合物在肾小管基底膜（TBM）中的沉积密切相关。 随后对原位表达的免疫球蛋白取样，发现GC和T：B中的免疫球蛋白库都受到限制 聚集与本地克隆选择一致。一种主要的 来自肾生殖中心的原位选择性抗体（GC-1）显示与远端肾小管特异性反应， 上皮细胞和肾小管基底膜免疫复合物。GC-1抗体不与 正常肾组织、正常或丙型肝炎肝活检或甚至来自非狼疮患者的肾活检 间质性肾炎基于这些和其他调查结果中描述的初步结果，我们建议， 是原位自身免疫的一种表现，是对特异性表达于细胞中的抗原的耐受性的破坏。 LIN患者的肾小管上皮细胞。 该模型将在以下特定目标中进行测试： 目标1.对LIN中原位免疫球蛋白库进行功能表征。 目标2.鉴定LIN中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.