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.
The goal of this research project is to determine how in situ immune responses contribute to the pathogenesis of human lupus nephritis. These investigations may lead to either new diagnostic tests for lupus nephritis or to identifying new therapeutic targets. Therefore, the proposed studies are of high relevance to the management of patients with lupus.
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