Targeted Transcriptional Analysis of IgA Vasculitis, IgA Nephropathy, and IgA-Dominant Infection-Related Glomerulonephritis Reveals Both Distinct and Overlapping Immune Signatures

KEY POINTS: Skin IL-9, calprotectin, and KIR gene expression may be predictive of subsequent kidney involvement in patients with IgAV. Histologically similar patients with IgAN, IgAV, and IgA-IRGN can be distinguished by their immune transcriptomes. Kidney biopsies from patients with IgA-IRGN are enriched for transcripts involved in granulocyte chemotaxis. BACKGROUND: IgA vasculitis (IgAV), IgA nephropathy (IgAN), and IgA-dominant infection-related glomerulonephritis (IgA-IRGN) have shared histopathologic features, but differences in clinical management and prognosis. The most serious IgAV organ involvement is in the kidneys (IgAV nephritis). In this study, we hypothesized that targeted immune transcript profiling could aid in (1) predicting the development of IgAV nephritis in patients with cutaneous IgAV and (2) differentiating IgAN, IgAV, and IgA-IRGN. METHODS: RNA was extracted from 24 formalin-fixed paraffin-embedded tissue specimens (16 kidney, 8 skin) from 21 patients with IgAV nephritis (n=7), IgAN (n=5), and IgA-IRGN (n=4), and IgAV skin biopsies from patients with (n=3) and without (n=5) IgAV nephritis. Differential gene expression and gene set enrichment analysis were performed on a total of 594 transcripts (Nanostring immunology panel) profiled using the nCounter system. RESULTS: Skin biopsies in patients with IgAV who develop kidney involvement exhibit reduced S100A8/S100A9, IL9, and killer cell immunoglobulin-like receptor expression. The kidney tissue immune transcriptomes of IgAN, IgAV, and IgA-IRGN are largely overlapping. IgA-IRGN kidney biopsies are, however, uniquely enriched for transcripts involved in granulocyte chemotaxis. CONCLUSION: This study identifies immune transcript signatures that may predict IgAV nephritis in skin biopsies and distinguish IgA-IRGN from IgAN and IgAV in kidney biopsies.