Spatially microdissected profiling of tonsillar germinal centers reveals a KLRG1-enriched immune signature in IgA nephropathy.

BACKGROUND

Geographic variability in the clinical efficacy of tonsillectomy for immunoglobulin A nephropathy (IgAN) suggests population-level differences in mucosal immune architecture. However, the molecular features of the tonsillar germinal center (GC) microenvironment-the central site for IgA class switching and mucosal B-cell activation-remain poorly characterized, particularly in relation to glomerular injury severity.

METHODS

In this exploratory case-control study, we analyzed tonsils from biopsy-proven IgAN (n=5) and matched habitual tonsillitis controls (n=5). Laser microdissection was used to isolate GC plus mantle zone and non-GC regions, followed by immune transcriptomic profiling using the Nanostring Human Immunology V2 Panel. Differential expression was assessed with FDR correction. KLRG1 expression patterns were validated by immunohistochemistry.

RESULTS

Laser microdissection revealed a GC-enriched immune signature in IgAN, characterized by upregulation of KLRG1 (fold change 3.2, p < 0.001) and ZBTB16, alongside downregulation of CCL18, FADD, and TNFRSF17. Immunohistochemistry demonstrated GC-localized KLRG1 expression in IgAN, which appeared more evident in cases with crescentic glomerular lesions. Non-crescentic IgAN showed marginal GC localization, while controls exhibited predominantly extrafollicular KLRG1 expression. Whole-tissue analysis supported enrichment of innate-like lymphocyte-associated genes, consistent with a mucosal activation-associated pattern.

CONCLUSION

This study identifies a spatially defined, KLRG1-enriched GC signature in IgAN. These findings suggest a potential association between GC-localized KLRG1 expression and glomerular injury severity; however, given the exploratory nature and small sample size, they should be considered hypothesis-generating. Further studies are required to validate these observations.