A Centripetal Antigen‐Sequestration Niche in the Sarcoidosis Granuloma Without Consistent Recruitment of Homeostatic CD10+ Macrophages

Background: The granuloma is the defining lesion of sarcoidosis, yet the internal architecture of the non-necrotising lesion — and whether the homeostatic CD10/MME+ macrophage identity enters it — is unresolved in lung.Objectives: To map the programme-level spatial anatomy of the sarcoidosis granuloma and test prespecified cross-disease predictions.Methods: We analysed 10x Visium spatial transcriptomes of three sarcoidosis lungs and one healthy control (GSE262998), four TSC1/2-deficient granuloma-model mouse lungs (GSE263088) and two validation cohorts (nine explanted sarcoidosis lungs, GSE288607; four tuberculous granuloma sections, GSE296400). Granuloma spots, partitioned into core, rim, mid and far zones, were scored for 25 macrophage modules and 49 convergence signatures.Results: A quadripartite programme — antigen presentation (core 1.48–1.80 vs 1.02–1.28), iron handling (1.30–1.45 vs 0.68–1.22), lysosomal mass (0.69–0.95 vs 0.19–0.51), cell fusion (+0.07 to +0.22 core−far in 3/3 sections) — peaked at the core in all three sarcoidosis sections, while hypoxia was flat, unlike the hypoxic-necrotic tuberculosis archetype; the gradients survived density matching, and deconvolution attributed 59–74% of core elevations to per-spot macrophage content (i.e., 26–41% of the elevations reflect per-cell state change rather than composition). The CD10/MME+ identity was not consistently recruited (core MME 0.22 versus 0.38 at far in one section; weak, inconsistent enrichment in two). All four programmes replicated across 80 sarcoidosis nodules (median Δz +0.20 to +0.52; hypoxia +0.03); tuberculous caseous cores displayed perinecrotic hypoxia cuffs with fusion depleted in the caseum (and not enriched in the viable cuff), and the prespecified foam check was falsified (sarcoidosis-strong).Conclusions: The sarcoidosis granuloma is a centripetally organised, perfusion-preserving antigen-sequestration niche without hypoxia; the homeostatic CD10+ identity is not a consistent niche component.