Single-Cell Profiling of Lymphoid and Myeloid Compartments Reveals Coordinated Immune Dysregulation and Enhanced...

Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent cartilaginous inflammation with unclear pathogenesis. The precise alterations in the peripheral immune landscape driving RP pathogenesis remain incompletely defined.

Single-cell RNA sequencing was performed on peripheral blood mononuclear cells from six patients with RP and five matched healthy controls. Bioinformatic analyses characterized cellular composition, transcriptomic profiles, differentially expressed genes, pathway enrichment, metabolic states, and intercellular communication. Plasma levels of alarmins and resistin were measured by enzyme-linked immunosorbent assay.

Patients with RP exhibited a significant reduction in circulating T cells and a trend toward increased CD14⁺ monocytes, neutrophils, and plasma cells. Within T cells, we observed expansion of CD8⁺ subsets and depletion of FCER1G⁺ T, γδT, and mucosal-associated invariant T cells. Transcriptional programs were indicative of enhanced chemotaxis, activation, differentiation, and interferon responses, alongside cytolytic ability in cytotoxic T subsets. B cells exhibited an activated phenotype, increased plasma cell differentiation potential, and metabolic reprogramming. Myeloid cells display robust up-regulation of alarmins (S100A8/9/12) and proinflammatory pathways. Intercellular communication analysis identified CD14⁺ monocytes as dominant signaling hubs, exerting extensive crosstalk via annexin, major histocompatibility complex, resistin, and chemokine ligand-receptor pairs, with enrichment of the ANXA1-FPR1 axis.

This study delineates a comprehensive, cell type-revolved atlas of peripheral immune dysregulation in RP, revealing coordinated alterations in T cell activation and redistribution, B cell differentiation, myeloid-driven inflammation, and prominent alarmin-related signatures. Monocyte-centric signaling networks, potentially orchestrated through the ANXA1-FPR1 pathway, may serve as key amplifiers of systemic inflammation and represent promising targets for therapeutic immune modulation in RP.