Background: Based on our previous work demonstrating that interactions between TIGIT ⁺ SLAMF7 ⁺ Tfh2 cells and SLAMF7 ⁺ B cells in peripheral blood mononuclear cells (PBMCs) from patients with IgG4-related disease (IgG4RD) drive differentiation into IgG4-secreting plasma cells.

Objectives: This study aimed to spatially define the pathogenic mechanisms underlying IgG4-producing plasma cell differentiation within IgG4RD mass-forming tissues. To this end, we applied spatial transcriptomic and proteomic profiling to IgG4RD-involved lymph nodes and salivary glands to map pathogenic cellular niches and cell–cell interactions governing IgG4 plasma cell differentiation in situ.

Methods: We employed spatial transcriptomic (Visium HD) and spatial proteomic (MACSima) platforms to systematically compare IgG4RD mass lesions in lymph nodes and salivary glands with normal control tissues, aiming to define the cellular interactions and spatial mechanisms driving the deposition and accumulation of IgG4-secreting plasma cells in IgG4RD.

Results: Spatial transcriptomic analysis revealed that clusters of TIGIT ⁺ SLAMF7 ⁺ Tfh2 cells and SLAMF7 ⁺ B cells were significantly expanded in IgG4RD mass-forming tissues compared with controls, accompanied by marked upregulation of SLAMF7 transcripts mediating cell–cell interactions. In parallel, IgG4 ⁺ plasmablast/plasma cell clusters were prominently expanded, with a significant increase in tissue IgG4 accumulation in IgG4RD lesions. These findings were validated by spatial proteomic analysis, which demonstrated direct interactions between TIGIT ⁺ SLAMF7 ⁺ Tfh2 cells and SLAMF7 ⁺ B cells, occurring at significantly higher frequencies in IgG4RD tissues than in controls. Ligand–receptor analysis identified these interactions to be mediated through the SLAMF7–SLAMF7 signaling axis. Notably, IgG4 deposition was enriched in the immediate spatial vicinity of these interacting cellular niches, indicating a tight spatial coupling between cellular interactions and pathogenic IgG4 production. Functional validation using in vitro co-culture experiments showed that blockade of SLAMF7-mediated Tfh2–B cell interactions significantly reduced differentiation into IgG4 ⁺ plasmablasts, supporting a causal role for SLAMF7-dependent Tfh2–B cell interactions in IgG4 plasma cell differentiation.

Conclusions: This study demonstrates that TIGIT ⁺ SLAMF7 ⁺ Tfh2 cells and SLAMF7 ⁺ B cells are selectively enriched within IgG4RD mass-forming tissues, accompanied by an increased IgG4/IgG ⁺ plasma cell ratio. Their spatial coexistence and interaction support a model in which SLAMF7-mediated Tfh2–B cell interactions promote local differentiation of IgG4-secreting plasma cells. Collectively, these findings define a previously unrecognized tissue-specific immune niche in IgG4RD and highlight SLAMF7 as a promising disease-specific therapeutic target and spatially informed biomarker.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.