Single‐cell atlas of B cell heterogeneity in lacrimal IgG4 ‐related disorders: Unraveling the transition from inflammatory exhaustion to clonal malignancy

This study analyzed B-cell heterogeneity in lacrimal gland tissues from 4 patients with IgG4-related ophthalmic disease (IgG4-ROD) and 2 patients with IgG4-positive MALT lymphoma using single-cell transcriptome sequencing (scRNA-seq). The results revealed that while the B-cell differentiation trajectories have similarities between the two diseases, critical differences were evident. IgG4-ROD was predominantly composed of naïve B cells, with memory B cells mainly being the central memory type. These cells were enriched in hormone/innate immunity pathways, and the plasma cells exhibited features of functional exhaustion. Conversely, MALT lymphoma was dominated by memory B cells, particularly enriched in terminally differentiated subtypes, with aberrant activation of oncogenic pathways (BCR/NF-κB). In MALT lymphoma, naïve B cells showed upregulated expression of immunoglobulin genes (IGHG3/IGHG4) and abnormal activation of EBV/BCR/T-cell differentiation pathways, despite having suppressed basal metabolism. Germinal center-like B cells in MALT lymphoma revealed upregulated gene expression enriched in T-cell activation and PD-1/PD-L1 pathways. Plasma cells in MALT lymphoma displayed monoclonal expansion (high expression of IGHG2/IGHG3/IGHG4) and enhanced antibody secretion. Therefore, MALT lymphoma is characterized by abnormal activation and malignant transformation of B cells, whereas IgG4-ROD manifests as functional exhaustion and metabolic suppression. The differentiation state of memory B cells may represent a critical juncture for malignant transformation.