CD74 links MHC class II risk to tumor immune microenvironment remodeling across the Sjögren-to-lymphoma axis

INTRODUCTION: Sjögren's syndrome creates a lymphoma-prone inflammatory niche and confers one of the highest autoimmune risks of B-cell non-Hodgkin lymphoma. Yet the genetic and cellular mechanisms that remodel this pre-neoplastic niche into a tumor-supportive immune microenvironment remain unclear. We integrated human genetics, single-cell transcriptomics and functional cell biology to identify an actionable mediator of this transition. METHODS: We combined bidirectional Mendelian randomization, directionality filtering, MHC-exclusion sensitivity analyses (chromosome 6: 25-35 Mb), colocalization and summary-based HLA fine-mapping. Single-cell RNA sequencing of salivary gland and splenic marginal-zone lymphoma was used to localize genetic risk, reconstruct cross-disease B-cell states and infer intercellular signaling. Mechanistic dependence was tested in IFN-γ-stimulated Raji B-lymphoma cells, and clinical relevance was evaluated in a public chronic lymphocytic leukemia cohort. RESULTS: Genetic liability to Sjögren's syndrome increased marginal-zone/MALT, diffuse large B-cell and overall non-Hodgkin lymphoma risk, and effects collapsed after MHC exclusion and resolved to the class II 8.1 ancestral haplotype. Single-cell analysis localized risk to salivary B cells and revealed disease-associated remodeling toward a lymphoid, MIF-rich, CD74-receiving microenvironment, with plasma cells as the largest MIF source. HLA-class-II/CD74 programs increased along the Sjögren-to-lymphoma B-cell trajectory. In Raji cells, MIF activated AKT/NF-κB/BCL-xL signaling and viability. ISO-1 or CD74 knockdown suppressed the pathway and increased cleaved PARP, whereas AKT activation partially rescued signaling and viability. Higher CD74 expression marked adverse outcome in an external B-cell malignancy cohort. CONCLUSION: Convergent genetic, single-cell and perturbation evidence positions CD74 as a candidate organizer of a lymphoma-supportive immune microenvironment linking inherited MHC class II risk to B-cell survival. The MIF-CD74 axis provides a translational tumor-microenvironment target that requires tissue-level and prospective validation.