IgG2c subclass dominance drives fatal lupus-like nephritis via FcγR and complement activation

Lupus nephritis (LN) is a leading cause of mortality in systemic lupus erythematosus. While the dominance of Fcγ receptor (FcγR)-activating IgG subclasses has been observed in both human and murine LN, whether this imbalance is causal or merely correlative remains unresolved. To address this, we generated a murine model that exclusively expresses the activating IgG2c while lacking all other IgG subclasses. Despite preserved B cell receptor diversity and intact humoral immunity, these mice developed rapidly progressive and fatal lupus-like nephritis, with 100% mortality by 30 weeks, characterized by extensive renal inflammation. Genetic ablation of FcγRs or complement C3 rescued this phenotype, establishing both as essential and non-redundant mediators of disease. Supporting clinical relevance, renal biopsies from patients with LN exhibited glomerular immune deposits enriched for FcγR-activating IgG1 and minimal inhibitory IgG4. Together, these results identify IgG subclass dominance as a direct driver of LN and provide a fully penetrant, rapid-onset disease model for therapeutic studies.