IgG4-Related Disease: Emerging Roles of Novel Genetic Variants, Immune Cell Subsets and Therapeutic Targets

IgG4, the least abundant IgG subclass in humans, is increasingly recognised for its involvement in allergic and autoimmune pathologies. Its unique properties, such as the tendency to form half-molecules (one heavy chain and one light chain) and its generally non-inflammatory nature, distinguish it from other IgG subclasses. Its role in immune dysregulation is further underscored by a distinct disease entity called IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder characterised by IgG4⁺ plasma cell tissue infiltration, storiform fibrosis and obliterative phlebitis, reflecting a dysregulated immune response affecting multiple organs. This review examines the current understanding of IgG4, its emerging roles in immune dysregulation and IgG4-RD, including clinical manifestations and treatment options. We also discuss the recent advances in understanding the genetic underpinnings of IgG4-RD, highlighting the significance of germline gene variants and implicated immune cell types. Finally, we explore future research directions, emphasising the need for deeper insights into pathogenesis, specific biomarkers and optimised treatment strategies.