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

Abstract

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.

Keywords: IgG4; IgG4‐related disease; fibrosis; immune dysregulation; inebilizumab.

FIGURE 1

There are four main factors influencing IgG4‐RD heterogeneity: gender and ethnic background, the microbiome, gene variants and immune phenotype.

FIGURE 2

Proposed underlying pathogenic mechanisms of IgG4‐RD in tertiary lymphoid structures and other affected tissue sites involve IL‐4, IL‐21 and IL‐10, released by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. These cytokines drive the class‐switching of naïve B cells into IgG4‐expressing memory B cells and plasmablasts. These B cells then generate autoantibodies against a variety of autoantigens, potentially contributing to the activation of myeloid cells, including macrophages, eosinophils and dendritic cells. Antigen presentation by B cells also leads to the clonal expansion of cytotoxic CD4⁺ T cells. Collectively, autoantibodies, cytotoxic molecules, along with pro‐inflammatory and pro‐fibrotic soluble factors released by myeloid cells, drive tissue pathology, extracellular matrix deposition and fibrosis.

FIGURE 3

Detailed characterisation of sub‐types of T cells in peripheral blood [83] and tertiary lymphoid structures of IgG4‐RD based on scRNA‐seq or flow cytometric analysis [84, 85, 86]. GATA3‐CD4⁺CXCR5⁺ Tfh‐like cells were found to be located near class‐switching B cells. In addition, CD4⁺ GZMA⁺ CTLs were found to be highly expanded in tissue lesions.

FIGURE 4

Imaging and histopathology of IgG4 disease demonstrating heterogeneous clinical presentations (A–E) and histopathology (F–H). (A–C) FDG PET Scan, (A) Demonstrates FDG‐avidity in the pancreatic head/uncinate process suggestive of pancreatic IgG4‐RD. (B) FDG‐avidity in the pericardial region in a patient with known IgG4 pericardial disease. (C) Increased activity seen in association with abnormal soft tissue stranding in the retroperitoneum, around the distal inferior vena cava (IVC) and aorta, bilateral common iliac and adjacent to the left internal iliac vessels, in keeping with active retroperitoneal fibrosis. (D) Computed Tomography (CT) scan of the abdomen and pelvis demonstrating extrahepatic bile duct thickening with mild intrahepatic biliary dilation in the right lower lobe suggestive of IgG4‐related cholangitis. (E) MRI of the abdomen demonstrating diffusely T2‐hypointense pancreatic parenchyma with sausage‐shaped morphology suggestive of IgG4‐RD.