Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease

Area of Science:

• Nephrology
• Immunology
• Pathophysiology

Background:

• The pathophysiology of membranous nephropathy (MN), particularly IgG4-related disease (IgG4-RD), remains unclear.
• This study investigates a distinct pathogenic process in a patient with MN and IgG4-RD, where IgG3 predominated over IgG4 in deposits, unlike typical idiopathic MN.
• The absence of anti-phospholipase A2 receptor antibodies suggests a different mechanism driving the disease.

Purpose of the Study:

• To elucidate the role of IgG4 antibodies in the pathogenesis of MN within the context of IgG4-related disease.
• To investigate the interaction of patient-derived IgG4 antibodies with podocyte surface antigens.
• To understand the downstream cellular effects of IgG4 binding to podocytes and its potential contribution to MN development.

Main Methods:

• Characterization of IgG4 antibodies from patient serum for reactivity against podocyte surface antigens.
• Immunofluorescence staining of kidney biopsy for carbonic anhydrase II (CAII) and IgG deposits.
• In vitro studies using cultured podocytes to assess the effects of patient IgG4 on intracellular pH, mitochondrial function, reactive oxygen species (ROS) production, and cytoskeletal organization.
• Analysis of mitochondrial superoxide-dismutase-2 (SOD2) externalization and its recognition by complement-binding antibodies.

Main Results:

• Patient-derived IgG4 antibodies were found to react against carbonic anhydrase II (CAII) on the podocyte surface.
• Glomerular CAII staining increased and co-localized with subepithelial IgG4 deposits in the patient's biopsy.
• Patient IgG4 induced intracellular acidification, mitochondrial dysfunction, and increased ROS production in cultured podocytes.
• These cellular changes promoted the externalization of mitochondrial SOD2, making it a potential neoantigen.
• Sera from IgG4-RD patients with IgG4 anti-CAII antibodies, but not others, replicated these cellular effects.

Conclusions:

• Circulating IgG4 anti-CAII antibodies can directly injure podocytes via intracellular acidification and mitochondrial oxidative stress.
• This process leads to the induction of neoantigens, such as externalized SOD2, in IgG4-related disease.
• The recognition of CAII by IgG4 antibodies and subsequent neoantigen exposure may contribute to the onset of membranous nephropathy in a subset of patients with IgG4-related disease.