Mesangial Deposition Can Strongly Involve Innate-Like IgA Molecules Lacking Affinity Maturation

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• IgA nephropathy (IgAN) is characterized by IgA deposition in the kidney's mesangium, often following infections.
• The pathogenic role of polymeric IgA deposits and specific IgA features like hinge region glycosylation in IgAN remains unclear.
• The contribution of adaptive versus innate-like B cell IgA responses to mesangial deposition is an open question.

Purpose of the Study:

• To investigate the impact of qualitative IgA variations on mesangial deposition and complement activation.
• To determine if altered affinity maturation influences IgA deposition and pathogenicity in IgAN.
• To explore the role of the IgA receptor CD89 in IgAN-related glomerular inflammation.

Main Methods:

• Utilized transgenic human IgA1-producing mouse models with IgA deposition.
• Included a model lacking activation-induced cytidine deaminase (AID) to assess the role of affinity maturation.
• Employed a model expressing the IgA receptor CD89 to study its function in glomerular inflammation.

Main Results:

• Human IgA induced glomerular damage independently of CD89.
• IgA deposition and complement activation increased significantly in mice with AID-enabled affinity maturation, contributing to IgAN pathogenesis.
• Hinge region hypoglycosylation was not a prerequisite for IgA deposition.
• Low-affinity, innate-like IgA showed greater involvement in glomerular deposition and pathogenic effects compared to high-affinity IgA.

Conclusions:

• Low-affinity IgA, generated without typical antigen-driven maturation, is more prone to glomerular deposition and pathogenic effects in IgAN.
• High-affinity IgA production does not necessarily lead to increased IgA deposition or IgAN pathogenesis.
• These findings highlight the distinct pathogenic potential of different IgA populations in IgA nephropathy.