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

Abstract

BACKGROUND:

IgA nephropathy (IgAN) often follows infections and features IgA mesangial deposition. Polymeric IgA deposits in the mesangium seem to have varied pathogenic potential, but understanding their pathogenicity remains a challenge. Most mesangial IgA1 in human IgAN has a hypogalactosylated hinge region, but it is unclear whether this is required for IgA deposition. Another important question is the role of adaptive IgA responses and high-affinity mature IgA antibodies and whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits.

METHODS:

To explore the effects of specific qualitative variations in IgA and whether altered affinity maturation can influence IgA mesangial deposition and activate complement, we used several transgenic human IgA1-producing models with IgA deposition, including one lacking the DNA-editing enzyme activation-induced cytidine deaminase (AID), which is required in affinity maturation. Also, to explore the potential role of the IgA receptor CD89 in glomerular inflammation, we used a model that expresses CD89 in a pattern observed in humans.

RESULTS:

We found that human IgA induced glomerular damage independent of CD89. When comparing mice able to produce high-affinity IgA antibodies with mice lacking AID-enabled Ig affinity maturation, we found that IgA deposition and complement activation significantly increased and led to IgAN pathogenesis, although without significant proteinuria or hematuria. We also observed that hinge hypoglycosylation was not mandatory for IgA deposition.

CONCLUSIONS:

In a mouse model of IgAN, compared with high-affinity IgA, low-affinity innate-like IgA, formed in the absence of normal antigen-driven maturation, was more readily involved in IgA glomerular deposition with pathogenic effects.

• Authors: Batoul Wehbi, Christelle Oblet, François Boyer, Arnaud Huard, Anne Druilhe, François Paraf, Etienne Cogné, Jeanne Moreau, Yolla El Makhour, Bassam Badran, Marjolein Van Egmond, Michel Cogné, Jean-Claude Aldigier
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 30 Issue 7 Pg. 1238-1249 (07 2019) ISSN: 1533-3450 [Electronic] United States
• PMID: 31227634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 by the American Society of Nephrology.

Chemical References

• Antigens, CD
• Fc(alpha) receptor
• Immunoglobulin A
• Receptors, Fc
• AICDA (activation-induced cytidine deaminase)
• Cytidine Deaminase

Topics

• Animals
• Antibody Affinity
• Antigens, CD (physiology)
• Complement Activation
• Cytidine Deaminase (physiology)
• Glomerular Mesangium (metabolism, pathology)
• Glomerulonephritis, IGA (etiology, immunology)
• Glycosylation
• Humans
• Immunoglobulin A (metabolism, toxicity)
• Mice
• Receptors, Fc (physiology)