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Abstract: SA-PO648

CARD9 Risk Locus for IgA Nephropathy Plays a Dichotomous Role Between Systemic and Mucosal Immunity Mediated by Retinoic Acid

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Gleeson, James, INSERM, Paris, Île-de-France, France
  • Metallinou, Eleftheria Theodora, INSERM, Paris, Île-de-France, France
  • Rafeh, Dina, INSERM, Paris, Île-de-France, France
  • Sokol, Harry, INSERM, Paris, Île-de-France, France
  • Monteiro, Renato C., INSERM, Paris, Île-de-France, France
Background

Caspase recruitment domain family member 9 (CARD9) has been identified as a susceptibility gene for IgA nephropathy (IgAN) by genome wide association studies. CARD9 is an adaptor protein involved in innate immune response and intestinal immune homeostasis. We aimed to study CARD9 in the mucosal immune compartment and examine its role in a mouse model of IgAN.

Methods

Serum and intestinal immunoglobulins of wt and CARD9-/- mice were measured. Humanised a1KI-CARD9-/- mice and a1KI-CD89tg-CARD9-/- mice were generated as models of IgAN. Mesenteric lymph nodes (MLNs) and splenocytes were isolated and cultured ex vivo. Bone marrow derived dendritic cells (BMDCs) were exposed to 2μM retinoic acid (RA) to induce a mucosal phenotype. Cholera Toxin subunit B (CTB) was administered by oral gavage for mucosal immunization or subcutaneously for systemic immunisation.

Results

Compared to wt mice, CARD9-/- mice had higher intestinal IgA and lower serum IgA. RA increased BMDC expression of CARD9. The effect of CARD9 KO on BMDC cytokine response was inverted by RA exposure such that in the absence of RA, CARD9 KO reduced cytokine production but, in the presence of RA CARD9 KO increased cytokine production, resulting in a significant interaction between RA and CARD9 for IL-10 (p<0.0001), IL-21 (p=0.01) and BAFF (p<0.0001). KO of CARD9 in a1KI mice caused decreased IgA1 secretion by splenocytes (p<0.05), but increased MLN IgA1 secretion (p<0.01). After mucosal immunization with CTB, CARD9 KO enhanced IgA adaptive response (p<0.0001) and weakened IgG adaptive response (<0.01) while after systemic immunisation no effect of CARD9 was seen. In a spontaneous mouse model of IgAN (a1KI-CD89tg) CARD9 KO mice had more severe glomerulonephritis than controls with greater IgA1 mesangial deposition (p<0.05), proteinuria (p<0.001) and higher serum cystatin C (p=ns). Vitamin A (RA) free diet reversed the effect of CARD9 KO on IgAN phenotype.

Conclusion

Loss of CARD9 function aggravates IgAN phenotype in a mouse model through increased activity of the mucosal IgA response. The effect of CARD9 in the mucosal compartment is mediated by retinoic acid from dietary vitamin A. These results support a role of mucosal CARD9 dysregulation in the immuno-pathogenesis of IgAN.