Background/Purpose: The etiology of IgA nephropathy (IgAN) remains only partly understood, but the presence of IgA antibodies together with the myeloid IgA-receptor FcαRI/CD89 complexes in the circulation of patients is considered a specific pathogenic factor for mesangial deposition. The absence of CD89 ortholog in rodents, coupled with the different IgA systems in humans and mice, hinders further exploration of IgAN pathogenesis. To better understand these effects, we developed a transgenic mouse model expressing human IgA1 and CD89, in which CD89 was expressed under the control of an endorgenous murine CD14 promotor on blood and tissue monocytes/macrophages. This model offers insights into the pathogenesis of IgAN and provides a relevant preclinical mouse model to evaluate CD89 and IgA1-targeted therapies.

Methods: This study describes the phenotypic validation process of the transgenic mouse model expressing both human IgA1 and human CD89. Using gene editing technology in C57BL/6J background mice, we generated B6-hIGHA1 mice expressing human IgA1 and B6-Cd14-hCD89 mice expressing human CD89 under the CD14 gene promoter. B6-Cd14-hCD89/hIGHA1 mice were generated by crossing these two strains. Serum and urine were collected from female mice, and the levels of protein to creatinine ratio (UPCR) in urine and human IgA in serum was measured. Pathological analyses of renal tissues from 27-week-old B6-Cd14-hCD89/hIGHA1 female mice were performed using H&E staining. Human IgA complex deposition in renal tissue was detected by Immunofluorescence staining using an anti-human-IgA antibody in 12-, 21-, 27-week-old female mice.

Results: Human CD89 and IgA1 expression in B6-Cd14-hCD89/hIGHA1 mice led to consistent leakage of low urine total protein (UPCR) from 7 weeks of age compared with wild-type mice. The expression of human IgA in the serum of female mice can be detected, which continued to increase gradually over time. At 12 weeks of age, B6-Cd14-hCD89/hIGHA1 female mice exhibited human IgA glomerular deposits, a hallmark of IgAN. With the increase in age, more intense human IgA deposition was detected at 21-week-old and 27-week-old. Histopathological analysis of the kidneys in 27-week-old female mice revealed various renal lesions, including fibrous tissue hyperplasia, thickening of the basement membrane of the renal corpuscle, renal tubular atrophy, and inflammatory cell infiltration.

Conclusion:  These results showed that the presence of both human IgA1 and CD89 promoted the increase of serum IgA levels, mesangial IgA1 deposition, proteinuria, and altered renal function in mice. B6-Cd14-hCD89/hIGHA1 mice exhibited an IgAN-like phenotype. This novel model can contribute significantly to unraveling the mechanisms underlying IgAN and provide a clinically relevant mouse model to evaluate novel therapeutics against IgAN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phenotypic-validation-of-humanized-iga1-and-cd89-transgenic-mice-as-a-model-for-iga-nephropathy-like-autoimmune-disease/