huIgA1 Mouse

The immunoglobulin heavy chain constant region α1 (IGHA1) gene encodes the IgA1 protein, a subtype of immunoglobulin A (IgA), primarily found in mucosal areas such as the respiratory and gastrointestinal tracts, playing a key role in immune defense by neutralizing pathogens and preventing their invasion ^[1]. IgA nephropathy (IgAN) is one of the most common forms of glomerulonephritis, accounting for 30% to 50% of primary glomerulonephritis cases, and is a major cause of end-stage renal disease (ESRD). IgAN is characterized by the deposition of IgA1-containing immune complexes in the glomeruli (the kidney's filtering units), leading to extensive pathological damage ranging from mesangial matrix expansion to proliferative glomerulonephritis, ultimately manifesting as clinical symptoms such as hematuria and proteinuria, and impairing kidney function ^[2-3]. Approximately one-third of IgAN patients eventually progress to renal failure. The pathogenesis of IgAN is associated with galactose-deficient IgA1 (Gd-IgA1) in the serum, which acts as an autoantigen, triggering an immune response that leads to the formation and deposition of immune complexes in the kidneys ^[2-4]. Additionally, these IgA1 antibodies can bind to the soluble form of the myeloid IgA receptor FcαRI (CD89/FCAR), further exacerbating the disease ^[4].

The huIgA1 mouse is a humanized model constructed by inserting the human IGHA1 gene sequence into the region between the mouse IgM enhancer (Eμ) and IgM constant region (Cμ), replacing the mouse IgM switch region (Sμ). B6-hIgA1 mice successfully express the human IGHA1 gene, and high levels of human IgA1 protein can be detected in their serum. Therefore, huIgA1 mice can be used to study B cell development, immunoglobulin formation, and autoimmune mechanisms. They can also be crossed with CD89 humanized mouse models to create IgA nephropathy (IgAN) mouse model that better reflect human genetic mechanisms and pathological phenotypes ^[4], facilitating the development of IgA1-targeted drugs.