B6-hIgA1 Mice

Catalog Number: C001565

Strain Name: C57BL/6NCya-sμtm1(hIGHA1)/Cya

Genetic Background: C57BL/6NCya

Reproduction: Homozygote x Homozygote

 

Strain Description

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 B6-hIgA1 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, B6-hIgA1 mice can be used to study B cell development, immunoglobulin formation, and autoimmune mechanisms. They can also be crossed with CD89 humanized mouse models (catalog number: C001563) to create IgA nephropathy (IgAN) mouse model that better reflect human genetic mechanisms and pathological phenotypes [4], facilitating the development of IgA1-targeted drugs.

Strain Strategy

The mouse Sμ (a SpeI-StuI fragment located downstream of the mouse Ighj4) was replaced with the human IGHA1 genomic DNA.


Application

  • Research on B cell development, immunoglobulin formation, and autoimmune mechanisms;
  • Construction and efficacy evaluation of IgA nephropathy (IgAN) models;
  • Preclinical evaluation of IgA1-targeted therapies.

 

Validation Data

1. Gene expression

Figure 1. Detection of human IGHA1 gene expression in wild-type (WT) mice and B6-hIgA1 mice (IGH-IGHA1) by RT-qPCR (male, 8 weeks old, n=3). Human IGHA1 gene expression in mice was detected using human-specific primers via RT-qPCR. Result shows human IGHA1 gene expression in the kidney and duodenum of B6-hIgA1 mice, with higher expression levels in the intestine.

2. Protein expression

Figure 2. Detection of human IgA1 protein expression in the serum of wild-type (WT) mice and B6-hIgA1 mice (hIGHA1) by ELISA (8 weeks old, n=3). Human-specific antibodies were used to detect human IgA1 protein expression in mouse serum via ELISA. The result shows high levels of human IgA1 protein in the serum of B6-hIgA1 mice, with male mice exhibiting higher levels of human IgA1 protein than female mice.

 

References

[1]Stamellou E, Seikrit C, Tang SCW, Boor P, Tesař V, Floege J, Barratt J, Kramann R. IgA nephropathy. Nat Rev Dis Primers. 2023 Nov 30;9(1):67.
[2]Suzuki H, Novak J. IgA Nephropathy: Significance of IgA1-Containing Immune Complexes in Clinical Settings. J Clin Med. 2024 Aug 1;13(15):4495.
[3]Cheung CK, Alexander S, Reich HN, Selvaskandan H, Zhang H, Barratt J. The pathogenesis of IgA nephropathy and implications for treatment. Nat Rev Nephrol. 2024 Sep 4:10.
[4]Papista C, Lechner S, Ben Mkaddem S, LeStang MB, Abbad L, Bex-Coudrat J, Pillebout E, Chemouny JM, Jablonski M, Flamant M, Daugas E, Vrtovsnik F, Yiangou M, Berthelot L, Monteiro RC. Gluten exacerbates IgA nephropathy in humanized mice through gliadin-CD89 interaction. Kidney Int. 2015 Aug;88(2):276-85.