Background: IgA nephropathy is the most common primary glomerulonephritis worldwide, and there is emerging evidence linking galactose-deficient IgA1 (Gd-IgA1) to the pathogenesis of the disease. However, mouse models that can be used to study Gd-IgA1’s origin of production, biochemical characteristics, and immune reactivity are lacking. Methods: We generated a humanized IgA1 mouse model with transgenic expression of the human IGHA1 gene from the mouse chromosomal locus of IgA heavy chain. The IGHA1 ^+/+ mice were crossed with complement factor H heterozygous mutant (FH^W/R) to generate IGHA1 ^+/+FH^W/R mice. IGHA1 ^+/+ mice were exposed to different levels of environmental pathogens in the first 4 months, as housed in either germ-free, specific pathogen-free, or conventional environments. In addition, wild-type C57BL/6J mice, IGHA1 ^+/+ mice, and IGHA1 ^+/+FH^W/R mice were inoculated with Lactobacillus casei cell bacterial wall extract (LCWE) mixed with complete Freund's adjuvant (CFA) at two months of age to develop a mouse model of IgA nephropathy. Results: Elevated levels of human IgA1 in blood circulation and mucosal sites were observed in IGHA1 ^+/+ mice from exposure to pathogens. Compared to buffer-treated control mice, LCWE plus CFA-treated mice had moderately elevated levels of circulating human IgA1 (by one fold) and human IgA1 immune complexes (by two folds). Serum Gd-IgA1 levels increased fourfold following LCWE treatments. Analyses of the O-glycopeptides of the IgA1 hinge region confirmed hypo-galactosylation of IgA1, with the variety of the glycoforms matching those seen in clinical samples. Furthermore, LCWE induced persistent IgA1 and C3 deposition in the glomerular mesangial areas in association with mesangial expansion and hypercellularity, which are frequently observed in IgA nephropathy biopsies. The IGHA1^+/+FH^W/R mice stimulated with LCWE and CFA developed albuminuria and hematuria. Conclusions: We observed elevated plasma Gd-IgA1 levels with kidney deposition of IgA1 in the IGHA1 ^+/+ mice following LCWE and CFA. In conjunction with factor H mutation, the mice exhibited severe glomerular alterations, associated with hematuria and albuminuria in resemblance of clinical IgA nephropathy.