BACKGROUND: Local type III hypersensitivity reactions are acute inflammatory events induced by immune complex (IC) deposition. CD22 and CD72 are B cell-specific cell surface molecules that negatively regulate B cell function. OBJECTIVE: To elucidate the roles of CD22 and CD72 in the development of IgG-mediated type III hypersensitivity reactions. METHOD: The reverse Arthus reaction model in the skin was induced in mice lacking CD22 (CD22-/-), CD72 (CD72-/-), and both of them (CD22-/-/CD72-/-). Edema at 4h and hemorrhage at 8h after IC challenge were evaluated. Inflammatory cell infiltration and cytokine and chemokine expression were also examined. RESULTS: Edema and hemorrhage were significantly reduced in CD22-/-/CD72-/- mice compared with wild-type mice. The loss of both membrane proteins resulted in a greater decrease in edema at 4h, but not hemorrhage at 8h, than the loss of each protein alone. Infiltration of neutrophils, macrophages, and T cells, and the expression of TNF-α, IL-6, MIP-1α, and CCR5 mRNA were also diminished in the knockout mice compared to wild-type mice, and most significantly reduced in CD22-/-/CD72-/- mice. Regulatory T (Treg) cells in the spleen were significantly increased in all knockout mice at 4h. Significant differences in the severity of edema and hemorrhage between wild-type and knockout mice were lost when Treg cells were depleted in the knockout mice. CONCLUSION: These results demonstrate that CD22 and CD72 expression contribute to the development of the reverse Arthus reaction model and CD22 and CD72 might be therapeutic targets for human IC-mediated diseases.