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Breakdown of Mucosal Immunity in the Gut and Resultant Systemic Sensitization by Oral Antigens in a Murine Model for Systemic Lupus Erythematosus ¹

Kenji Akadegawa^*,, Sho Ishikawa^*, Taku Sato^*, Jun Suzuki^*, Hideaki Yurino^*, Masahiro Kitabatake^*, Toshihiro Ito^*, Takayuki Kuriyama and Kouji Matsushima^2,*

^* Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan

Secreted IgA plays a pivotal role in the mucosal immunity to maintain the front line of body defense. We found that the level of fecal IgA was dramatically decreased in aged (NZB x NZW)F₁ (BWF₁) mice developing lupus nephritis, whereas levels in similarly aged New Zealand Black (NZB) and New Zealand White (NZW) mice remained unchanged compared with young mice. The number of cells obtained from Peyer’s patches was markedly decreased in aged BWF₁ mice. Aged BWF₁ mice showed increased susceptibility to pathogenic bacterial infection. Furthermore, oral administration of OVA failed to inhibit secondary IgG response induced by systemic immunization, suggesting defective oral tolerance in aged BWF₁ mice. A significant amount of orally administered OVA was incorporated directly into the intestinal lamina propria in aged BWF₁ mice whereas it was mainly localized in subepithelial domes and interfollicular region in Peyer’s patches in young mice. T cells obtained from renal and pulmonary lymph nodes of aged BWF₁ mice that had been orally administered with OVA showed an Ag-specific T cell proliferation, whereas those from young BWF₁, aged NZB, and aged NZW mice did not. Interestingly, aerosol exposure to OVA of aged BWF₁ mice, which had been orally administered with the same Ag, provoked an eosinophil infiltration in the lung. These results demonstrate that mucosal immunity in the gut is impaired and oral Ags induce systemic sensitization instead of oral tolerance in the development of murine lupus.