Intestinal inflammation can be accompanied by osteoporosis, but their relationship, mediated by immune responses, remains unclear. Here, we investigated a non-IgE-mediated food-allergic enteropathy model of ovalbumin (OVA) 23-3 mice expressing OVA-specific T-cell-receptor transgenes. Mesenteric lymph nodes (MLNs) and their pathogenic CD4+T cells were important to enteropathy occurrence and exacerbation when the mice were fed an egg-white (EW) diet. EW-fed OVA23-3 mice also developed bone loss and increased CD44hiCD62LloCD4+T cells in the MLNs and bone marrow (BM); these changes were attenuated by MLN, but not spleen, resection. We fed an EW diet to F1 cross offspring from OVA23-3 mice and a mouse line expressing the photoconvertible protein KikGR to track MLN CD4+T cells. Photoconverted MLN CD44hiCD62LloCD4+T cells migrated predominantly to the BM; pit formation assay proved their ability to promote bone damage via osteoclasts. Significantly greater expression of IL-4 mRNA in MLN CD44hiCD62LloCD4+T cells and bone was observed in EW-fed OVA23-3 mice. Anti-IL-4 monoclonal antibody injection canceled bone loss in the primary inflammation phase in EW-fed mice, but less so in the chronic phase. This novel report shows the specific inflammatory relationship, via Th2-dominant-OVA-specific T cells and IL-4 production, between MLNs and bone, a distant organ, in food-allergic enteropathy.
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We thank Erika Hiraide, Mamiko Morinaga, Tomiko Asakura, Takashi Matsuwaki, Yoshikazu Saito, Takuya Miyakawa, and Jun Kunisawa (the University of Tokyo); staff of the Institute of Medical Science and the FACS Core Laboratory at the University of Tokyo; Naoyuki Takahashi (Matsumoto Dental University); Ken Kato, Atsushi Serizawa, and Takayuki Nara (Megmilk Snow Brand Co., Ltd.); Toshimitsu Yoshioka and Takashi Fujita (Bean Stalk Snow Co., Ltd.); and Akemi Ito (Ito Bone Histomorphometry Institute) for their technical advice and support.
This work was supported by grants from the Kieikai Research Foundation (H.N.A., 2017S063, 2018T019), a Grant-in-Aid for Scientific Research (C) (H.N.A., 18K05502) from the Japan Society for the promotion of science, a grant from The Food Science Institute Foundation (Ryoushoku-kenkyukai; H.N.A., No. 2019A01), and grants from Megmilk Snow Brand Co., Ltd. (H.N.A., H.K., and S.H.). The authors declare no conflict of interest associated with this manuscript.
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Ono-Ohmachi, A., Yamada, S., Uno, S. et al. Effector memory CD4+T cells in mesenteric lymph nodes mediate bone loss in food-allergic enteropathy model mice, creating IL-4 dominance. Mucosal Immunol 14, 1335–1346 (2021). https://doi.org/10.1038/s41385-021-00434-2