TGFBR1M318R^+/− Knock-In mice recapitulate the immune phenotypes of Loeys-Dietz syndrome.

Abstract

Loeys-Dietz syndrome (LDS) is an autosomal dominant disorder caused by mutations in genes encoding proteins in the transforming growth factor beta (TGFβ) signaling pathway. Patients heterozygous for a point mutation in the kinase domain of TGFβR1 (TGFBR1M318R) exhibit classic manifestations of LDS. Mice with this mutation were made with the hope that an animal model of LDS will lead to better understanding of the mechanisms underlying LDS symptoms. TGFBR1M318R^+/− mice exhibit the hallmark skeletal and cardiovascular phenotypes of LDS. We sought to determine if TGFBR1M318R^+/− mice also recapitulate the immune phenotypes characteristic of LDS. We find that like their human counterparts, TGFBR1M318R^+/− mice spontaneously develop elevated serum IgE and eosinophilic esophagitis (EoE), characterized by esophageal dilation, increased collagen, food impaction, and increased infiltration of eosinophils, T cells, mast cells, and myeloid antigen presenting cells. We made bone marrow (BM) chimeras to determine whether altered TGFβR signaling in hematopoietic and/or stromal cells led to EoE. Both irradiated TGFBR1M318R^+/− mice reconstituted with WT BM, and WT mice reconstituted with TGFBR1M318R^+/− BM had EoE 8 weeks post-reconstitution, indicating that aberrant TGFβ signaling in either BM-derived or non-hematopoietic cells can be associated with EoE, but that neither is absolutely required. To determine which hematopoietic cells are essential to the development of EoE we generated RAG2^−/− TGFBR1M318R^+/− mice and found that they too developed EoE, demonstrating that neither T or B cells were essential. Using TGFBR1M318R^+/− mice to study the immune pathology of LDS should lead to better therapeutic strategies for the treatment of EoE.