The role of Sp140 revealed in IgE and mast cell responses in Collaborative Cross mice
Kazufumi Matsushita, Xin Li, Yuki Nakamura, Danyue Dong, Kaori Mukai, Mindy Tsai, Stephen B. Montgomery, Stephen J. Galli
Kazufumi Matsushita, Xin Li, Yuki Nakamura, Danyue Dong, Kaori Mukai, Mindy Tsai, Stephen B. Montgomery, Stephen J. Galli
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Research Article Immunology Inflammation

The role of Sp140 revealed in IgE and mast cell responses in Collaborative Cross mice

Abstract

Mouse IgE and mast cell (MC) functions have been studied primarily using inbred strains. Here, we (a) identified effects of genetic background on mouse IgE and MC phenotypes, (b) defined the suitability of various strains for studying IgE and MC functions, and (c) began to study potentially novel genes involved in such functions. We screened 47 Collaborative Cross (CC) strains, as well as C57BL/6J and BALB/cJ mice, for strength of passive cutaneous anaphylaxis (PCA) and responses to the intestinal parasite Strongyloides venezuelensis (S.v.). CC mice exhibited a diversity in PCA strength and S.v. responses. Among strains tested, C57BL/6J and CC027 mice showed, respectively, moderate and uniquely potent MC activity. Quantitative trait locus analysis and RNA sequencing of BM-derived cultured MCs (BMCMCs) from CC027 mice suggested Sp140 as a candidate gene for MC activation. siRNA-mediated knock-down of Sp140 in BMCMCs decreased IgE-dependent histamine release and cytokine production. Our results demonstrated marked variations in IgE and MC activity in vivo, and in responses to S.v., across CC strains. C57BL/6J and CC027 represent useful models for studying MC functions. Additionally, we identified Sp140 as a gene that contributes to IgE-dependent MC activation.

Authors

Kazufumi Matsushita, Xin Li, Yuki Nakamura, Danyue Dong, Kaori Mukai, Mindy Tsai, Stephen B. Montgomery, Stephen J. Galli

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Figure 4

Chromosome 1, region 81.7–92.9 Mb, from NOD/ShiLtJ associates with stronger MC responses in CC mice.

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Chromosome 1, region 81.7–92.9 Mb, from NOD/ShiLtJ associates with stron...
(A, C, and E) QTL analysis for chromosomal regions associated with PCA values (A), S.v. expulsion date (C), and IgE-fold change (E). The red lines indicate the LOD score threshold for P = 0.05. (B, D, and F) Analysis for founder effects associated with the PCA values (B), S.v. expulsion date (D), and IgE-fold change (F) within chromosome 1. (G–I) Intercorrelation among maximum PCA value, S.v. expulsion date, and IgE-fold change in CC mice as in Figure 2. The founder strain of each CC mouse’s chromosome 1, 82.3–84.1 Mbp, is indicated in 7 different colors. (J and K) CC mice were classified into 7 groups according to their founders of chromosome 1, 82.3–84.1 Mbp (J), or divided into 2 groups according to their chromosome 1, 82.3 to 84.1 Mbp, was from NOD/ShiLtJ or not (K). Notched box plots (J) and dot plots (K) of maximum PCA value, S.v. expulsion date, and IgE-fold change of each group are shown. Each dot indicates 1 mouse. Data are shown as mean ± SD. P values were determined by Student’s t test.