Establishment of a transgenic mouse model with liver-specific expression of secretory immunoglobulin D

Ping Wang,Chen Xu,Tan Huang,Kemian Gou,Xifeng Wang,Min Zheng,Xueqian Cheng,Bowen Yan,Zhiguo Wei,Meili Wang,Yi Sun,Yunping Dai

doi:10.1007/s11427-012-4301-3

Abstract

Mutation of mevalonate kinase (MVK) is thought to account for most cases of hyperimmunoglobulinemia D syndrome (HIDS) with recurrent fever. However, its mechanism and the relationship between elevated serum immunoglobulin D (IgD) and the clinical features of HIDS are unclear. In this study, we generated by fusion PCR a vector to express high levels of chimeric secretory IgD (csIgD) specifically in the liver. We then generated seven founder lines of transgenic mice by co-microinjection, and verified them using genomic PCR and Southern blotting. We detected the expression of csIgD by reverse transcription PCR, quantitative PCR, western blotting, and enzyme-linked immunosorbent assays. We demonstrated that csIgD could be specifically and stably expressed in the liver. We used flow cytometry to show that overexpression of csIgD in the bone marrow and spleen cells had no effect on B cell development. Morphologic and anatomical observation of the transgenic mice revealed skin damage, hepatosplenomegaly, and nephromegaly in some transgenic mice; in these mice, pathological sections showed high levels of cell necrosis and protein-like sediments in the liver, spleen, and kidney. We demonstrated that the genomic insertion sites of the transgenes did not disrupt the MVK gene on mouse chromosome 5. This transgenic mouse will be useful to explore the pathogenesis of HIDS.

Highlights

Mutation of mevalonate kinase (MVK) is thought to account for most cases of hyperimmunoglobulinemia D syndrome (HIDS) with recurrent fever
We demonstrated that chimeric secretory IgD (csIgD) could be and stably expressed in the liver
We demonstrated that the genomic insertion sites of the transgenes did not disrupt the MVK gene on mouse chromosome 5

Summary

Introduction

Mutation of mevalonate kinase (MVK) is thought to account for most cases of hyperimmunoglobulinemia D syndrome (HIDS) with recurrent fever. Hyperimmunoglobulinemia D syndrome (HIDS), called receptor-associated periodic syndrome or etiocholanolone fever, is characterized by high serum levels of immunoglobulin D (IgD) and recurrent febrile attacks, and may include arthritis, lymphadenopathy, hepatosplenomegaly, and skin rash [1,2,3]. It was originally described in patients of Dutch ancestry by Van der Meer et al in 1984 [4] but has been reported all over the world, including in Japan [5,6]. The second most common mutation is I268T [12,13]

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Results

Conclusion