Skip to main content
PMC home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2012 Apr 14;55(3):219–227. doi: 10.1007/s11427-012-4301-3

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

Ping Wang 1, ZhiGuo Wei 2, BoWen Yan 1, Tan Huang 1, KeMian Gou 1, YunPing Dai 1, Min Zheng 1, MeiLi Wang 1, XueQian Cheng 1, XiFeng Wang 1, Chen Xu 1, Yi Sun 1,✉
PMCID: PMC7089205  PMID: 22527518

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.

Keywords: sIgD, liver-specific expression vector, HIDS, MVK

Footnotes

This article is published with open access at Springerlink.com

References

  • 1.Drenth J. P., Prieur A. M. Occurrence of arthritis in hyper-immunoglobulinaemia D. Ann Rheum Dis. 1993;52:765–766. doi: 10.1136/ard.52.10.765-b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Drenth J. P., Boom B. W., Toonstra J., et al. Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome. International Hyper IgD Study Group. Arch Dermatol. 1994;130:59–65. [PubMed] [Google Scholar]
  • 3.Drenth J. P., Haagsma C. J., van der Meer J. W. Hyperimmuno-globulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore) 1994;73:133–144. doi: 10.1097/00005792-199405000-00002. [DOI] [PubMed] [Google Scholar]
  • 4.van der Meer J. W., Vossen J. M., Radl J., et al. Hyperimmuno-globulinaemia D and periodic fever: a new syndrome. Lancet. 1984;1:1087–1090. doi: 10.1016/S0140-6736(84)92505-4. [DOI] [PubMed] [Google Scholar]
  • 5.Naruto T., Nakagishi Y., Mori M., et al. Hyper-IgD syndrome with novel mutation in a Japanese girl. Mod Rheumatol. 2009;19:96–99. doi: 10.3109/s10165-008-0130-4. [DOI] [PubMed] [Google Scholar]
  • 6.Yoshimura K., Wakiguchi H. Hyperimmunoglobulinemia D syndrome successfully treated with a corticosteroid. Pediatr Int. 2002;44:326–327. doi: 10.1046/j.1442-200X.2002.01541.x. [DOI] [PubMed] [Google Scholar]
  • 7.Klasen I. S., Goertz J. H., van de Wiel G. A., et al. Hyper-immuno-globulin A in the hyperimmunoglobulinemia D syndrome. Clin Diagn Lab Immun. 2001;8:58–61. doi: 10.1128/CDLI.8.1.58-61.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Frenkel J., Rijkers G. T., Mandey S. H., et al. Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmuno-globulinemia D and periodic fever syndrome. Arthrit Rheumat. 2002;46:2794–2803. doi: 10.1002/art.10550. [DOI] [PubMed] [Google Scholar]
  • 9.Drenth J. P., Cuisset L., Grateau G., et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet. 1999;22:178–181. doi: 10.1038/9696. [DOI] [PubMed] [Google Scholar]
  • 10.Simon A., Cuisset L., Vincent M. F., et al. Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-igd and periodic fever syndrome: its application as a diagnostic tool. Ann Intern Med. 2001;135:338–343. doi: 10.7326/0003-4819-135-5-200109040-00010. [DOI] [PubMed] [Google Scholar]
  • 11.Houten S. M., van Woerden C. S., Wijburg F. A., et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003;11:196–200. doi: 10.1038/sj.ejhg.5200933. [DOI] [PubMed] [Google Scholar]
  • 12.Aringer M. Periodic fever syndromes—a clinical overview. Acta Med Austriaca. 2004;31:8–12. [PubMed] [Google Scholar]
  • 13.Drenth J. P., van der Meer J. W. Hereditary periodic fever. N Engl J Med. 2001;345:1748–1757. doi: 10.1056/NEJMra010200. [DOI] [PubMed] [Google Scholar]
  • 14.Hager E. J., Tse H. M., Piganelli J. D., et al. Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome. J Inherit Metab Dis. 2007;30:888–895. doi: 10.1007/s10545-007-0776-7. [DOI] [PubMed] [Google Scholar]
  • 15.Ammouri W., Cuisset L., Rouaghe S., et al. Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. Rheumatology. 2007;46:1597–1600. doi: 10.1093/rheumatology/kem200. [DOI] [PubMed] [Google Scholar]
  • 16.Dikeacou T. C., van Joost T., Cormane R. H. The recruitment of inflammatory cells using the skin-window technique. Arch Dermatol Res. 1979;265:1–7. doi: 10.1007/BF00412695. [DOI] [PubMed] [Google Scholar]
  • 17.Chen K., Cerutti A. New insights into the enigma of immunoglobulin D. Immunol Rev. 2010;237:160–179. doi: 10.1111/j.1600-065X.2010.00929.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Vladutiu A. O. Immunoglobulin D: properties, measurement, and clinical relevance. Clin Diagn Lab Immun. 2000;7:131–140. doi: 10.1128/cdli.7.2.131-140.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Gorski K., Carneiro M., Schibler U. Tissue-specific in vitro transcription from the mouse albumin promoter. Cell. 1986;47:767–776. doi: 10.1016/0092-8674(86)90519-2. [DOI] [PubMed] [Google Scholar]
  • 20.Herbomel P., Rollier A., Tronche F., et al. The rat albumin promoter is composed of six distinct positive elements within 130 nucleotides. Mol Cell Biol. 1989;9:4750–4758. doi: 10.1128/MCB.9.11.4750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Heard J. M., Herbomel P., Ott M. O., et al. Determinants of rat albumin promoter tissue specificity analyzed by an improved transient expression system. Mol Cell Biol. 1987;7:2425–2434. doi: 10.1128/MCB.7.7.2425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Kraus C. L., Culican S. M. Nummular keratopathy in a patient with Hyper-IgD Syndrome. Pediatr Rheumatol Online J. 2009;7:14. doi: 10.1186/1546-0096-7-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Sornsakrin M., Wenner K., Ganschow R. B cell cytopenia in two brothers with hyper-IgD and periodic fever syndrome. Eur J Pediatr. 2009;168:825–831. doi: 10.1007/s00431-008-0843-6. [DOI] [PubMed] [Google Scholar]
  • 24.Attout H., Guez S., Ranaivo I., et al. A patient with hyper-IgD syndrome responding to simvastatin treatment. Eur J Intern Med. 2008;19:e82–83. doi: 10.1016/j.ejim.2008.04.009. [DOI] [PubMed] [Google Scholar]
  • 25.Coban E., Terzioglu E. A patient with hyper-IgD syndrome in Antalya, Turkey. Clin Rheumatol. 2004;23:177–178. doi: 10.1007/s10067-003-0858-3. [DOI] [PubMed] [Google Scholar]
  • 26.Tronche F., Rollier A., Bach I., et al. The rat albumin promoter: cooperation with upstream elements is required when binding of APF/HNF1 to the proximal element is partially impaired by mutation or bacterial methylation. Mol Cell Biol. 1989;9:4759–4766. doi: 10.1128/MCB.9.11.4759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Zhang D. E., Ge X., Rabek J. P., et al. Functional analysis of the trans-acting factor binding sites of the mouse alpha-fetoprotein proximal promoter by site-directed mutagenesis. J Biol Chem. 1991;266:21179–21185. [PubMed] [Google Scholar]
  • 28.Izban M. G., Papaconstantinou J. Cell-specific expression of mouse albumin promoter—evidence for cell-specific DNA elements within the proximal promoter region and cis-acting DNA elements upstream of −160. J Biol Chem. 1989;264:9171–9179. [PubMed] [Google Scholar]
  • 29.Pinkert C. A., Ornitz D. M., Brinster R. L., et al. An albumin enhancer located 10-kb upstream functions along with its promoter to direct efficient, liver-specific expression in transgenic mice. Gene Dev. 1987;1:268–276. doi: 10.1101/gad.1.3.268. [DOI] [PubMed] [Google Scholar]
  • 30.Hu J. M., Camper S. A., Tilghman S. M., et al. Functional analyses of albumin expression in a series of hepatocyte cell lines and in primary hepatocytes. Cell Growth Differ. 1992;3:577–588. [PubMed] [Google Scholar]
  • 31.Clark A. J., Cowper A., Wallace R., et al. Rescuing transgene expression by co-integration. Biotechnology (NY) 1992;10:1450–1454. doi: 10.1038/nbt1192-1450. [DOI] [PubMed] [Google Scholar]
  • 32.Tang B., Yu S., Zheng M., et al. High level expression of a functional human/mouse chimeric anti-CD20 monoclonal antibody in milk of transgenic mice. Transgenic Res. 2008;17:727–732. doi: 10.1007/s11248-007-9162-3. [DOI] [PubMed] [Google Scholar]
  • 33.Enjuanes L., Sola I., Castilla J., et al. Transgenic mice secreting coronavirus neutralizing antibodies into the milk. J Virology. 1998;72:3762–3772. doi: 10.1128/jvi.72.5.3762-3772.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Fine J. M., Rivat C., Lambin P., et al. Monoclonal IgD. A comparative study of 60 sera with IgD “M” component. Biomedicine. 1974;21:119–125. [PubMed] [Google Scholar]
  • 35.Fibbe W. E., Jansen J. Prognostic factors in IgD myeloma: a study of 21 cases. Scand J Haematol. 1984;33:471–475. doi: 10.1111/j.1600-0609.1984.tb00727.x. [DOI] [PubMed] [Google Scholar]
  • 36.Rowe D. S., Hug K., Forni L., et al. Immunoglobulin-D as a lymphocyte receptor. J Exp Med. 1973;138:965–972. doi: 10.1084/jem.138.4.965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ligthart G. J., Schuit H. R., Hijmans W. Subpopulations of mononuclear cells in ageing: expansion of the null cell compartment and decrease in the number of T and B cells in human blood. Immunology. 1985;55:15–21. [PMC free article] [PubMed] [Google Scholar]
  • 38.Chen K., Xu W., Wilson M., et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nat Immunol. 2009;10:889–898. doi: 10.1038/ni.1748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Obici L., Manno C., Muda A. O., et al. First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheum. 2004;50:2966–2969. doi: 10.1002/art.20490. [DOI] [PubMed] [Google Scholar]

Articles from Science China. Life Sciences are provided here courtesy of Nature Publishing Group

RESOURCES