Animal Models of Human Primary Immunodeficiency Diseases

Michael P Blundell, UCL Institute of Child Health, London, UK
Christine Kinnon, UCL Institute of Child Health, London, UK

Published online: June 2012

DOI: 10.1002/9780470015902.a0001238.pub2

Animals with immunodeficiencies provide useful model systems for the study of corresponding immunological disorders in man. There has been substantial progress made in the availability and numbers of animal models since the 1970s when naturally occurring models were the only source. Improved molecular biology techniques, embryonic stem (ES) cell technologies and the sequencing of whole animal genomes has not only increased the number of models but also has led to improved models, particularly in mice. The increased understanding of the immune system, immune disorders and the generation of novel therapies owes much to animal models of disease. Further work is now in generating larger animal models which in addition to expressing the immunological disorders have a more directly comparable physiology.

Key Concepts:

  • Animal models of human immunodeficiency have been useful in studying the immune system.
  • The phenotypes resulting from genetic defects in animals do not always mirror those seen in humans.
  • Technologies exist to knock‐out, knock‐in and knock‐down relevant genes as well as replace them with human loci in animal models to improve the comparability of the phenotype.
  • Murine models are the most commonly described and used animal models but technologies are being developed for larger animal models.
  • Animal models have been crucial in the development of novel therapies for immunodeficiencies.

Keywords: immunodeficient; animal models; X‐linked; inherited disease; innate and adaptive immune system; knock‐out and knock‐in mice; gene targeting; spontaneous mutation

 References
    Adachi O, Kawai T, Takeda K et al. (1998) Targeted disruption of the MyD88 gene results in loss of IL‐1‐ and IL‐18‐mediated function. Immunity 9: 143–150.
    Bacchelli C, Buckland KF, Buckridge S et al. (2011) The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B‐cell homeostasis in heterozygous and homozygous mice. Journal of Allergy and Clinical Immunology 127: 1253–1259.
    Barbosa MD, Nguyen QA, Tchernev VT et al. (1996) Identification of the homologous beige and Chediak‐Higashi syndrome genes. Nature 382: 262–265.
    Berglof A, Sandstedt K, Feinstein R, Bolske G and Smith CI (1997) B cell‐deficient muMT mice as an experimental model for Mycoplasma infections in X‐linked agammaglobulinemia. European Journal of Immunology 27: 2118–2121.
    Blackburn MR, Datta SK and Kellems RE (1998) Adenosine deaminase‐deficient mice generated using a two‐stage genetic engineering strategy exhibit a combined immunodeficiency. Journal of Biological Chemistry 273: 5093–5100.
    Blundell MP, Worth A, Bouma G and Thrasher AJ (2010) The Wiskott‐Aldrich syndrome: the actin cytoskeleton and immune cell function. Disease Markers 29: 157–175.
    Chaible LM, Corat MA, Abdelhay E and Dagli ML (2010) Genetically modified animals for use in research and biotechnology. Genetics and Molecular Research 9: 1469–1482.
    Cunningham‐Rundles C (2011) Autoimmunity in primary immune deficiency: taking lessons from our patients. Clinical & Experimental Immunology 164(suppl 2): 6–11.
    Czar MJ, Kersh EN, Mijares LA et al. (2001) Altered lymphocyte responses and cytokine production in mice deficient in the X‐linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proceedings of the National Academy of Sciences of the USA 98: 7449–7454.
    DiSanto JP, Muller W, Guy‐Grand D, Fischer A and Rajewsky K (1995) Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proceedings of the National Academy of Sciences of the USA 92: 377–381.
    Fischer A (2007) Human primary immunodeficiency diseases. Immunity 27: 835–845.
    Gordon JW and Ruddle FH (1981) Integration and stable germ line transmission of genes injected into mouse pronuclei. Science 214: 1244–1246.
    Hermans MH, Ward AC, Antonissen C et al. (1998) Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony‐stimulating factor receptor gene associated with severe chronic neutropenia. Blood 92: 32–39.
    Kagi D, Ledermann B, Burki K et al. (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin‐deficient mice. Nature 369: 31–37.
    Kawai T, Choi U, Cardwell L et al. (2007) WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C‐terminus‐truncated CXCR4. Blood 109: 78–84.
    Koller BH and Smithies O (1992) Altering genes in animals by gene targeting. Annual Review of Immunology 10: 705–730.
    Lyon MF, Peters J, Glenister PH, Ball S and Wright E (1990) The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott‐Aldrich syndrome. Proceedings of the National Academy of Sciences of the USA 87: 2433–2437.
    Marrella V, Maina V and Villa A (2011) Omenn syndrome does not live by V(D)J recombination alone. Current Opinion in Allergy and Clinical Immunology 11: 525–531.
    Meek K, Kienker L, Dallas C et al. (2001) SCID in Jack Russell terriers: a new animal model of DNA‐PKcs deficiency. Journal of Immunology 167: 2142–2150.
    Mestas J and Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. Journal of Immunology 172: 2731–2738.
    Migchielsen AA, Breuer ML, van Roon MA et al. (1995) Adenosine‐deaminase‐deficient mice die perinatally and exhibit liver‐cell degeneration, atelectasis and small intestinal cell death. Nature Genetics 10: 279–287.
    Mombaerts P, Iacomini J, Johnson RS et al. (1992) RAG‐1‐deficient mice have no mature B and T lymphocytes. Cell 68: 869–877.
    Muller U, Steinhoff U, Reis LF et al. (1994) Functional role of type I and type II interferons in antiviral defense. Science 264: 1918–1921.
    book Murphy K, Travers P and Walport M (2008) Janeway's Immunobiology New York: Garland Publishing.
    Negishi I, Motoyama N, Nakayama K et al. (1995) Essential role for ZAP‐70 in both positive and negative selection of thymocytes. Nature 376: 435–438.
    Ohbo K, Suda T, Hashiyama M et al. (1996) Modulation of hematopoiesis in mice with a truncated mutant of the interleukin‐2 receptor gamma chain. Blood 87: 956–967.
    Pearson T, Greiner DL and Shultz LD (2008) Humanized SCID mouse models for biomedical research. Current Topics in Microbiology and Immunology 324: 25–51.
    Pollock JD, Williams DA, Gifford MA et al. (1995) Mouse model of X‐linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nature Genetics 9: 202–209.
    Randall KL, Lambe T, Johnson A et al. (2009) Dock8 mutations cripple B cell immunological synapses, germinal centers and long‐lived antibody production. Nature Immunology 10: 1283–1291.
    Remy S, Tesson L, Usal C et al. (2010) New lines of GFP transgenic rats relevant for regenerative medicine and gene therapy. Transgenic Research 19: 745–763.
    Rezaei N, Hedayat M, Aghamohammadi A and Nichols KE (2011) Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. Journal of Allergy and Clinical Immunology 127: 1329–1341.
    Rooney S, Sekiguchi J, Zhu C et al. (2002) Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis‐deficient mice. Molecular Cell 10: 1379–1390.
    Shinkai Y, Rathbun G, Lam KP et al. (1992) RAG‐2‐deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68: 855–867.
    Shultz LD, Ishikawa F and Greiner DL (2007) Humanized mice in translational biomedical research. Nature Reviews Immunology 7: 118–130.
    Smith CI, Backesjo CM, Berglof A et al. (1998) X‐linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase. Springer Seminars in Immunopathology 19: 369–381.
    Snapper SB, Rosen FS, Mizoguchi E et al. (1998) Wiskott‐Aldrich syndrome protein‐deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9: 81–91.
    Suzuki N, Suzuki S, Duncan GS et al. (2002) Severe impairment of interleukin‐1 and Toll‐like receptor signalling in mice lacking IRAK‐4. Nature 416: 750–756.
    Thomis DC, Gurniak CB, Tivol E, Sharpe AH and Berg LJ (1995) Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270: 794–797.
    Trobridge GD and Kiem HP (2010) Large animal models of hematopoietic stem cell gene therapy. Gene therapy 17: 939–948.
    van de Ven AA, Compeer EB, van Montfrans JM and Boes M (2011) B‐cell defects in common variable immunodeficiency: BCR signaling, protein clustering and hardwired gene mutations. Critical Reviews in Immunology 31: 85–98.
    Westerberg LS, Meelu P, Baptista M et al. (2010) Activating WASP mutations associated with X‐linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes. Journal of Experimental Medicine 207: 1145–1152.
    Wiler R, Leber R, Moore BB et al. (1995) Equine severe combined immunodeficiency: a defect in V(D)J recombination and DNA‐dependent protein kinase activity. Proceedings of the National Academy of Sciences of the USA 92: 11485–11489.
    Yan Z, Sun X and Engelhardt JF (2009) Progress and prospects: techniques for site‐directed mutagenesis in animal models. Gene Therapy 16: 581–588.
 Further Reading
    Blair K, Wray J and Smith A (2011) The liberation of embryonic stem cells. PLoS Genetics 7(4): e1002019.
    Pessach IM and Notarangelo LD (2011) Primary immunodeficiency modeling with induced pluripotent stem cells. Current Opinion in Allergy and Clinical Immunology 11(6): 505–511.
    Rémy S, Tesson L, Ménoret S et al. (2010) Zinc‐finger nucleases: a powerful tool for genetic engineering of animals. Transgenic Research 19(3): 363–371.
 Web Links
    ePath International Knockout Mouse Consortium http://www.knockoutmouse.org/
    ePath Mouse Genome Informatics http://www.informatics.jax.org/
    ePath The Jackson Laboratory http://jaxmice.jax.org/index.html

Related Sub-Topics:

Immunodeficiency | Diagnostics, Therapeutics and Methods | Model Organisms and Human Disease
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Animal Models of Human Primary Immunodeficiency Diseases
 
How to Cite close
Blundell, Michael P, and Kinnon, Christine(Jun 2012) Animal Models of Human Primary Immunodeficiency Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001238.pub2]