Transgenic Animal Models of B‐ and T‐Cell Autoreactivity

Abstract

Transgenic animals can be made to express self‐reactive antigen receptors by constructing heritable genetic modifications of their germline. The development of transgenic technology has been used to learn about the pathogenic role and regulation of autoreactive B and T lymphocytes. Examples highlighted here include T‐cell receptors that contribute to T‐cell‐mediated diabetes mellitus and B‐cell receptors against facultative or obligate self antigens that are regulated by B‐cell anergy or clonal deletion. An unexpected finding was the discovery of receptor editing in B cells expressing site‐directed, transgenic antideoxyribonucleic acid (DNA) B‐cell receptors. In these B cells, the products of further immunoglobulin gene rearrangements displace the autoreactive antigen receptor. Notably, the same anti‐DNA receptor can participate in an autoimmune response, if the immunoglobulin transgene is backcrossed on an autoimmune genetic background. Because the analysis of transgenic antigen receptors has led to many exciting discoveries it is likely that transgenic animals will remain front and centre of immunology research for years to come.

Keywords: B‐cell development; allelic exclusion; autoimmunity; antigen receptors; microinjection; receptor editing

Figure 1.

Procedures for the production of transgenic mice. A one‐celled embryo is obtained from the mating of a superovulated female mouse and a male mouse, and placed into a petri dish. The gene of interest is injected into the embryo that is kept in place with a holding pipette and observed through the microscope. Following micromanipulation, embryos are reimplanted into a foster female mouse, litters are born and their genomic DNA is analysed by standard techniques.

Figure 2.

Immunoglobulin transgenes advance B‐cell development. Mice that are unable to rearrange their endogenous immunoglobulin genes arrest B‐cell development at stage C of pro‐B cells. A functional heavy (H) chain gene advances the development to the pre‐B‐cell stage. A combination of H and light (L) chain genes can support full development of B lymphocytes, provided that the resulting antigen receptor is not autoreactive against a membrane‐bound major histocompatibility complex (MHC) class I antigen. Rag1, recombination‐activating gene 1; Ig, immunoglobulin.

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Further Reading

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Radic, Marko Z(Dec 2008) Transgenic Animal Models of B‐ and T‐Cell Autoreactivity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001225.pub2]