Geoff Butcher
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Geoff Butcher's Group

In a healthy individual it is critically important that the number of mature T and B lymphocytes is maintained at a steady level. This process is termed lymphocyte homeostasis. The generation of new cells from haematopoietic precursors in the bone marrow and thymus is balanced by the loss of mature cells in peripheral compartments of the body. Sometimes numbers of lymphocytes can dramatically increase, for example during infection with Epstein Barr Virus. Once the infection has been successfully defeated lymphocyte numbers return to a normal level. Numerous homeostatic mechanisms contribute to the overall stability of the mature lymphocyte pools: the importance of this is evident from several immune diseases associated with having too few lymphocytes (lymphopenias) or too many (e.g. lymphadenopathies). The regulation of lymphocyte survival vs. programmed cell death (apoptosis) is therefore essential to the survival of the healthy organism. Significant efforts are underway, worldwide, to gain knowledge of the genes and proteins involved in control of this process.

Geoff Butcher's group is studying a family of cell signalling molecules which may play a part in the maintenance of lymphocyte populations. These are the GIMAPs (GTPase of immunity associated proteins; formerly known as IANs) which are a small family of 7-8 putative guanine nucleotide hydrolases (GTPases) encoded in a cluster in mammals on a single autosome (chromosome 7 in humans). They all share the so-called AIG1 domain, which defines a particular subfamily of the universe of GTPases. Particular attention was attracted to this family in 2002 when a recessive mutation in one of its members, GIMAP5, was shown to be the basis of severe peripheral lymphopenia in the BB strain of rats that develops autoimmune diabetes mellitus spontaneously. This suggested that GIMAP5 is an anti-apoptotic regulator of normal T lymphocyte survival and this idea has been supported by experiments in mice. Meanwhile, work on a different GIMAP protein, namely GIMAP4, suggests that this family member, by contrast, accelerates apoptosis. Such a process may be advantageous after acute expansions of lymphocyte numbers in response to infections, in order to return the lymphocyte pool to its normal state as rapidly as possible.

So far, very little is understood of the cellular mechanisms by which GIMAP proteins produce their effects. The Butcher group is using a variety of approaches - genetic manipulation of mice; protein biochemistry and immunoprecipitation; generation of novel serological reagents; in vitro survival assays; etc. in order to uncover the function and mechanisms of action of the GIMAP family. One member of the family, GIMAP8, has a particularly intriguing predicted protein structure in that it possesses three tandem GTP-binding domains (1). Having more than a single such domain present within a single polypeptide is a rarity and to have three is so far unique to this GIMAP protein.

As stated above, a mutation in the rat GIMAP5 gene is responsible for the severe lymphopenia seen in the BB rat. This mutation is a key susceptibility locus for this autoimmune diabetic disease model. In conjunction with collaborators from the Dunn School of Pathology in Oxford, the Butcher group have developed a second disease model under the control of this GIMAP5 mutation. This is the PVG-RT1^u,lyp/lyp rat which develops an inflammatory bowel disease with an allergic-type (Th2) aetiology which may be a useful model for a group of autoimmune eosinophilic disorders recognised in humans and companion animals.