IgE Structure, Function & Regulation

Gould, with Fear and Corrigan have discovered that somatic hypermutation, class switching and IgE protein synthesis occur in the nose in allergic rhinitis and airways of both atopic and non-atopic asthmatics, suggesting that anti-IgE strategies may be beneficial in both groups of patients. Gould discovered that VH5 is over-represented in the nasal allergenic IgE response suggesting that a superantigen, such as the S. aureus enterotoxins, may play a role in the pathogenesis of allergic disease. They are also cloning and expressing whole IgE antibodies, as well as the corresponding scFv fragments, specific for grass pollen allergens and S. aureus superantigens for functional analysis of the IgE molecules, and crystal structure determination of the Fv-allergen/superantigen complexes (Sutton). An MRC Programme grant was awarded to Sutton, Gould and Beavil in 2006 to support this research, which has been renewed in 2011 to include additional collaborations with McDonnell and Lack to study the IgE and IgG4 response to peanut allergens.

Gould and Fear have also shown that both the germline IgE epsilon and IgG gamma chain genes are constitutively expressed (revealing open chromatin structure) in nearly all naïve B cells, disproving a long held dogma that IL-4 stimulates switching to IgE in B cells by causing the unfolding of chromatin structure in the region of the IgE epsilon heavy-chain gene. They have also studied the mechanism of DNA recombination events associated with class-switching, using ultra-high resolution microscopy.

Cousins, Lavender and Lee have been studying the mechanism of T cell differentiation using both transcriptomic and epigenetic analysis, this work has revealed the identity of a number of cell-type specific transcripts and begun to show that this differential gene expression is facilitated by establishment of cell type specific chromatin environments and expression of non-coding RNA transcripts that are likely to be involved in maintaining transcriptional competence of loci during lineage commitment. Similar work is being undertaked on Airway smooth muscle cells, to establish whether altered expression of both mRNAs and microRNAs in muscle from people with asthma is influenced by altered chromatin environments at these genes. A second objective of these studies is to identify the histone modifying enzymes responsible for the establishment of these chromatin environments.

With Susan John, Lavender and Cousins have demonstrated a role for STAT5 in transcriptional regulation of the transcription factor c-Maf and shown regulation of expression of this factor by the IL-2 pathway.