Determining the role of HLA variation in inflammatory bowel disease

Summary

Inflammatory Bowel Diseases (IBD) are inflammatory disorders that affect the gastrointestinal tract, of which the main types are Crohn’s disease (CD) and ulcerative colitis (UC). There is no cure for these often life-changing severe diseases, but a number of medications have been introduced that target the body's immune response in an attempt to control symptoms. Biologics, as they are known, are an important addition to these medications. The most widely used biologics target an immune modulator known as Tumour Necrosis Factor, or TNF, which contributes to the characteristic inflammation seen in CD and UC patients. While highly effective therapies in some individuals, the use of biologics is limited by a percentage of patients (10-40%) who do not respond at all to these therapies (primary non-response) and by loss of response (in 24-46% of patients) to treatment in the first year. Secondary loss of response is commonly due to a patient's development of antibodies against the medication, rendering it less effective over time.  

A group of genes and proteins, known as HLA molecules, are of great interest in IBD, as these have now been implicated as causal or contributory to both disease progression and severity, as well as loss of response in both CD and UC patients. Specifically, large scale genomics studies have implicated the specific HLA class II molecule, HLA-DRA/DRB1*01:03 as having a primary role in determining both severity and susceptibility in both CD and UC, while the molecule HLA-DQA1*05/DQB1*02 has been implicated in the development of antibodies against biologic therapies. 

We will investigate the roles of HLA-DRA/DRB1*01:03 and HLA-DQA1*05/DQB1*02 in the development and progression of CD and UC, as well as in the development of antibodies against anti-TNF therapies for CD and UC. Focusing specifically on antigen processing and presentation, our aim is to characterise the preferred protein binding sequence of these HLA molecules and determine the host, pathogen, or environmental antigens to which they bind; or the parts of the infliximab and adalimumab molecules which are involved in the production of neutralising antibodies.