Differences of opinion in coeliac disease

Victorian researchers have discovered different immune responses to gluten in people with coeliac disease depending on which genetic variant they carry.

Coeliac disease - in which the gluten protein from wheat, rye and barley inflames and damages the lining of the small intestine - is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8.

HLA genes are part of the major histocompatibility complex (MHC), which plays a pivotal role in the immune system.

HLA-DQ2 mediated coeliac disease is common in people of European ancestry, with about 90 per cent of sufferers positive for DQ2. Another five per cent possess HLA DQ8.

In China and East Asia, DQ2 genes are rare while DQ8 genes are as common as in Europe.

It had been assumed that the molecular workings underpinning the immune response in the DQ2 and DQ8 forms of the disease were similar and that any potential treatments could apply equally to both forms.

However, scientists from the Walter and Eliza Hall Institute (WEHI), Monash University and the University of Melbourne have found this is not the case.

The team of Kate Henderson and Professor Jamie Rossjohn from Monash, Dr Jason Tye-Din and Dr Bob Anderson from WEHI, Professor Jim McCluskey from Melbourne University and others discovered that the immune response in people with the DQ8 form of coeliac disease was quite different to that of DQ2.

Anderson said crucial to the research was the discovery that T-cells in people with DQ8-associated coeliac disease reacted quite differently to the small proteins in gluten than the T-cells in people with the DQ2 form of the disease.

"At the molecular level there's quite a different immune response to the gluten," Anderson said. "It is sufficiently different to the reaction with DQ2 that different therapies would be appropriate for people with the DQ8 form of coeliac disease."

At the moment a gluten-free diet is the only treatment for coeliac disease but nearly half the people on the diet still have damage to their small intestine. Consequently other therapies, including a vaccine and three different drugs, are in various stages of development.

The research team believes coeliac disease might be the first example of an immune disease where treatments are customised according to the genetic make-up of the patient.

"When developing drugs for coeliac disease you have to take into account people's genetic background," Anderson said. "Until four years ago no one was using the gene test for coeliac disease. Now it's the most commonly requested genetic test for any medical condition in Australia.

"Now that we know what's happening at a molecular level in both the DQ2 and DQ8 forms of the disease that genetic test will tell patients with coeliac disease and their doctors what treatment they will most benefit from."

A Structural and Immunologoical Basis for the Role of Human Leukocyte Antigen DQ8 in Celiac Disease appears in the July 1-12 issue of Immunity.