Human secreted IgD: structure, interactions and mechanisms in allergic inflammation and asthma

The incidence of allergic disease worldwide has increased alarmingly in recent decades, no more so than in the UK where, for example, the prevalence of asthma is among the highest in the world. One in six children in the UK suffers from asthma, and life-threatening anaphylactic reactions to common food allergens such as peanuts, once rare, are now increasingly common. Allergic reactions occur when apparently innocuous substances are recognised by the immune system and treated as dangerous foreign "antigens". The antibodies produced by the immune system in response to these allergenic substances are of a type called IgE (immunoglobulin E), with different properties to the more commonly produced protective IgG, IgM and IgA antibodies with which the body defends itself again bacterial, viral and other "foreign" invaders. IgE antibodies bind to specific "receptor" proteins on the surface of cells (e.g. mast cells in the airways, skin or gut, and basophils in the blood) which, when triggered by allergen, release substances that lead to immediate hypersensitivity reactions characteristic of allergic disease. Targeting IgE is a viable therapeutic strategy, but an anti-IgE agent recently developed (omalizumab) is not only very expensive but also it is not effective in all patients. We have recently discovered in asthma patients a fifth and largely overlooked type of antibody, IgD, which may play a more fundamental role in allergic inflammation.

Of the five different types of human antibodies, IgM and IgD were the first to evolve with the emergence of an immune system in the jawed vertebrates (e.g. sharks) 500 million years ago. The other antibody classes evolved later, but IgM and IgD have been conserved to the present day, and while much is known about the important role that IgM plays, particularly in the primary immune response upon first encounter with a foreign antigen, very little is known about IgD. That it has also been conserved throughout the evolution of the immune system points to a critical function. Yet remarkably, while we know in detail the three dimensional structures and their interactions with cell receptors for IgM, IgA, IgG and IgE, we have none of this information for IgD. It is a major gap in our understanding of fundamental immunology.

We have discovered that IgD antibodies are produced in the respiratory tract of people with asthma, and that the antibodies show evidence (from analysis of their gene sequences) of being directed against specific allergens or antigens. Others have found IgD antibodies directed against food allergens in the blood of allergic patients. Intriguingly, it is also known that surface proteins expressed by certain commensal bacteria (M. catharralis and H. influenzae), commonly found in the respiratory tract, bind tightly to IgD. We hypothesise that the production of these IgD antibodies and their interactions with receptors on mast cells and basophils, different to those receptors for IgE, represents an early stage in the process that eventually leads to the generation of an IgE response and the symptoms of allergic disease and asthma.

In order to understand the IgD stage of this process, and the role of commensal bacteria, we will study the interactions of IgD antibodies with allergens, the bacterial proteins, and also the receptor(s) on mast cells and basophils. We hope that by delineating these mechanisms at the molecular level, we will identify opportunities to intervene more effectively at this early stage in the development of allergic airway inflammation and asthma. It is also very likely that IgD antibodies play a role in other diseases, and the work proposed here will substantially improve our understanding of an area of fundamental immunology which, remarkably, has yet to be explored.

We will investigate the structures, interactions and functional mechanisms of secreted IgD antibodies. The research project seeks to identify and characterise the key molecules that regulate these processes. The project proposes five interconnected strands of work:

1. Development of a novel set of anti-IgD antibodies, selected for the ability to inhibit interactions between IgD and specific IgD ligands. These selective inhibitors will allow intervention and elucidation of interaction pathways that mediate IgD's pro-inflammatory effects.
2. Identification and characterisation of the cellular receptor(s) for IgD.
3. Characterisation of the molecular interactions between IgD antibodies and antigens and superantigens, receptors, and anti-IgD antibodies, using a suite of biophysical methods.
4. Determination of high-resolution three-dimensional structures for IgD and IgD complexes with receptors and various ligands, utilising an integrated structural biology approach.
5. Examination of the effector functions of antigen-specific IgD antibodies in cellular assays using well-defined recombinant proteins and cell lines, and in vitro studies using patient derived cells. These experiments will test specific hypotheses developed from the molecular studies to elucidate roles of IgD in allergic inflammation.