Overview:
A system biology approach for dissecting the immune response
Benny Chain¹, Niclas Thomas¹, James Heather¹, Katharine Best¹, Theres Matjeka¹ , John Shawe-Taylor², Mahdad Noursadeghi^1
1Infection and Immunity, UCL, London, United Kingdom
²Computer sciences, UCL, London, United Kingdom

The human immune system has a complex, multi-layered structure which has evolved to detect and respond to changes in the internal microenvironment of the body. Recognition occurs at the molecular or submolecular scale, via many reversible receptor:ligand interactions, and can lead to a response with great sensitivity and speed. Remarkably, recognition can be coupled to memory, such that responses are modulated by events which occurred years or even decades before. Although the immune system in general responds differently and more vigorously to stimuli entering the body from the outside (e.g. infections or transplants) this is an emergent property of the system: many of the recognition molecules themselves have no inherent bias towards external stimuli (non-self) but also bind targets found within the body (self) . It is quite clear that the immune response registers pathophysiological changes in general. Cancer, wounding and chronic tissue injury are some obvious examples. The immune system `state' therefore tracks the internal processes of the body, and is likely to encode information regarding both current and past disease processes. Moreover the distributed nature of most immune responses (e.g. typically involving lymphoid tissue, non-lymphoid tissue, bone marrow, blood, extracellular interstitial spaces etc.) means that many of the changes associated with immune responses are manifested systemically, and specifically can be detected in blood. This provides a very convenient route to sampling immune cells. We consider two different and complementary ways of querying the human immune `state' using high dimensional genomic screening methodologies, and discuss the potentials of these approaches and some of the technological and computational challenges to be overcome.
The first approach is to analyse the global transcriptional landscape of whole blood samples. This approach seeks to capture the complex sequence of intra-cellular and inter-cellular changes which arise following the interaction of immune receptors with their targets. An analysis of these changes, and how they map onto known intra- and inter-cellular molecular networks reveals much information on the qualitative nature of a particular immune response. The second approach is to sequence and count the frequency of all T and/or B cell antigen receptor chains in a specific blood sample. Each B and T lymphocyte predominantly expresses receptors of one unique specificity, and the number of cells carrying a specific receptor increases following exposure to the cognate antigen. The frequency of cells carrying each specific receptor as a function of time therefore carries quantitative information on the response to specific antigen. By combining qualitative and quantitative analysis, we aim to obtain an integrated picture of the immune response, and use it to reveal underlying pathological processes which may be difficult to access using conventional diagnostic tools.