Autoimmunity and Immune Regulation
1. Overview
Our aim is to understand how the immune system is formed and regulated, the causes of autoimmunity, particularly the systemic autoimmune diseases such as SLE and vasculitis, and how B cells are selected by antigens. Adverse immunological reactions to self and foreign antigens that lead to autoimmune or inflammatory disease place a major economic and social burden on world health and individual quality of life. We are also interested in how people differ in their inherited susceptibility to these diseases and why these differences are sustained in human populations by natural selection. Advances in this area will have a large impact on the management of human disease. Our laboratory is part of the Medical Research Council Human Immunology Unit. Our work is funded by the Medical Research Council, the Wellcome Trust and the Oxford Biomedical Research Centre. We are based in the Henry Wellcome Building for Molecular Physiology, which is a division of the Wellcome Trust Centre for Human Genetics.
2. New pathways affecting the response to foreign and self-antigens
Much of our knowledge about immune control has come form studying a relatively small number of rare spontaneous mouse and human mutations, and so it is arguable that the rate of naturally occurring mutations has been a main factor limiting the discovery of new mechanisms and therapeutic targets. To address this issue, we are founders of a Wellcome Trust funded Infection and Immunity Genomics Consortium (IIGC), which aims to create new mouse variants using the chemical mutagen ethylnitrosourea (ENU). Our partners are the Australian National University (Chris Goodnow and Carola Vinuesa) and University of Sydney (Warwick Britton). ENU increases the natural mutation frequency ~100-fold and enables us generate families of mice that we can screen for heritable phenotypes affecting immune function. It causes nucleotide base pair substitutions and therefore mirrors natural variation in populations, and like human variants reveals the multiple functions of genes by altering individual protein domains and splicing products. This means that it creates a wide variety of genetic alleles, and enables us to identify new functions proteins and study genes that would be embryonic lethal as null alleles. We have shown that the mutant strains identified in this way can then become entry points into further novel pathways and mechanisms. The aim of the programme is to generate a library of new mutants for the scientific community with defects affecting autoimmunity and tuberculosis. An important aspect of this process is developing ways to refine our screens and accelerate the identification of mutations.
3. Autoimmunity and self-tolerance
The analysis of the immune tolerance depends on a wide range of transgenic models and other assays developed in the last few years in Oxford that make it possible for us to study the development and function of antigen-specific lymphocytes. This approach makes it possible to compare uniform populations of cells from mice with ENU, spontaneous and gene-targeted mutations that affect lymphocyte regulation. The ability to track B and T cell receptor transgenic lymphocytes has underpinned many of the key advances in our understanding of self-tolerance in the last 20 years. The same technology makes it possible to study the response to foreign antigens and follow the movement of antigen-specific cells in vivo.
We have generated transgenics expressing hen egg lysozyme (HEL) as a membrane bound (mHEL-KK) or soluble (sHEL-KDEL) antigen specifically to model self-tolerance to intracellular self-antigens, which are targeted in systemic autoimmunity such as SLE. The sequestered mHEL-KK antigen positively select autoreactive B1 B cells into the primary repertoire and behaves like other typical lupus antigens. In collaboration with John Forrester in Aberdeen we have also created tools to explore tolerance to self-antigens in melanocytes (to model vitiligo and potentially to study immunity to melanoma) and in the retina (to model uveitis).
3. The genetics and functional basis of human autoimmune diseases
One aim of this programme is develop new ways to measure immune function in patients with autoimmune disease and immunodeficiency. We want to discover the extent to which these diseases are caused by rare or private mutations in humans, and we want to develop biological agents that can inhibit adverse immune responses. The other aim is to use whole genome sequencing strategies pioneered in the ENU programme to identify rare genetic variants causing autoimmune disease and immunodeficiency in human disease.