Pathways Involved in Immune Regulation and B Cell Selection

Our aim is to understand the genetics of immune disease in humans, and to develop new therapeutic strategies that can interrupt the development of autoimmunity. To understand how abnormal regulation of the immune system leads to autoimmune disease we are studying the cells involved in ‘immunological memory’ which is the basis for all vaccination strategies and leads to the development of long-term immunity to infectious disease. We have developed new methods of tracking cells and characterizing the events involved in generation of immunity and we are using these to study self tolerance to antigens inside cells – for example those involved in the autoimmune disease systemic lupus erythematosus (SLE). We have used a model to look for defects in the immune response to self and foreign antigens, and are linking genes with their biological outcomes. We have identified a protein called Roquin, as a potentially important protein in the development of rheumatoid arthritis and SLE and we are now working on molecules that could be used as a therapy to reduce the self-directed immune response in these two debilitating diseases.

Goals To understand how the immune system regulates the response to antigens - in particular how B cells are selected and how dysregulation leads to autoimmune disease. Our focus is on how cells involved in long-term immunity are generated and sustained as part of immunological memory. We have developed functional approaches to track cells and characterize pathways involved both in the immune response and in self tolerance. Using these methods we have investigated self-tolerance to intracellular antigens such as those targeted in the autoimmune disease systemic lupus erythematosus (SLE). We have shown that when mHEL, highly tolerogenic on the cell surface, is tethered in the ER by an ER retention moiety it becomes immunogeneic and positively selects self-renewing B1 B cells and high titres of high affinity IgM autoantibody (1). We have used genetic strategies to identify new pathways regulating the immune response to antigens. Genome-wide ENU mutagenesis has been used to screen for defects in the immune response to self and foreign antigens, and we have refined strategies for dissecting immunological defects and for linking biochemical pathways between genes and phenotypes. By using ENU we identified the autoimmune regulator Roquin and determined its role in the negative regulation of follicular helper T (TFH) cells from a screen for autoimmune mice (2). Roquin mediates the destruction of mRNA encoding the T cell costimulatory molecule ICOS, important as TFH cells and ICOS dependent signals are required for germinal centre formation and high affinity antibodies. As TFH cells are activated in rheumatoid arthritis and increased in frequency in SLR, we have developed a potential therapeutic blocking antibody against the human ICOS ligand, as well as PD-1 superagonists, to target TFH cells. With our collaborators at the MRC Genome Stability Unit (University of Sussex) we have contributed to the field of stem cell biology by showing how DNA repair of double strand breaks by DNA ligase IV is essential for the maintenance of stem cells during aging (3). The identification and characterization of Themis, a novel protein required for survival and positive selection of T cells (4) illustrates how rare variants can open up new lines of research. Our recent development of a screening method for defects in immunization led us to identify two ENU mutant strains of mice, both deficient in the guanine nucleotide exchange factor (GEF) DOCK8. Both of these strains failed to sustain an antibody response to T-dependent antigen. Future research plans Our future work will focus on: (a) study of the role of DOCK family proteins in immune function, B cell selection and memory; (b) creation of a consortium to study the genetics of immune disease in humans; (c) development of new therapeutic strategies targeting autoimmiune pathways in humans. References: (1) Ferry et al 2003 J Exp Med 198: 1415 (2) Vinuesa et al 2005 Nature 435:452 (3) Nijnik et al 2007 Nature 447: 686 (4) Johnson et al. 2009 Nature Immunology 10: 831 (5) Randall et al. 2009 Nature Immunology 10:1283 546/3444