Goodnow Lab

Our research is focused on understanding a critical process for our health: how the immune system distinguishes the normal parts of our body (‘self’) from microbes that invade our body (‘non-self’) or cancer cells that arise in our body (‘altered self’) so that only microbes and cancer cells are targeted by destructive immune reactions. Our research pioneered the discovery that a series of immune tolerance ‘checkpoints’ ensure that antibodies and other immune reactions are correctly targeted away from self.

HOPE: Identifying the root cause of autoimmune disease

As the hub for a network of interdisciplinary collaborators in the HOPE Research Program, we are revealing how immune tolerance checkpoints break down in the 100 different autoimmune diseases, including Sjögren’s syndrome, vasculitis, kidney glomerulonephritis, arteritis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic and other autoimmune arthritis, scleroderma, autoimmune anaemia/thrombocytopenia/neutropenia, demyelinating neuropathies including myasthenia gravis, multiple sclerosis, myositis, coeliac disease, inflammatory bowel disease, thyroiditis and type 1 diabetes.

A key thrust of the HOPE Research Program employs cutting-edge genomic technologies and computational tools, in particular single cell RNA/DNA/protein analysis, to reveal ‘rogue’ clones of lymphocytes that cause a person’s autoimmune disease. In a growing number of autoimmune diseases, we have identified rogue clones and discovered how they evaded immune tolerance checkpoints: by acquiring somatic mutations in antibody genes and in the genes that govern the checkpoints. The same mutations also drive the rogue clones responsible for common blood cancers such as chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, Waldenstrom’s macroglobulinaemia, monoclonal gammopathy of unknown significance and T cell large granular lymphocytic leukaemia.

The HOPE Research Program is thus revealing that the root cause of some autoimmune diseases is also the benign stage of blood cancer. This surprising connection opens up strategies to improve the treatment of autoimmune disease and of early-stage cancer with new targeted therapies that are currently in use for late-stage blood cancers.

The HOPE Research Program is also revealing how inherited gene differences, epigenetic abnormalities and environmental triggers such as common infections (e.g. hepatitis C virus, Campylobacter jejuni, Epstein-Barr virus) or diet (e.g. gluten) also drive the development of rogue clones, leading to autoimmune disease.

Improving checkpoint inhibitor treatment of cancer

Circumventing immune tolerance checkpoints with ‘checkpoint inhibitor drugs is now a powerful third pillar of cancer treatment. One line of research in the lab is using genomic technologies and computational tools to reveal why immune reactions to destroy cancer cells are better in some people treated with checkpoint inhibitors than others, and why this correlates with the cancer treatment also triggering an autoimmune disease. By learning from patients who are 'exceptional responders’, our research has illuminated a potential strategy to improve checkpoint inhibitor treatment for cancer.