Clinical and Cellular Response to Abatacept Therapy and Haematopoietic Stem Cell Transplantation in LRBA Deficiency

The lipopolysaccharide-responsive beige-like anchor (LRBA) gene comprises 58 exons, is located at chromosome 4q31, and encodes one of nine human BEACH proteins that participate in intracellular protein trafficking. Although ubiquitously expressed, LRBA is particularly vital to the function of regulatory T cells where it traffics CTLA4 to the cell surface, and prevents its lysosomal degradation. CTLA4 is an inhibitory receptor that competes with CD28 to bind CD80/CD86 on antigen presenting cells, thus preventing T cell activation. By interaction with CTLA4, LRBA plays an important role in maintaining immune homeostasis. Biallelic deleterious mutations throughout LRBA abolish expression of LRBA protein in almost all described cases, and cause a rare clinical syndrome characterised by cytopenia, inflammatory bowel disease, lymphadenopathy, and recurrent sinopulmonary disease. For reasons that are not completely understood, the spectrum of disease severity and manifestations is broad, ranging from asymptomatic individuals through to patients requiring profound immune suppression. Targeted therapy with the CTLA4-IgG fusion protein Abatacept has shown promise in some patients but cure is only possible through haematopoietic stem cell transplantation, a high-risk procedure with mixed early outcomes in LRBA deficiency. This thesis follows a cohort of 16 LRBA-deficient patients from diagnosis through to the introduction of Abatacept therapy, and finally bone marrow transplantation with reduced intensity conditioning. In-depth immune system interrogation was performed to characterise the impact of LRBA deficiency on T- and B-lymphocytes, as well as the innate immune system, which had not previously been studied in this disease. This study found that Abatacept therapy successfully modulates disease activity, both clinically and immunologically, but does not halt disease progression. Transplantation with reduced intensity conditioning can lead to complete disease remission with full donor chimerism, and correction of most immunological defects. A range of biological markers of disease activity were identified across the immune system, which can aid the monitoring of response to therapeutic interventions