Somatic mutation in human macrophages: defining ontogeny and mechanisms of inflammatory disease (360G-Wellcome-219562_Z_19_Z)

Acquired somatic mutation continually modifies the genomes of multicellular organisms, inevitably causing human disease. The over-arching aim of this proposal, is to define how somatic mutation impacts upon macrophages, immune cells that are critical for defence, regulation, and repair. Macrophages were thought to arise through continual recruitment of monocytes, but recent data indicate that they originate and renew in diverse ways. The first aim is to use silent mutation to study the origin of human macrophages. This will discern the difference between microglia, thought to arise exclusively from a primitive origin, self-renewing macrophages derived from definitive haematopoiesis, and macrophages that require a continual input of monocytes. The second ai, will study macrophages in clonal haematopoiesis. Somatic mutation in the bone marrow has the potential to alter macrophage function and accelerate prevalent diseases such as atherosclerosis. The final aim is to explore somatic mutation in clonal macrophage populations as a novel aetiology of idiopathic inflammatory disorders IgG4-related disease, granulomatosis with polyangiitis and sarcoidosis. These are noted for their overlap with histiocytosis, the archetype of a new class of inflammatory myeloid neoplasm. Together these studies will define novel functions of macrophages in pathology that reflect their independence or connection with haematopoiesis.