BACKGROUND: Autophagy has emerged as a critical homeostatic mechanism in T lymphocytes, influencing proliferation and differentiation. Autophagy in B cells has been less studied, but genetic deficiency causes impairment of early and late developmental stages OBJECTIVES: To explore the role of autophagy in the pathogenesis of human and murine lupus, a disease in which B cells are critical effectors of pathology. METHODS: Autophagy was assessed using multiple techniques in NZB/W and control mice, and in patients with systemic lupus erythematosus (SLE) compared to healthy controls. We evaluated the phenotype of the B cell compartment in Vav-Atg7(-/-) mice in vivo, and examined human and murine plasmablast formation following inhibition of autophagy. RESULTS: We found activation of autophagy in early developmental and transitional stages of B cell development in a lupus mouse model even before disease onset, and which progressively increased with age. In human disease, again autophagy was activated compared with healthy controls, principally in naïve B cells. B cells isolated from Vav-Atg7(F/F) mice failed to effectively differentiate into plasma cells following stimulation in vitro. Similarly, human B cells stimulated in the presence of autophagy inhibition did not differentiate into plasmablasts. CONCLUSIONS: Our data suggest activation of autophagy is a mechanism for survival of autoreactive B cells, and also demonstrate that it is required for plasmablast differentiation, processes that induce significant cellular stress. The implication of autophagy in two major pathogenic pathways in SLE suggests the potential to use inhibition of autophagy as a novel treatment target in this frequently severe autoimmune disease.
Ann Rheum Dis
912 - 920
Autoimmunity, B cells, Systemic Lupus Erythematosus, Adult, Animals, Autophagy, B-Lymphocytes, Case-Control Studies, Cell Differentiation, Disease Models, Animal, Female, Humans, Lupus Erythematosus, Systemic, Lymphocyte Activation, Male, Mice, Plasma Cells, Precursor Cells, B-Lymphoid