title: Autophagy in plasma cell pathophysiology.
abstract: Plasma cells (PCs) are the effectors responsible for antibody (Ab)-mediated immunity. They differentiate from B lymphocytes through a complete remodeling of their original structure and function. Stress is a constitutive element of PC differentiation. Macroautophagy, conventionally referred to as autophagy, is a conserved lysosomal recycling strategy that integrates cellular metabolism and enables adaptation to stress. In metazoa, autophagy plays diverse roles in cell differentiation. Recently, a number of autophagic functions have been recognized in innate and adaptive immunity, including clearance of intracellular pathogens, inflammasome regulation, lymphocyte ontogenesis, and antigen presentation. We identified a previously unrecognized role played by autophagy in PC differentiation and activity. Following B cell activation, autophagy moderates the expression of the transcriptional repressor Blimp-1 and immunoglobulins through a selective negative control exerted on the size of the endoplasmic reticulum and its stress signaling response, including the essential PC transcription factor, XBP-1. This containment of PC differentiation and function, i.e., Ab production, is essential to optimize energy metabolism and viability. As a result, autophagy sustains Ab responses in vivo. Moreover, autophagy is an essential intrinsic determinant of long-lived PCs in their as yet poorly understood bone marrow niche. In this essay, we discuss these findings in the context of the established biological functions of autophagy, and their manifold implications for adaptive immunity and PC diseases, in primis multiple myeloma.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute , Milan , Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Oliva
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute , Milan , Italy ; Università Vita-Salute San Raffaele , Milan , Italy ; Bone Pathophysiology Program (BoNetwork), Division of Genetics and Cell Biology, San Raffaele Scientific Institute , Milan , Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Cenci
keywords: XBP-1; antibody; autophagy; endoplasmic reticulum; multiple myeloma; plasma cell; proteostasis; unfolded protein response