Metabolic Gatekeepers of Pathological B Cell Activation

• Published in: Annual review of pathology Vol. 16; no. 1; pp. 323 - 349
• Main Authors: Sadras, Teresa, Chan, Lai N, Xiao, Gang, Müschen, Markus
• Format: Journal Article
• Language: English
• Published: United States Annual Reviews 24.01.2021
• Subjects: Animals; B cell; B-Lymphocytes - metabolism; Cell Transformation, Neoplastic - metabolism; Clonal Anergy - physiology; Humans; malignant transformation; metabolism; Receptors, Antigen, B-Cell - metabolism; Self Tolerance - physiology; signaling; transcription; B cell; metabolism; signaling; malignant transformation; transcription
• ISSN: 1553-4006; 1553-4014
• DOI: 10.1146/annurev-pathol-061020-050135

Unlike other cell types, B cells undergo multiple rounds of V(D)J recombination and hypermutation to evolve high-affinity antibodies. Reflecting high frequencies of DNA double-strand breaks, adaptive immune protection by B cells comes with an increased risk of malignant transformation. In addition, the vast majority of newly generated B cells express an autoreactive B cell receptor (BCR). Thus, B cells are under intense selective pressure to remove autoreactive and premalignant clones. Despite stringent negative selection, B cells frequently give rise to autoimmune disease and B cell malignancies. In this review, we discuss mechanisms that we term metabolic gatekeepers to eliminate pathogenic B cell clones on the basis of energy depletion. Chronic activation signals from autoreactive BCRs or transforming oncogenes increase energy demands in autoreactive and premalignant B cells. Thus, metabolic gatekeepers limit energy supply to levels that are insufficient to fuel either a transforming oncogene or hyperactive signaling from an autoreactive BCR.