Trends in Immunology
Volume 39, Issue 1, January 2018, Pages 19-27
Journal home page for Trends in Immunology

Review
Series: Immunometabolism
Metabolic Links between Plasma Cell Survival, Secretion, and Stress

https://doi.org/10.1016/j.it.2017.08.007Get rights and content

Trends

Plasma cells secrete enormous quantities of antibodies and play crucial roles in humoral immunity and autoimmunity. This secretory activity underlies very specific metabolic requirements in this cell type.

As B cells differentiate into plasma cells, marked changes in nutrient uptake and intermediary metabolism promote antibody synthesis and expansion of the ER.

Some of the same substrates used for antibody synthesis and ER biogenesis are also used to generate energy and prevent plasma cell apoptosis. Differences in nutrient uptake thus correlate with plasma cell lifespan and antibody secretion rates.

Expansion of the secretory apparatus in plasma cells triggers compensatory stress responses. Potential links between intermediary metabolism, ER stress, and plasma cell lifespan are starting to emerge.

Humoral immunity is generated and maintained by antigen-specific antibodies that counter infectious pathogens. Plasma cells are the major producers of antibodies during and after infections, and each plasma cell produces some thousands of antibody molecules per second. This magnitude of secretion requires enormous quantities of amino acids and glycosylation sugars to properly build and fold antibodies, biosynthetic substrates to fuel endoplasmic reticulum (ER) biogenesis, and additional carbon sources to generate energy. Many of these processes are likely to be linked, thereby affording possibilities to improve vaccine design and to develop new therapies for autoimmunity. We review here aspects of plasma cell biology with an emphasis on recent studies and the relationships between intermediary metabolism, antibody production, and lifespan.

Section snippets

Plasma Cell Formation and Subset Heterogeneity

The quality, quantity, and duration of antibody production by plasma cells are the major determinants of immunological protection against many infections and for almost all clinically used vaccines [1]. Plasma cells represent a unique lineage within the immune system, single-mindedly producing enormous quantities of antibodies for as long as they live. Recent studies have begun to uncover the intrinsic diversity of plasma cells, and with this information mechanistic details have emerged that

Intermediary Metabolism in Plasma Cell Formation and Maintenance

Much of the research on B cell metabolism during development and activation before plasma cell formation has been recently reviewed [3]. Thus, in this article we will focus on some key findings specifically related to intermediary metabolism, the process by which nutrients are converted into ATP and other cellular biosynthetic products. Naïve resting B cells have scant cytoplasm and ER, appear to have relatively few energy or biosynthetic requirements, and as such are recalcitrant to genetic

Antibody Secretion and ER Stress Responses in Plasma Cells

Though there are few unequivocal answers, to begin to address this question some background is required regarding how plasma cells metabolically acquire their secretory capacity and mount ER stress responses. Plasma cells are estimated to secrete several thousand antibody molecules per second [58]. To place this observation into a physiological context, only 1 μl of passively transferred immune serum is sufficient to protect an immunodeficient mouse from an otherwise lethal West Nile virus

Concluding Remarks

Despite the uncertainties listed above, some compelling evidence links specific ER stress, nutrient uptake, and antibody secretion pathways. Prdm1 not only promotes amino acid uptake in plasma cells but also promotes the expression of Xbp1 6, 7. Xbp1s then directs the diversion of glucose into the hexosamine pathway by enhancing the expression of rate-limiting enzymes [80], which may in turn promote antibody secretion 31, 56. Finally, the uptake of amino acids and glucose is linked to plasma

Acknowledgments

The authors are supported by National Institutes of Health (NIH) grant R01AI099108, the New York Stem Cell Foundation (NYSCF-R-I14), and a Research Scholar grant from the American Cancer Society (125091-RSG-13-252-01-LIB). D.B. is a New York Stem Cell Foundation Robertson Investigator.

Glossary

Aerobic glycolysis
metabolic pathway that converts glucose into pyruvate and then into lactate despite the presence of oxygen. Normally, when oxygen is present, pyruvate is carried into the mitochondria for oxidative phosphorylation, a highly efficient method for generating ATP. When pyruvate is instead converted into lactate in oxygen-replete conditions, this process is often referred to as Warburg metabolism, named after its discoverer Otto Warburg. Aerobic glycolysis is preferentially

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