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Excessive interferon-α signaling in autoimmunity alters glycosphingolipid processing in B cells


From Left: Arleen Sanny, Ng Sze Wai, Nurhidayah Basri, Dr Andy Tan, Dr Ho Ying Swan and Dr Alison Lee

Authors

Andy Hee-Meng Tana, Arleen Sannya, Sze-Wai Nga, Ying-Swan Hoa, Nurhidayah Basria, Alison Ping Leea and Kong-Peng Lama,b,c,d

a Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore
Departments of b Physiology, c Microbiology and Immunology, and d Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Published in Journal of Autoimmunity 2017 89:53-62 (Online Version)

 

Abstract

The host immune system protects the body from infection by foreign pathogens. It does this through the action of many immune cell types including lipid-reactive natural killer T (NKT) and B cells. During normal immunity to infection, NKT cells help B cells produce antibodies that bind the pathogen and neutralize their harmful effects to the host. However, this process can become deleterious to the host when NKT cells instead help B cells produce antibodies that react to self-molecules, thus causing damage to host tissue. This phenomenon is known as autoimmunity.

We showed in a previous study that B cells in autoimmune mice can reciprocally modulate NKT cell responses through their presentation of self-lipid antigens to activate NKT cells, resulting in death of the latter. Removing the ability of B cells to present self-lipids substantially rescued NKT cell deficiency in autoimmune mice. Doing the same, however, did not affect NKT cell survival in normal mice. Collectively, these data suggest self-lipids presented by autoimmune B cells to NKT cells were altered. In this current work, we sought to decipher the factors which elicited alterations in lipid composition of autoimmune compared with normal B cells. Firstly, we observed that autoimmune B cells produced excessive amounts of cytokines, including interferon-α (IFN-α). Normal B cells treated with IFN-α had altered expression of self-lipids, in particular, glycolipids. In addition, IFN-α-treated B cells co-cultured with NKT cells led to depletion of the latter in vitro which can be largely reversed by blocking the capacity of these B cells to present. Furthermore, blocking IFN-α signalling could also rescue NKT cell deficiency in autoimmune mice in vivo. Thus, IFN-α is one of the cytokines produced by autoimmune B cells that likely induced changes in their glycolipid composition.

How does IFN-α induce aberrant glycolipid expression in autoimmune B cells? Our subsequent work demonstrated that IFN-α affected expression of enzymes which that catalyze critical steps in glycolipid processing. Restoring the levels of expression of these enzymes in IFN-α-activated B cells using chemical inhibition or ectopic expression prevented their depletion of co-cultured NKT cells. Taken together, our study indicated that excessive IFN-α perturbs glycolipid metabolism in B cells which in turn compromises NKT homeostasis. Repurposing clinically approved drugs to target appropriate glycolipid processing pathways is an attractive therapeutic strategy to ameliorate autoimmune defects.

 

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