Strategic Thrusts Banner
Engineering CELLS,
   Engineering RESPONSES

Research Highlights

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


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)



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.


Please refer to here for more information on the “-Omics” Technologies Group.