Article by Beatrix Wang

Graphic design by Joshua Koentjoro

We rely on our immune system to fight off pathogenic microbes and guard against the growth of malignant cells.¹ In recent decades, much progress has been made in mapping out the body’s strategy to defend against infection and immune disease, but fundamental questions remain within the field. How exactly are immune responses regulated? And, just as importantly, what are the mechanisms that lead to immune dysfunction and consequent disease?

“Everything,” Dr. Katherine Siminovitch says, “is about balance.” A healthy and functional immune system exists in a state of homeostasis wherein tightly regulated pathways are able to respond to invading pathogens appropriately.² This response involves a fine-tuned combination of immune activation and deactivation to ensure that the system neither over- nor under-reacts to stimuli. When this balance is disrupted, immune cells may begin attacking the body—a phenomenon known as autoimmunity—or lose their ability to respond to external (antigenic) stimuli, both of which can lead to debilitating health issues.

Dr. Siminovitch, a Professor of Medicine and Immunology at the University of Toronto and Senior Investigator at the Lunenfeld-Tanenbaum Research Institute, has made it the goal of her research career to identify the cellular and molecular pathways modulating immune function and involved in immune dysfunction, with a particular focus on autoimmune disorders.

“Major gaps still exist in our understanding of how autoimmune diseases develop and persist,” Dr. Siminovitch says. For some conditions, such as systemic sclerosis or vasculitis, the precise mechanisms underlying pathogenesis remain almost entirely unknown. Furthermore, even for extensively studied disorders such as lupus, there is a lack of therapies that go beyond symptom management and immunosuppression.

Identifying drivers of disease and discovering potential therapeutics have been complicated by the extensive heterogeneity that exists within individual immunologic conditions. “Different molecular pathways can lead to the same clinical phenotype,” Dr. Siminovitch says. “Clinical heterogeneity is very obvious, for example, in lupus. It becomes very challenging to find effective treatments when lupus patients are grouped into a study without initial sub-classification or sub-categorization, ignoring the likelihood the disease-causal pathways may differ among these patients and, as such, may need to be managed differently.”

Enormous efforts are continuing to elucidate the mechanisms by which different genes and molecules lead to the immune dysfunction underpinning disease. Dr. Siminovitch has played a vital role in this research. During her postdoctoral training, she became interested in an often-fatal immune deficiency disorder known as Wiskott-Aldrich syndrome (WAS). During this time, she contributed significantly to identifying the genetic cause of the illness, mapping the gene responsible, and characterizing various gene mutations that lead to WAS.³ The gene in question turned out to encode Wiskott-Aldrich syndrome protein (WASp), a large adaptor protein that mediates signal transduction, directs immune cell cytoskeletal activity, and is an essential immune regulator.⁴ Furthermore, these findings allowed for the development of genetic tests to diagnose WAS and identify carriers of the mutant gene.

Dr. Siminovitch subsequently became interested in other adaptor proteins within the WASp family, including WAVE2, another actin cytoskeletal regulator with the potential to play a role in immune function. “Not many people have been working on WAVE2,” Dr. Siminovitch says, “but my group was very interested in this protein’s functions because it is expressed at high levels in immune cells and because of our ongoing interest in cytoskeletal regulatory protein roles in immunity.”

It wasn’t until relatively recently that Dr. Siminovitch and her team had an opportunity to study this protein’s function in immune cells, her group having generated a conditional knockout mouse in which WAVE2 expression is specifically deleted in T lymphocytes. The results were striking. “The mice have an obvious phenotype of very severe autoimmune disease,” Dr. Siminovitch says. “And paradoxically, along with autoimmune disease, they also exhibit profound immune deficiency. So, the lack of WAVE2 in T cells leads to a disease representing both ends of the immunologic spectrum.” Using this mouse model, Dr. Siminovitch and her team identified WAVE2 as a suppressor of the TOR protein, a key regulator of cell metabolism, proliferation, apoptosis, and multiple other functions.^5,6 They found that in the absence of WAVE2, TOR is hyperactivated, leading to spontaneous T cell activation, with loss of immune homeostasis and diminished responsiveness to antigenic stimuli. These abnormalities, in turn, cause the severe immune disease observed in the mice.⁵

This work has served as an exciting starting point for Dr. Siminovitch and her team. Moving forward, Dr. Siminovitch believes there is much to learn about how WAVE2 functions in other immune cell types and is particularly interested in exploring an unexpected link between WAVE2 and neurodegenerative disease. Furthermore, the link between TOR hyperactivity and immune dysfunction suggests that drugs that inhibit the TOR pathway may have relevance to the treatment of autoimmune and other immune-mediated disease. 

Notably, Dr. Siminovitch’s findings also demonstrate how much more there is to learn about proteins and pathways even after they have been assigned specific functions. For both WASp and WAVE2, regulation of the cytoskeleton is only the beginning of the story. “These proteins have been primarily studied as cytoskeletal regulators because they contain domains that allow them to promote actin polymerization,” Dr. Siminovitch says. “But they have additional functions and I believe our current understanding of their functions represents only the tip of the iceberg of their biological contributions.”

Dr. Siminovitch has no doubt that the coming years will bring a wealth of answers to many complex questions about immune disease. “This is an incredible time to be involved in biomedical research,” she says. “I thought the same thing when I first set up my lab, but now the research tools available to scientists—technical and computational—are truly unprecedented in terms of the types of questions you can ask and reasonably hope to answer.” In this context, immunologists like Dr. Siminovitch are poised to address fundamental questions about the immune response and how it becomes dysregulated in disease. The ultimate hope is that this research will illuminate the complex combinations of factors that can trigger autoimmunity and can then be clinically translated to allow improved detection, more effective treatment, and prevention of immune disorders.

References:

1. Chaplin DD. Overview of the Immune Response. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S3-23. 
2. da Gama Duarte J, Woods K, Andrews MC, et al. The good, the (not so) bad and the ugly of immune homeostasis in melanoma. Immunology & Cell Biology. 2018;96(5):497–506. 
3. Kolluri R, Shehabeldin A, Peacocke M, et al. Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus. Hum Mol Genet. 1995 Jul;4(7):1119–26. 
4. Ngoenkam J, Paensuwan P, Wipa P, et al. Wiskott-Aldrich Syndrome Protein: Roles in Signal Transduction in T Cells. Frontiers in Cell and Developmental Biology [Internet]. 2021 [cited 2022 Jun 5];9. Available from: https://www.frontiersin.org/article/10.3389/fcell.2021.674572
5. Liu M, Zhang J, Pinder BD, et al. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. 2021 Mar 26;371(6536):eaaz4544. 6. Zou Z, Tao T, Li H, et al. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell & Bioscience. 2020 Mar 10;10(1):31.