Tackling Immune Dysregulation – A Key Driver of Disease

Numerous specialized cells, organs and signaling pathways contribute to immunity. These mechanisms are not only shared, but often play a central role, in a range of pathologies from cancer and diabetes to neurodegeneration and autoimmunity. Understanding the mechanisms underpinning immune dysregulation enables us to overcome challenges associated with therapeutic intervention. We spoke with Dr Fabienne Charrier-Savournin, Corporate Product Manager at Cisbio, to learn more about this topic.

Q: What is meant by immune dysregulation and how does this relate to disease?

A: Our immune system plays a central role in organism homeostasis, enabling our bodies to fight and recover from infections. Like any other process involved in the maintenance of homeostasis, imbalance can lead to an unhealthy state. For instance, overactivation of the immune system, whether the origin is genetic or environmental, induces an inflammatory state which in turn may impair organ function. Take type 2 diabetes as an example. We all know that excessive consumption of fat and sugar combined with a sedentary lifestyle represent major causes of obesity. What happens in adipose tissues from obese patients? Dying overloaded adipocytes recruit immune cells, in particular macrophages — which produce inflammatory cytokines and chemokines. These inflammatory chemical signals in turn recruit more immune cells to the site, exacerbating the problem. Consequently, peripheral tissues such as adipose, muscle or liver, which are the primary glucose absorption sites, start becoming resistant to insulin. A reduction in insulin efficacy leads to increased glucose levels in the blood stream, impairing glucose homeostasis and resulting in type 2 diabetes. 

Q: Could you provide an overview of some of the conditions that are associated with dysregulation of the immune system?

A: In autoimmune diseases, an important class of immune dysregulation conditions, immune cells mistakenly attack healthy cells, tissues, and organs. This weakens the body’s functions and can be life-threatening. More than 80 autoimmune diseases are reported, including type 1 diabetes, rheumatoid arthritis (RA), lupus, multiple sclerosis (MS) and Crohn’s disease.

Some metabolic diseases, like non-alcoholic steatohepatitis (NASH), arise from the activity of resident liver macrophages, namely the Kupffer cells. Human immunodeficiency virus (HIV), is another example of a disease that results from a direct attack on self T helper lymphocytes and can lead to acquired immune deficiency syndrome (AIDS). More recently, it has been postulated that the inflammation process plays a role in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Resident brain macrophages called microglial cells cause neuroinflammation by producing inflammatory mediators. 

Unlike autoimmune, metabolic or neurodegenerative diseases which are linked with overzealous immune responses, cancer is associated with immune response silencing. In a normal situation, our immune system is educated to scan, recognize and destroy invaders and abnormal cells like tumor cells. However, among other strategies to sustain their uncontrolled growth, tumor cells can mask or dampen the immune reaction escaping this destruction.

Q: What tools can be used to investigate the molecular pathways associated with these types of diseases? Are there any specific pathways you would like to highlight?

A: Even though the pathophysiology of autoimmune, metabolic, neurodegenerative diseases or cancers are different, the molecular basis underlying immune system dysregulation have common signatures.

For instance, activation of innate immune pathways, such as Toll-like receptors, cytoplasmic sensors (like STING) or inflammasome signaling, contributes to the pathogenesis of numerous diseases such as RA, Lupus, MS, AD, PD, NASH and diabetes. Understanding these pathways in the context of one pathology, can therefore benefit others. This also applies to therapeutic approaches, where one therapeutic compound may have broader indications than initially defined. Signaling pathways require enzymatic activity; phosphorylation is mediated by kinases, dephosphorylation by phosphatases, acetylation by acetylases and so on. This also means we need complex biological models that can replicate these pathological conditions. Thanks to innovations in biotechnology over the past two decades, solutions for molecular pathway investigation, whether based on genome sequencing, immunoassays, imaging etc. constitute a comprehensive technological arsenal for improving drug discovery. Our commitment to supporting immunology research is evidenced by the recent publication of our immunology guide which provides an overview on the current knowledge of the immune system pathways, including both innate and adaptative pathways.

Q: What are some of the challenges associated with therapeutically targeting conditions caused by immune dysregulation?

A: With regards to therapeutic intervention, side-effects and toxicity are considered with extreme caution. Remember the clinical trial phase 1 using a superagonistic anti-CD28 antibody TGN1412, caused a massive cytokine storm, characterized by the rapid and strong induction of pro-inflammatory cytokine release. Dramatic consequences for the patients were observed: pulmonary and lung injury, renal failure and coagulation issues, cardiovascular shock and acute respiratory distress, necessitating transfer to intensive care. All these deleterious effects, directly related to an undesired overaction of the immune system, was not predicted by preclinical animal studies.

Identifying the appropriate therapy among the increasing number of therapeutic agents, should be based on the risk-benefit for each patient. Indeed, different molecular basis account for the diversity of autoimmune diseases.  Patients exhibit different symptoms depending on the disease state and their response to treatment. Therefore, identifying new specific disease targets, and more predictive biomarkers for a better stratification of patients, developing non-toxic and innovative and effective therapeutics should result in better patients care.

Q: What advice would you give to researchers working to uncover the molecular pathophysiology of these diseases?

A: See what’s happening on the other side of the door, especially regarding autoimmunity and immuno-oncology. This is not rocket science but the differing fields of immunology can learn from one another; if you need to upregulate one pathway in the context of autoimmunity, you would probably need to downregulate it in the context of immuno-oncology.