Experts from Oxford Immune Algorithmics highlight how the Immune system has come under the spotlight in Human Biology, particularly as a consequence of the COVID-19 pandemic
There is increasing recognition that the immune system has a fundamental role in the development of most, if not all diseases. The role of the immune system in infection and autoimmune conditions is long established. Emerging evidence now indicates that the immune system underpins how human biology responds to all internal and environmental flux, as a consequence of damage or disease, as well as normal life events such as ageing and pregnancy. The COVID-19 pandemic has spurred us to reconsider how we approach our health and healthcare resources, and reflect on personal accountability to stay healthy. At Oxford Immune Algorithmics, we believe that a deeper understanding of an individual’s immune system thus has the potential to transform personalised healthcare.
The ‘invisible’ role of the immune system is the development of disease: No longer invisible
The contribution of the immune system is increasingly being recognised in widespread disease processes. Cancer is a prime example. The immune system has specialised white blood cells (WBC) called T and B lymphocytes, Natural Killer cells, neutrophils, and macrophages. These cells are strongly implicated in the development of tumour or cancer cells by influencing how cells replicate. All cells, good and bad, continuously respond to stimuli and stresses. The immune system provides surveillance of this response. This knowledge is currently being leveraged to generate new therapies that harness and manipulate the immune response to eradicate such tumour cells. The immune system also has a role in the development of cardiovascular diseases, including heart attacks and diabetes. In parallel, the same is being recognised in neurodegenerative diseases of the brain, such as Alzheimer’s and Parkinson’s disease, dementia and depression.
The link between our gut bacteria and immune function…
As is evident by current food trends in consuming ‘healthy bacteria’ in the form of live fermented yogurts, (kefir), and fermented vegetables like sauerkraut, we now understand that the immune system has a role to play in promoting healthy colonies of gastrointestinal bacteria called the ‘microbiome’. The immune consequences of a dysregulated microbiome are linked to a range of diseases including autism, multiple sclerosis, asthma, liver disease, metabolic disorders, irritable bowel syndrome, diabetes and rheumatoid arthritis.
Pain and the immune system
The immune system is also critical for the response to injuries, from trivial falls to major accidents. During injury and disease, the immune system is involved in the perception of pain (sensory and emotional) and its consequences for repair and regeneration. Even in the absence of any recognisable injury or disease, the immune system has a key role in orchestrating a ‘normal balance’ or ‘homeostasis’ in humans. There are also important differences in immune responses in men and women, which are believed to underpin the different susceptibility of the sexes to disease. The immune system also changes with age and inflammation. This is a novel concept in which chronic, ongoing low-grade inflammation contributes to the development of age-related diseases.
Sleep and the immune system
The immune system is also important in regulating sleep cycles and the consequences of sleep disturbances. Unsurprisingly, it also plays a central role in the gut-brain axis, a signalling pathway that influences how much food we need to and should consume, which no doubt is important in obesity. During pregnancy, maternal immune activation or dysfunction, precipitated by chronic conditions aforementioned, autoimmune disease, infection or psychosocial stress, is thought to lead to potential long-term consequences for the foetus, including predisposition to neurodevelopmental disorders; this is one of the reasons why pregnant women amongst other vulnerable groups were advised to shield during the COVID-19 pandemic.
Immunotyping: Our immune system is as individual as we are
It is clear from this evidence that if we can better understand micro-fluctuations of an individual’s immune system, this could potentially transform our ability to risk stratify diseases, develop more effective preventative interventions, make earlier diagnoses and develop superior treatments. There is increasing recognition that the immune system is highly variable between individuals and that discrete ‘immunophenotypes’ exist. This simply means that in a population there will be groups of individuals with various immune system behaviours and traits which may be of benefit or detriment to them. These ‘immunophenotypes’ may be a more cohesive determinant of health outcomes.
Immune system: The challenges of interrogating a complex — and only partially understood — dynamic network The immune system is exceptionally complex and incorporates a very large number of cells, proteins and small molecule mediators that interact in very complicated pathways. This inordinate level of complexity may seem like a deterrent from attempting to decipher the ‘personalised’ associations between changes in the immune system and diseases for individuals. Based on this rationale, one might argue that the technical, logistic and economic challenges alone are likely to prevent ‘deep immune characterisation’ of individuals outside of research settings for decades. However, this rationale assumes that personalised immune characterisation is entirely dependent on complex and costly diagnostic tests. Contrary to this viewpoint, we believe that transformative insights can be generated from examining data generated from ‘simple’ and common blood tests.
How can we monitor the immune system: is a full blood count an apt starting point?
What is a full blood count?
The simplest ‘survey’ of an individual’s immune system is a routinely performed blood test called a Full Blood Count (FBC). The FBC counts the number and frequency of cells in the blood, including white blood cells and their main subtypes which are important components of the immune system. As discussed, these are called neutrophils, lymphocytes, monocytes, eosinophils and basophils, red blood cells and platelets. The FBC is the most commonly performed medical diagnostic test performed worldwide. It is estimated that there are more than 4 billion tests for FBC per year globally, and that it is incorporated as part of the vast majority of blood tests performed.
The utility of FBC in diagnosis and disease surveillance and response to treatment is well established for many conditions, including infections, various anaemias, and leukaemias amongst other blood disorders.
Interpreting an FBC: A fresh perspective to personalise data
The widely accepted assessment of an FBC result as ‘normal’ or ‘abnormal’ for a given population seems to contradict the use of a FBC as a personalised measure of the individual’s immune system. This is because these population normal ranges are surprisingly broad, ranging from 4.0 – 11.0 million cells per microlitre of blood for total white blood cells (WBC). The equivalent population normal reference values for other white blood cell subtypes such as neutrophils and lymphocytes are 2.0-7.5 and 1.0 – 4.5 million cells per microlitre of blood respectively. In short, an individual’s WBC result could increase 250% from 4.0 to 10 and still be deemed as ‘normal’ and uneventful, because the values fall within population norms; this represents a surprisingly crude approach to understanding the significance of FBC data. Scientifically, this assumption is flawed as it discounts the fundamental mechanisms within immune biology that drive these changes.
The question at hand is whether we should be following a dogmatic assessment of an FBC in the knowledge that a personalised approach could yield us valuable data. At OIA, we seek to raise the validity of this rather outdated population-based method in today’s age of technology.
Impact on public health: Case example Sepsis
Clinically speaking, it is not uncommon for the diagnosis of infection or sepsis to be ‘missed’ or delayed because the WBC blood test is ‘normal’, particularly when the individuals ‘baseline’ blood results are not established, providing no basis for comparison. In health, blood tests are conducted so infrequently, and because data is not integrated into a centralised system, if present, the data can be difficult to access. From a public health perspective, this would be invaluable in preventing death from sepsis. As a point of reference, the Global Sepsis Alliance published that in the UK in 2021 there were 245,000 cases of sepsis, with 48,500 deaths, of which 14,000 were estimated as being preventable.
Not attempting to capture this data and investing in the digital infrastructure to integrate the data with other known health parameters, is a colossal loss of opportunity in improving personalised care and health outcomes.
Monitoring the immune system: Opportunities
Emerging evidence supports the assertion that variations in immune cells within the ‘normal’ range can have important health implications. A study by Shah et al, published in the British Journal of Medicine in 2017 highlighted that the total WBC count in ‘healthy’ individuals was found to be predictive of risk of short-term and long-term death, even when other known risk factors like age, smoking, diabetes, high blood pressure, ethnicity and blood cholesterol levels were accounted for. In this study of over 194,000 individuals, those with a higher ‘normal’ WBC of 8.65- 10.05 were almost three times more likely to die within 6 months than those with a lower ‘normal’ WBC of 5.35-6.25. To illustrate this further, Alpert et al, published a 2019 paper in Nature Medicine Journal that discussed that the immune system of healthy individuals as assessed by the number of a subset of their lymphocytes, which is a sub-type of white cell, was a better predictor of the risk of death than age. This led to the development of the concept of Immune Age.
These studies, and there are several more, provide compelling reasons for a paradigm shift in how we monitor immune health from a population-based approach to a personalised one. To better understand disease, and to enable accelerated personalised diagnosis, monitoring and treatment, we must redefine norms with respect to a patient’s individual physiology. As discussed, this involves establishing an individual’s baseline values and generating data in health and in disease, to truly understand ‘what is a personal normal’ and thus bridge the gap between population and personalised healthcare.
It is important to note that a white cell count is an accessible starting point when considering how to monitor immune health, but in no way comprehensive. How frequently an FBC should be repeated really depends on an individual’s ‘co-morbidities’ or current medical conditions, financial resources and personal motivation to stratify health-related risk.
A call to action
The key for more insightful understanding of the role of the immune system in health and disease is, therefore, the routine collection of longitudinal data that allows changes in the immune system to be tracked over time and be correlated with internal and external factors, including symptoms and sign of disease and normal life stress. The delivery of this promise requires three pillars: One: Democratising access to blood testing, so that people have convenient, accurate, frequent and affordable access to regular health monitoring; Two: Collection of all relevant physiological and clinical data, such as clinical symptoms and treatments; and Three: The ability to collate, integrate and analyse these data using state- of-the-art AI and Machine Learning approaches to generate novel insights. If performed ethically and sustainably, with the right changes in medical culture, this approach has the potential for significant transformation in how we think about our own medical data.
Shah, A.D., et al., White cell count in the normal range and short-term and long term mortality: international comparisons of electronic health record cohorts in England and New Zealand. BMJ Open, 2017. 7(2): p. e013100.
Alpert, A., et al., A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat Med, 2019. 25(3): p. 487-495.
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