Immune system variation and flexibility

Immune system variation and flexibility

The clinical manifestations following SARS-CoV-2 infection are highly variable, ranging from asymptomatic or mild symptoms to severe pneumonia that can progress to acute respiratory distress syndrome[3]. Whilst it is still unclear whether this disease progression is related to the viral infection (load, and variant) itself, to the host immune response, to host comorbidities or to a combination of these different factors, what is clear is that there are wide variations of immune responses. The human immune system possesses immense individual-to-individual diversity, and also has specialised compartmentalisation[1]. (Which means many variations in response, local tissue activity, recovery and outcome on every challenge). Immunity is intrinsically variable because it is controlled by the most polymorphic (occurring in several different forms) genes and is shaped by highly sensitive, modifiable environmental sensors that can push immunity into myriad functional configurations[2].

Varied Functional Configurations

These varied functional configuration outcomes are reflective of the intrinsic biases toward particular immune response types each of us has. On initial infection from SARS-CoV-2 early defence mechanisms (found in the innate immune system) likely limit viral replication in most individuals and prevent further disease progression. These may include physiochemical barriers (mucus and metabolites), as well as innate immune defence proteins (cytokines, natural killer cells and interferons) that are constitutively produced or induced upon infection[4]. Thus, while most healthy humans have the capacity to turn on adaptive immune regulatory T cells (Tregs), type 1 helper T cells (TH1 cells), TH2 cells, TH17 cells, type I interferons, inflammasome activation, and a multitude of other states, individuals differ widely in the degree to which they are primed via the innate immune responses and in particular antigen-presenting cell conversions for each functional configuration. Each and any subsequent triggering event will also result in individual variational adaptive responses[5].

Immunity Evolves

These interindividual differences are relatively low at birth but continually expand as we age, gain weight, experience adverse stress or trauma and encounter new environments. Yet they are both stable and robust to perturbation including pathogen exposure, and vaccine exposure. The origin of this diversity is rooted in our evolutionary pasts, with genes that control immune traits being among the most divergent in archaic genomes (Neanderthals and Denisovans)[6]. In modern humans, a diverse range of immune-associated disorders, autoimmune diseases and infectious responses reflect the clinical consequences of this diversity in immunological states. This diversity also provides challenges for the successful application of immunotherapeutic strategies (of all types) and explains why there are inevitably various levels of interpersonal responses to a global vaccine rollout [7].

The variations in response are one of the reasons anecdotal stories and by this, I mean individual experiences are so impressively able to be found or experienced (and eulogised) to meet and match both expectations and desired outcomes. i.e it will always be possible to translate observation and ‘need’ into a compelling human story where the immune system is intrinsic, as it is by its very nature – variable and variant. However, the larger the number of people exposed to immunotherapeutics or pathogens, the consequence of each and the analysis of the captured data, the greater the level of confidence that the impact in terms of a stated outcome is either met or missed.

Why immune system variation matters

Rather than unsustainable convergence toward a homogenous state of infection–resistance (which was to a large extent the initial objective of vaccine and non-pharmacological orientated public health strategy), evolution has selected immune genes for the maintenance of rapid immune diversity as a species protective mechanism – we are adaptable. When potential pathogens (i.e SARS CoV-2) rapidly specialise to take advantage of a fixed niche, an evolutionary advantage can be gained from possessing an immune system wired into a functional configuration that is different from that of the prior host or at least is able to confer an adaptive capacity to evolve, and mitigate or neutralise the threat.

That means that whilst neutralising antibodies induced by the SARS-CoV-2 vaccines may wane or be blunted over time, our adaptive immune system (once exposed) has the capacity to flex and adjust to subsequent variant changes (subject to the individual response capabilities mentioned above) translated by the innate immune cells. Hence why some people develop more substantive immunological resilience post-infection, than they do post-vaccination – and also why hybridisation of vaccine and infection offers better immunological training and enhanced neutralising antibody production than either does individually[8].

Although vaccines constitute the best-controlled systems-immunology challenge context, experimental and natural infections provide the most physiologically relevant. The SARS-CoV-2 pandemic has provided the most intensively studied natural infection context, with a multitude of systems-immunology studies identifying immunological variations associated with protection from severe infection.

That means extensive knowledge has been gathered relating to natural infection-related immune responses as well as vaccine-induced responses, including learning more about the variables under our management. For example, the role of the human microbiome in immune responsiveness based on a myriad of human and animal studies suggests that microbiome variation between individuals contributes to the observed immune diversity. But causality remains a challenge! Yet, the microbiome may be the nexus that integrates many of the associated variables and provides the direct causative mechanisms underlying immunological variation and therefore may be a prime contender for manipulation via diet[9].

Under your control

Understanding variation in response to environmental factors in particular, such as diet, exercise, sleep, recovery, supplementation, microbiome-related eubiosis, and environmental exposure, holds the promise of using simple, safe environmental manipulations in a targeted manner to reroute an individual’s immune system toward a less pathogenic and more resilient configuration.

In simple terms, whilst vaccines are a public health policy, self-care, and recognition of the flexibility of the immune system’s capacity to adapt and improve, means we have a two-edged sword to support the transition from pandemic to endemic. Variants may be more or less problematic each time, but variants will continue to emerge, and a well-supported immune system provides us with the opportunity to flex genetic complexity and generate enhanced immune flexibility[10].


References

[1] Smith, N., Goncalves, P., Charbit, B. et al. Distinct systemic and mucosal immune responses during acute SARS-CoV-2 infection. Nat Immunol 22, 1428–1439 (2021)

[2] Kaczorowski, K. J. et al. Continuous immunotypes describe human immune variation and predict diverse responses. Proc. Natl Acad. Sci. USA 114, E6097–E6106 (2017)

[3] Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).

[4] Cervia, C. et al. Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19. J. Allergy Clin. Immunol (2020).

[5] Carr, E. J. et al. The cellular composition of the human immune system is shaped by age and cohabitation. Nat. Immunol. 17, 461–468 (2016)


[6] Colbran, L. L. et al. Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences. Nat. Ecol. Evol. 3, 1598–1606 (2019).


[7] Quintana-Murci, L. Human immunology through the lens of evolutionary genetics. Cell 177, 184–199 (2019).


[8] Crotty S. Hybrid Immunity. Science Perspective 25 June 2021


[9]  Yeoh YK, Zuo T, Lui GC, et al Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19 Gut 2021;70:698-706.


[10] Shao T, Verma HK, Pande B, Costanzo V, Ye W, Cai Y and Bhaskar LVKS (2021) Physical Activity and Nutritional Influence on Immune Function: An Important Strategy to Improve Immunity and Health Status. Front. Physiol. 12:751374

Written By:
Elisabeth Philipps

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