Medical Research

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Defining the Immune System

Our body’s immune system is designed to fight against viruses like COVID-19. There is strong evidence to suggest we should all be taking proactive steps immediately to educate and empower each Australian with evidence-based recommendations that promote nutritional adequacy and a healthy diet of fresh whole foods loaded with antioxidants, anti-inflammatories, and antimicrobials.

The overall function of the immune system is to prevent or limit infection. A functioning immune system is able to distinguish between healthy cells and unhealthy cells by recognising a variety of danger associated molecular patterns (DAMPs)[7,8] on our unhealthy cells caused by infection or cellular damage [9–11]. Infectious microbes such as viruses and bacteria release another set of signals recognised by the immune system called pathogen associated molecular patterns (PAMPs)[7,8,12,13] which our Pattern Recognition Receptors (PRRs) respond to. PRRs include Toll-Like Receptors (TLR)[9–11,14] on the cells of the body’s first line of defense, NOD-like receptors (NLRs)[9–11,14,15] that are primarily involved in bacterial recognition and RIG-Like receptors (RLRs)[16] primarily involved in viral recognition [17,18]. Their purpose is to launch a response through inflammation, chemotaxis (the ability of our white blood cells to move to the target area), antimicrobial gene expression, apoptosis of damaged cells, and the promotion of antigen presentation for immunological memory. The body must, essentially, demonstrate strong and early activation of the innate immune system to prevent infection [19], host an appropriately strong response throughout the course of infection to prevent its systemic spread and severity, and use its adaptive immune response [20] to lead to improved disease outcomes.

The human immune system and its related responses is highly variable and dependent on heritable and non-heritable factors, in addition to the symbiotic and pathogenic microbes to which one has been exposed [21,22]. Nonetheless, there are many underlying common factors that influence immunological health and the subsequent risk of immune-mediated, immune-associated and infectious diseases.

In all human beings, for example, both innate and adaptive immune responses need to be well functioning, phagocytic cells (neutrophils, monocytes, and macrophages), inflammatory cells (basophils, mast cells, and eosinophils), and natural killer (NK) cells need to be present and able to mount appropriate responses, and cellular interactions between antigen-specific B- and T-lymphocytes via an antigen presenting cells (APCs) must all contribute to a protective immune response [21–23].

The immune system is complex and pervasive, with multiple organs and tissues responsible for creating barriers to pathogens. Organs and tissues associated with the immune system that must maintain good health to mount appropriate responses include the skin, bone marrow, thymus, white blood cells, lymphatic system, lymph nodes, spleen and mucous membranes [24].

An appropriate response of the immune system to an unhealthy cell or infectious microbe includes [7],[25]:

  • Early response/activation of the innate immune system: Is predominantly represented by release of neutrophils and macrophages. These chemicals release enzymes that digest proteins and reactive chemicals that kill. They then engulf and digest what they have destroyed through a process called phagocytosis. For any infections that are not destroyed by the innate immune response will attract a response from the adaptive immune system.
  • The adaptive immune system: responds to antigens (antibody generators) through white blood cells called lymphocytes classified by B Cells and T Cells, responsible for antibody responses and cell-mediated immune responses, respectively. In antibody responses, B Cells release antibodies, which in turn bind and inactivate viruses and microbial toxins that stimulated their production. This binding also tags the infectious microbe to enable easier identification and destruction by the innate immune system. In cell-mediated responses, the second class of adaptive immune response, activated T cells react against a foreign antigen that is presented to them on the surface of a host cell that has viral antigens on the surface – effectively destroying the infected cell before it is able to replicate itself.

Consequences Associated with Weakened Immune Function

The effects of a weakened immune function is best seen in the manifestations of primary immune deficiency [26–29], human immunodeficiency virus (HIV)[30,31] or common immunodeficiency disorders (CVID)[32–34]. The shared symptoms of these conditions include one’s susceptibility to infection, characterised by increased frequency, severity and duration of that infection. The infections can often be recurrent, with the risk of complications being high, and with increased occurrence of opportunistic infections that develop less frequently in individuals with sufficient immune sufficiency. It is the job of the immune system to ward off such manifestations, but many find themselves susceptible for various reasons.

What Weakens the Immune Response?

Though there are some non-modifiable risk factors and conditions that result in the expression of immune deficiencies or weaknesses, such as severe combined immunodeficiency (SCID)[35], older age [36–39], or temporarily immunosuppression that occurs during chemotherapy treatment [40], our focus will be on the ability of the general population to maintain health through a sufficient immune response. More specifically, we focus on the manageable and modifiable factors that negatively impact the immune systems of the general population. These include nutritional deficiencies, chronic inflammation, metabolic syndrome, metabolic dysbiosis, and other lifestyle factors like exercise and sleep [41,42].

With the progress of modern research, the specific influences that shape an individual’s immune system is becoming increasingly clear, allowing integration of these findings into protocols and lifestyle recommendations that are simple practical for any member of the public to self-administer.

Nutritional Deficiencies

Nutrition is a key modifiable factor in the function of a healthy immune system [43]. Nutrition influences the development of the immune system right from foetal growth [43,44] and throughout the lifespan, with insufficient macronutrient and micronutrient intakes having an established role in immune function [45,46]. Without adequate nutrition, the immune system is deprived of the components needed to generate an effective immune response.

Protein/energy malnutrition is the primary cause of immunodeficiency worldwide [47,48]. It causes damage to a number of tissues that comprise the immune system (especially the mucosal lining) enabling greater invasion by pathogens, with a weaker response to those pathogens [49,50]. This inadequacy is heightened during fever and illness as dietary intake typically decreases, further reducing the ability for the immune system to mount an appropriate response [51].

Micronutrients have many and varied essential roles within the immune systems maintenance and function [52–54]. Creating experimental deficiencies of one or more of these nutrients is unethical in humans, however, studies of undernourished populations and rare cases presenting with these deficiencies have informed our understanding that these nutrients are essential to the healthy function of the immune system. The role of these nutrients in the body are complex, however, the established understanding of immune pathways indicates that deficiency of certain vitamins and minerals significantly suppress the immune response and are associated with a greater susceptibility to infection [55–57]. Vitamin A [58–62] and D [63], iron [64–66], zinc [67–74], and selenium [75,76] among many other micronutrients have immunomodulating functions and influence both the susceptibility of the host to infectious diseases and the course and outcome of these diseases and should be regularly monitored throughout the lifespan [77]. Inadequacy of these nutrients are related to, but not limited to, reduced phagocytic activity, lower function of cell-mediated immunity (T-cells), and severity of certain viral conditions.

There is a reason government organisations have set recommended daily intakes, knowing that nutrient inadequacy can have detrimental effects. Nutritional adequacy is a keystone to health. Unfortunately, as evidenced by the rise of chronic diseases like diabetes, cardiovascular disease and osteomalacia, healthy diets are not the norm [78–82]. We are also aware that food deserts or financial situations set limitations to what food can be accessed, so we incorporate alternatives into our program and promote certain nutrient-rich foods over others.

Chronic Inflammation

Inflammation is the immune system’s response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation. It acts by removing injurious stimuli and initiating the healing process[83,84]. Inflammation is therefore a defense mechanism that is vital to health. Usually, during acute inflammatory responses, cellular and molecular events and interactions efficiently minimize impending injury or infection. This mitigation process contributes to restoration of tissue homeostasis and resolution of the acute inflammation[85].

However, uncontrolled acute inflammation may become chronic, contributing to a variety of chronic diseases [86,87]. The medical consequences of chronic inflammation can lead to potentially permanent metabolic alterations[88,89], including cardiovascular disease [90,91], diabetes[92], neurodegeneration[93–95], and increased risk of carcinoma[96]. It is this chronic state of inflammation that sets the stage for some of the most challenging and debilitating diseases for populations and individuals alike, such as rheumatoid arthritis, weakened bones[97,98], cancer[99–101], and many other conditions outside the scope of this document. The cellular and molecular profiles of immune activation in chronic inflammatory disorders overlap with the patterns we expect to observe in healthy, effective, self-limiting immune responses to pathogens[102]. Supporting this, there are a number of studies showing a link between low grade inflammation and the greater susceptibility of infection – a finding repeated in a number of healthy and diseased populations around the world[85,87,88].

Currently, research on this complex interplay between chronic inflammation and other multidimensional mechanisms that may collectively contribute to immune deficiencies is ongoing[85]. However, it is clear that chronic inflammation and prolonged inflammatory responses are not desirable factors that promote an effective immune response[103,104]. We also know that there are many factors within our control, including diet[105], that can moderate such inflammatory pathways[106,107].

Metabolic Syndrome & Obesity

Obesity & metabolic syndrome are significant public health concerns because of their high global prevalence (31% and 29% of adults in Australia, respectively [108]) and association with an increased risk for developing chronic diseases. Currently, metabolic syndrome is a condition characterized by a clustering of 3 or more of the following components: central adiposity, elevated blood glucose, plasma triglycerides (TGs), blood pressure, and low plasma HDL-cholesterol[109,110]. In addition to these qualifying parameters, obesity and metabolic syndrome are associated with endothelial dysfunction, atherogenic dyslipidemia, insulin resistance, and chronic low-grade inflammation[110–112]. This results in the immune activation in tissues such as adipose tissue, liver, pancreas, and the vasculature. Hence, the immune cells play a role in the perpetuation of chronic disease, and it has further been established that obesity and metabolic syndrome negatively affects immunity[113–116]. This is evidenced through both changes in known immune system pathways and important clinical outcomes relating to immunity. Obesity has been shown to influence lymphoid tissue architecture and integrity[117,118], leukocyte populations and promotion of inflammatory phenotypes[119], all related to poorer immune function. Clinically, obesity and metabolic syndrome are associated with higher rates of vaccine failure, greater susceptibility to infection and more severe complications from infection[114,120,121].

However, of significant importance is the role of nutrition in ameliorating both obesity and metabolic syndrome[122]. Application of an overall healthy dietary pattern (discussed above) and lifestyle have been shown to significantly improve markers of metabolic syndrome and obesity, and related markers of inflammation that are in turn related to immunity. In brief, for the individuals with obesity and/or metabolic syndrome, their metabolic phenotype is related to a less effective immune response. As individuals with these conditions represent a significant portion of the population, attention to these factors are essential when considering strategies to improve overall immunity.

Other Factors with Associations to Immune Function:

Physical Activity     Although exercise immunology is considered relatively new, since 1990 a significant literature has been established[123,124]. Studies have assessed the effect of individual bouts of exercise of varying duration on immune markers, the clinical effect of infection prevention after exercise interventions, and assessed the effect of exercise on the ageing immune system[125]. Generally, there is consensus within the literature that increased physical fitness and participation is associated with a lower risk of infection, and more favourable inflammatory, oxidative stress and immune marker profile[125].

Findings indicate that an acute bout of exercise, less than 60 minutes in duration, results in increased immunosurveillance, represented by an increase in anti-pathogen activity of macrophages, an enhancement of innate and adaptive immune system activity, increases the release of anti-inflammatory cytokines, improves glycaemic control. In brief, enhancing pathogen fighting capacity while reducing barriers to healthy immune function, i.e. anti-inflammation[126–130]. However, bouts of intensive exercise longer than 120 minutes, elicit an increase in oxidative species, muscle tissue injury, a pro-inflammatory cytokine profile and strong innate immunity response[131,132].

Exercise interventions that have compared a control/’no exercise’ group to those engaged in regular physical activity, show that those who are exercising regularly experience significantly lower incidence of upper respiratory infections even after a period of 8 weeks, with potentially increasing benefits from 9 to 12 months of intervention[133–136]. Long term adaptations of greater anti-inflammatory action, higher frequency of increased immunosurveillance, greater metabolic and glycaemic control and reduced oxidative stress are considered to drive the lower susceptibility to infection. These long term effects are also realised by older individuals, such that habitual exercise is capable of regulating the immune system and delaying immunosenescence[137–139]. In contrast, very high volume training over time leads to immunosuppression and an increased susceptibility of upper respiratory tract infection compared to those who exercise at moderate volume over the same time period. Considering the modifiable nature and multi-faceted benefits that accompany physical activity, it is an important consideration when aiming to enhance the immune response of a population or individual.

Sleep Deprivation     Sleep is essential to normal functioning of the immune system and overall health maintenance[140,141]. Effects of inadequate or poor quality sleep influence 33-45% of adults in Australia[142]. Sleep deprivation in rodent models is fatal, with immune deficiency resulting in infection being one of the key hypotheses for this result[142,143]. In humans, short habitual sleep (<6 hours per night) is associated with reduced lifespan, increased vulnerability to viral infection[144], with sleep deprivation negatively impacting antibody titers after influenza vaccination[145].

The initial findings have investigated the effect of sleep duration on markers of immune function. On balance, the majority of studies indicate a suppression of immune markers, with clinical studies indicating a higher susceptibility of infection for lower amounts of sleep[142,143]. When compared to individuals sleeping 7 to 8 hours per night, those sleeping consistently less than 5 hours per night experience a higher incidence of viral and/or upper respiratory tract infections[146,147]. Poor sleep has been associated with metabolic disease[148], cardiovascular disease[148–150], neurodegenerative conditions[151–154], and overall mortality[155–157].

A growing literature that describes the relationship between sleep and immune function continues to confirm the findings presented above[158,159]. Addressing the factors that contribute to adequate quality sleep is an important consideration when addressing population and individual immunity[143,160,161].

Gut and the Microbiome     Among the many factors that influence metabolic homeostasis, dysbiosis has some to light in recent years as an important contributor to immune-related diseases[115,162]. A healthy microbiome should be diverse, stable, resistant, and resilient[163–166]. The dynamic multispecies community that make up the microbiome of the digestive tract differ from person to person[167,168] and yet there are common factors found to have a strong impact on our homeostasis and immunostasis[169–171].

When states of disease, oxidative stress, chronic inflammation, food intolerances or other factors destroy commensal bacteria, allow pathobionts to flourish, or reduce the diversity of the gut biome, it leaves the host open for infection and a reduced ability to mount a proper and appropriate immune response. Reducing the state of dysbiosis has been shown to improve conditions of auto-immune diseases[172–174], allergic reactions[175,176], neurodegenerative diseases[177–179] among others.

As such, dietary and lifestyle interventions that address the dysbiosis-associated diseases will directly and indirectly reduce the prevalence and severity of immune-mediated and immune-associated diseases as mentioned above.

Pollution     While a non-modifiable risk factor for individuals, there is a substantial literature base describing the effect of air pollution on immune health[180]. Airborne participate matter and ozone, in both short and long term studies, are associated with mortality and cardiovascular and respiratory hospital admissions[180–182]. A growing evidence now exists for a relationship between immune function and airborne pollutant levels. Air pollution has an adverse effect on oxidative stress, macrophage activity and other related markers of the immune system[169]. Individuals with a higher air pollution exposure have a greater susceptibility to respiratory viral infections[169] including pneumonia and influenza, i.e. a lower immunity, . The pollutants that have been shown to have this effect include: nitrogen dioxide[183,184], ozone[185,186], and particulate matter[187,188].

In addition to air pollutants, studies have found that industrial products can have direct and indirect impacts on overall health and immunity[189–191]. Though there are many exposures that may be beyond one’s control, the limitation of food additives is one that can be promoted. Due to the impact certain food additives can have on inflammatory, autoimmune diseases, digestive health and overall immunological homeostasis[192–194], encouraging the selection of quality whole food is one approach to minimizing exposure to pollutants.

Oxidative Stress     The detrimental effects of free radicals on cellular health are known, and evidence indicates that protecting tissues against environmental oxidative stress can help with natural barriers to infection[195,196]. Even in conditions of acquired infections, when the body increases its metabolic output to mount an immune response, antioxidant intake has shown promise in the prevention and treatment of respiratory and systemic infections[195]. Furthermore, though many might opt for supplementation[197–199] in the hopes of finding nutrient adequacy, evidence points to the synergistic effects of nutrients from whole foods that contain flavonoids, anthocyanins, fibre and other beneficial nutrients, further encouraging the approach of healthy diet and lifestyle for longevity[200–205].

Plant foods offer protection against the development of chronic diseases related to oxidative stress[206,207], whereas high doses of exogenous antioxidants may not[208]. The reason for the preference for naturally antioxidant and nutrient-rich foods is because of their synergistic effects in cellular repair and removing cellular damage[209,210].