Zinc Homeostasis and Immune Response: Comprehensive Notes
Impacts on the Immune System
Factors influencing the immune system:
Exercise/Sports: Regular physical activity can modulate immune function, with moderate exercise generally enhancing immune responses while exhaustive exercise may temporarily suppress it.
Nutrition: Adequate intake of essential nutrients, including vitamins, minerals, and antioxidants, is crucial for optimal immune function. Deficiencies can impair immune cell development and activity.
Sleep: Sufficient sleep is essential for immune regulation. Sleep deprivation can suppress immune cell function and increase susceptibility to infections.
Drugs: Certain medications, such as immunosuppressants and corticosteroids, can significantly impact immune function, often suppressing inflammatory responses.
Age: Immune function declines with age (immunosenescence), leading to reduced responses to new antigens and increased susceptibility to infections.
Gender: Hormonal differences between males and females can influence immune responses. Estrogen, for example, can enhance certain immune functions.
Hormones: Hormones like cortisol and adrenaline, released during stress, can modulate immune cell activity.
Psyche: Mental health and psychological state can influence immune function. Chronic stress and depression can suppress immune responses.
Stress: Acute and chronic stress can impact immune function. Chronic stress, in particular, can lead to immune dysregulation.
Environment: Environmental factors such as pollution, toxins, and sunlight exposure can affect immune function.
The Doctor's Dilemma & Nutrition
George Bernard Shaw (1906) quote highlights the role of phagocytes (white blood cells) in eliminating pathogens. Phagocytes engulf and destroy bacteria, viruses, and cellular debris.
The quote suggests stimulating phagocyte production as a universal treatment for diseases. Enhancing phagocyte activity can boost the body's ability to clear infections.
Nutrition is also discussed as a critical factor for maintaining health, with a mention of the difficulties faced by those with poor nutrition. Malnutrition can impair immune cell development and function, increasing susceptibility to infections.
Zinc: An Essential Trace Element
Essential trace element: Zinc is vital for numerous physiological functions.
Total body content: 2-4g: This amount is distributed throughout the body's tissues and fluids.
Plasma concentration: 12-16 µM (10-18 µM): This level indicates the amount of zinc circulating in the blood.
Bound to albumin, -macroglobulin, transferrin: These proteins transport zinc in the bloodstream.
Cofactor of more than 300 enzymes: Zinc is essential for the activity of a wide range of enzymes involved in metabolism, DNA synthesis, and other critical processes.
Cell growth and proliferation are strictly dependent on zinc (immune system, skin, sperm production): Zinc plays a key role in cell division, differentiation, and overall tissue maintenance.
There is no storage system for zinc: The body cannot store zinc, so a regular dietary intake is necessary to maintain adequate levels.
Zinc Deficiency in Man
First described by Prof. Dr. Ananda S. Prasad.
Prasad et al. (1963) studied zinc metabolism in patients with iron deficiency, hypogonadism, and dwarfism. This pioneering research highlighted the importance of zinc in human health and development.
Health Issues Associated with Zinc Deficiency
Growth, Hair & Skin
Acrodermatitis: A skin condition characterized by inflammation and lesions, often around the mouth, anus, and extremities.
Hair loss: Zinc deficiency can lead to hair thinning and alopecia.
Brain & Mental Health
Development: Zinc is crucial for brain development and cognitive function.
Depression: Zinc deficiency has been linked to symptoms of depression.
Alzheimer’s Disease: Zinc dysregulation may play a role in the pathogenesis of Alzheimer's.
Stroke: Zinc is involved in neuronal protection and recovery after stroke.
Cortical Plasticity: Zinc influences the brain's ability to reorganize and adapt.
Reproductive System
Fertility: Zinc is essential for reproductive health in both men and women.
Pregnancy Outcome: Zinc deficiency during pregnancy can lead to adverse outcomes.
Immune system
Thymic Atrophy: The thymus gland, which is crucial for T cell development, can shrink in size due to zinc deficiency.
Frequent Infections: Zinc deficiency impairs immune cell function, increasing susceptibility to infections.
Increased Allergies: Zinc is involved in regulating allergic responses, and deficiency can exacerbate allergies.
Eyes
Macular Degeneration: Zinc plays a role in maintaining the health of the retina, and deficiency can contribute to macular degeneration.
Cancer
Breast Cancer: Some studies suggest a link between zinc levels and breast cancer risk.
Prostate Cancer: Zinc is involved in prostate health, and deficiency may contribute to prostate cancer development.
Pancreas
Diabetes: Zinc is important for insulin production and glucose metabolism, and deficiency can impair these processes.
Gastrointestinal Tract
Acidification: Zinc is involved in maintaining the integrity of the gastrointestinal lining.
Liver
Liver Cirrhosis: Zinc deficiency can worsen liver damage and contribute to cirrhosis.
Cardiovascular System
Atherosclerosis: Zinc is involved in maintaining the health of blood vessels, and deficiency may contribute to atherosclerosis.
Zinc Deficiency: Global Impact
Risk factors include underweight, unsafe sex, unsafe water, sanitation and hygiene, and indoor smoke from solid fuels. These factors are more prevalent in developing countries.
Significant contributor to the global burden of disease, particularly in developing countries. Zinc deficiency affects millions worldwide, leading to increased morbidity and mortality.
Attributable DALYS (% of total 833 million DALYS):
Zinc Deficiency: Zinc deficiency contributes significantly to disability-adjusted life years (DALYs).
Iron deficiency: Iron deficiency also contributes substantially to DALYs.
Vitamin A deficiency: Vitamin A deficiency is another major contributor to the global burden of disease.
Zinc Deficiency in Industrial Countries
Severe Zinc Deficiency: 1-13% in Europe and North America [Brown et al. Food Nutr. Bull. 2001]
Latent Zinc Deficiency: Over 50% of Elderly [Haase et al. Biogerontology 2006]
Children, Teenagers and Women [Ibs & Rink Humana Press 2004]
Secondary Zinc Deficiency:
Alcoholism, Diabetes, Chronic Bowel Diseases, Renal Insufficiency etc. [Maret & Sandstead J.Trace Elem. Med. Biol. 2006]: These conditions can impair zinc absorption and utilization.
Zinc Deficiency in Germany
Total population:
32% of men and 21% of women did not reach the recommended daily intake [German National Nutrition Study (Nationale Verzehrstudie II) 2008]: This highlights the prevalence of inadequate zinc intake in the general population.
Elderly (65-80 years):
44% of men and 27% of women did not reach the recommended daily intake [German National Nutrition Study (Nationale Verzehrstudie II) 2008]
Number of zinc-deficient elderly increases to over 75% if EFSA recommendations are used: The elderly are particularly vulnerable to zinc deficiency due to age-related changes in absorption and dietary habits.
Zinc Distribution in the Human Body
2-4 g Zinc in the Human Body
Muscle: 57.0%: Muscles store a significant portion of the body's zinc.
Bones: 29.0%: Bones also serve as a zinc reservoir.
Skin: 6.0%: Zinc is important for skin integrity and wound healing.
Liver: 5.0%: The liver plays a role in zinc metabolism.
Brain: 1.5%: Zinc is crucial for brain function and neurotransmission.
Kidney: 0.7%: The kidneys are involved in zinc excretion and reabsorption.
Heart: 0.4%: Zinc is important for cardiovascular health.
Hair: 0.1%: Zinc contributes to hair growth and strength.
Plasma: 0.1%: Plasma zinc levels are used to assess zinc status.
Zinc Uptake
10 mg (8-15mg) Zinc per day essential: This is the recommended daily intake to maintain adequate zinc levels.
Resorption in the small intestine: Zinc is absorbed primarily in the small intestine.
14 ZIP Zinc “import” proteins (SLC39A1-14): These proteins facilitate zinc uptake into cells.
10 ZnT Zinc “export” proteins (SLC30A1-10): These proteins transport zinc out of cells.
Zinc malabsorption disease Acrodermatitis enteropathica is characterized by immune deficiency (ZIP 4 defect): This genetic disorder impairs zinc absorption, leading to severe deficiency and immune dysfunction.
Cellular Aspects of Zinc
Zinc's Role in Cellular Processes:
Apoptosis: Zinc can influence programmed cell death.
Metabolism: Zinc is a cofactor for numerous metabolic enzymes.
Gene expression: Zinc regulates gene transcription and protein synthesis.
Proliferation: Zinc is essential for cell division and growth.
Differentiation: Zinc influences cell specialization and maturation.
Zinc transporters, ion channels, and redox status are crucial for zinc homeostasis and its effects on signal transduction. These factors regulate zinc levels within cells and influence cell signaling pathways.
Specific zinc detection mechanisms are present within cells. Cells can sense and respond to changes in zinc concentrations.
Zinc Transporters and Cellular Distribution
Zinc is transported across cell membranes by ZIP and ZnT transporters. These transporters control zinc influx and efflux.
It is bound to proteins like albumin, alpha-macroglobulin, and transferrin in the plasma. These proteins transport zinc in the bloodstream.
Zinc is stored in metallothionein, zincosomes, or vesicles within the cell. These storage compartments regulate intracellular zinc levels.
Age-Related Serum Zinc Concentration
Serum zinc levels decrease with age. This decline can contribute to age-related immune dysfunction.
Clinical and subclinical zinc deficiency is more prevalent in older adults. Older adults are more likely to have inadequate zinc levels.
Normal value (11-18 µM)
Immunosenescence and Zinc
The relationship between immune capacity and zinc status across the lifespan. Zinc plays a critical role in maintaining immune function throughout life.
Zinc adequacy is essential for maintaining immune capacity. Adequate zinc levels support optimal immune cell activity.
Zinc deficiency (serum zinc <70µg/dL or 10,7µM) leads to a decline in immune capacity. Low zinc levels impair immune responses.
Accelerated aging conditions, such as Down syndrome, exacerbate immune decline. Individuals with Down syndrome experience premature immunosenescence.
Zinc Deficiency and COVID-19
Factors contributing to zinc deficiency and increased susceptibility to COVID-19:
Low-quality hygiene: Poor hygiene practices increase the risk of infections.
High exposure to infected subjects: Close contact with infected individuals increases the risk of transmission.
Air pollution: Air pollution can impair immune function and increase susceptibility to respiratory infections.
Obesity: Obesity is associated with chronic inflammation and impaired immune responses.
Arteriosclerosis: Cardiovascular disease can compromise immune function.
Elderly: Older adults are more vulnerable to zinc deficiency and immune dysfunction.
Small children: Young children are at higher risk of zinc deficiency due to increased requirements for growth and development.
Bronchial asthma: Asthma is associated with airway inflammation and impaired immune responses.
Diabetes: Diabetes can impair immune function and increase susceptibility to infections.
Changes of the Immune System During Aging
Impact of age on immune capacity from premature infancy to old age.
COVID-19 Mortality in Germany
Number of Deaths until March 16th 2022
<50 = 1.60%
<60 = 5.58%
>60 = 94.42%
>70 = 83.58%
<80 = 65.78%
Immunosenescence and COVID-19
Immune capacity decreases with age, increasing vulnerability to COVID-19. Older adults have reduced immune function, making them more susceptible to severe COVID-19.
COVID-19 deaths are disproportionately higher in older age groups. The majority of COVID-19 deaths occur in older adults.
Zinc and COVID-19: Mechanisms of Action
Zinc enhances anti-viral tissue response by:
Increasing cilia beat frequency and length in lung epithelial cells: This improves the clearance of pathogens from the airways.
Enhancing interferon-alpha (IFNα) production: IFNα is a key antiviral cytokine.
Strengthening tight junctions through occludin, claudin-1, and ZO-1: This reduces viral entry into cells.
Zinc's antiviral effects:
Inhibiting viral replication by blocking RdRp (RNA-dependent RNA polymerase): RdRp is essential for viral replication.
Activating RNaseL and PKR to degrade viral RNA: These enzymes degrade viral RNA.
Zinc and the Lung
Diagram illustrating the role of zinc in maintaining lung health and combating infection
Homeostasis of the Immune System
The immune system's response to: Infection, Tumors and Autoimmune Diseases.
Impact of Anti-Inflammatory Drugs
Effects of anti-inflammatory drugs on the immune system, considering:
Infection: Anti-inflammatory drugs can suppress immune responses, increasing the risk of infection.
Tumor: Anti-inflammatory drugs may influence tumor growth and metastasis.
AID: Anti-inflammatory drugs can modulate immune responses in autoimmune diseases.
Transplant rejection: Anti-inflammatory drugs are used to prevent transplant rejection.
Impact of Zinc Deficiency
Illustrates the effects of zinc deficiency on the immune system in the context of infection, tumor, AID, and transplant rejection.
Decreased Parameters of the Immune System During Zinc Deficiency
Zinc deficiency impairs several immune functions:
Thymocyte and T cell counts and proliferation: Zinc is essential for T cell development and activation.
Delayed-type hypersensitivity reaction: Zinc deficiency impairs cell-mediated immunity.
Cytotoxic (CTL) and T-helper (Th) cell-functions: Zinc is critical for the function of these immune cells.
Antibody production: Zinc is involved in B cell function and antibody production.
NK cell activity: Zinc influences natural killer cell activity.
Macrophage functions (phagocytosis, killing): Zinc is important for macrophage function.
Neutrophil functions (respiratory burst, chemotaxis): Zinc is involved in neutrophil function.
Disturbed Immune Functions in Elderly
Dysregulation of immune responses in the elderly
Enhanced unspecific B cell activation: This can lead to increased autoantibody production.
Reduced B cell help for immunoglobulin class switch: This impairs the ability to generate effective antibody responses.
Pro-inflammatory cytokine production: This contributes to chronic inflammation.
Zinc Supplementation in Elderly: Effects on Zinc Levels
Zinc supplementation increases serum and intracellular zinc concentrations in vivo. Supplementation can restore zinc levels in deficient individuals.
Serum Zinc Increase 11%.
Intracellular Zinc Increase 61%.
Zinc Supplementation in Elderly: Impact on IL-6 Release
Zinc supplementation reduces spontaneous IL-6 release in vivo. This suggests that zinc can reduce inflammation.
Zinc and Monocyte Differentiation
Zinc's influence on monocyte differentiation in vitro
Zinc Deficiency Opens the IL-1β-Promoter
Zinc deficiency increases IL-1β production in vitro. This suggests that zinc deficiency can promote inflammation.
Zinc Polarizes Macrophages
Zinc modulates macrophage polarization in vitro, impacting M1 and M2 phenotypes. This suggests that zinc can influence the type of immune response.
Disturbed Immune Functions in Elderly
Dysregulation of immune responses in the elderly
Enhanced unspecific B cell activation
Reduced B cell help for immunoglobulin class switch
Pro-inflammatory cytokine production
Zinc-Dependent Interferon-α-Production in Seniors
Positive correlation between serum zinc levels and interferon-alpha (IFN-α) production in seniors. This suggests that zinc is important for antiviral immunity.
Zinc Supplementation Effects
Restored IFN-α-Production after Zinc Supplementation in Vegetarians and Vegans in vivo
Balanced Immune Function in Elderly
Balanced Immune Function in Elderly after Zinc Supplementation
Increased TH1-Cytokine Production in Elderly
Increased TH1-Cytokine Production (IFN-gamma and TNF) in Elderly after Zinc Supplementation.
Shows data on IFN-gamma and TNF production before and after zinc supplementation.
Zinc Modulates IL-2 Production
The effect of zinc on IL-2 production by different T helper cell subsets (TH1, TH2, TH17, Treg) in vitro.
Vicious Cycle of Zinc Deficiency
Illustrates the vicious cycle of zinc deficiency both in vivo and in vitro.
Zinc-APP in Geriatric Patients
Study on Zinc-APP in Geriatric Patients in vivo
Recovery of T Cell Activity with Zinc
Illustrates the Recovery of T Cell Activity with Zinc in vivo.
Zinc Deficiency in Vegetarians and Vegans
Zinc Deficiency in Vegetarians and Vegans in vivo
CREMα RNA
Reduced Regulatory T cells in Vegetarians and Vegans in vivo
Distinguishing and Signals
Use of FluoZin-3 for Zinc and Fluo-4 for Calcium Detection in vitro
IL-2-Dependent T Cell Proliferation
The role of zinc in IL-2-dependent T cell proliferation.
IL-2-induced Signals
Presents data on IL-2-induced signals in vitro.
Phosphatase Inhibition I
Shows data on Phosphatase Inhibition I in vitro.
Phosphatase Inhibition II
Shows data on Phosphatase Inhibition II in vitro.
Zinc Regulates IL-2-Signaling
Zinc's Regulatory Role
Zinc regulates IL-2 signaling by modulating various pathways, including PI3K/Akt, ERK1/2, and STAT5.
Treg and TH1 Cells Need a Zinc Signal
The differing requirements for and signals in T helper cells
Balanced Immune Function in Elderly
Balanced Immune Function in Elderly after Zinc Supplementation
Inhibition of Spontaneous IL-6-Release
Inhibition of Spontaneous IL-6-Release in vivo
Impact of Zinc Deficiency
Illustrates the effects of zinc deficiency on the immune system in the context of infection, tumor, AID, and transplant rejection.
Regulation of the Immune Response
Zinc's role in regulating the immune response against viruses, parasites, and bacteria.
Regulation of the Immune Response & Autoimmunity/Allergy
Zinc is critical in preventing autoimmunity and allergy by suppressing T cells reactive to harmless or autoantigens
Zinc Intake Inhibits Alloreactivity
The effect of zinc intake on inhibiting alloreactivity in vivo.
Zinc Increased Regulatory T cells in MLC
Zinc Increased Regulatory T cells in MLC in vitro
Zinc Induced Regulatory T cells in vivo
Zinc Induced Regulatory T cells in vivo
Zinc Reduced Activated T cells but Increased Regulatory T cells
Zinc Reduced Activated T cells but Increased Regulatory T cells in vitro
Zinc Promotes the Induction of Regulatory T cells during Allergic Responses
Zinc's role in promoting the induction of regulatory T cells during allergic responses in vitro
Zinc Inhibits Induction of EAE (Experimentell Autoimmune Encephalomyelitis)
Zinc's role in Inhibiting Induction of EAE (Experimentell Autoimmune Encephalomyelitis) in vivo
Zinc Promotes the Induction of Regulatory T cells during Allergic Responses
Zinc's role in promoting the induction of Treg cells during allergic responses, which were assessed using:
Zinc Inhibits MLC, but not the Antigen-specific T cell Stimulation
Demonstrates the effect of zinc on inhibiting mixed lymphocyte culture (MLC) but not antigen-specific T cell stimulation in vitro
Zinc and Ciclosporine
The combined effect of zinc and ciclosporine on T cell function in vitro
Zinc Substitution Increased IFN-γ-Production
The contrasting effects of zinc substitution on IFN-γ production in elderly individuals (increased) and in MLC (decreased).
not activated rel. IFN-γ secretion activated
The zinc's effects are different depending on whether the immune cells are activated or not.
Balanced Immune Function in Elderly
Balanced Immune Function in Elderly after Zinc Supplementation
Activated B Cells Accumulate Zinc
Shows that activated B cells accumulate zinc both in vitro and in vivo.
Zinc Homeostasis
Zinc Homeostasis is Immune Homeostasis
Different Effects of Sodium and Zinc in MLC
Different Effects of Sodium and Zinc in MLC in vitro
Zinc as Gatekeeper of Immune Function
Summary of Zinc's Role in Immune Function
Zinc Deficiency: leads to overproduction of pro-inflammatory cytokines, thymus atrophy, TH1/T2 dysbalance, less naive B cells, less Treg, more TH17
Zinc Homeostasis: results in balanced immune cell numbers & functions and balance between tolerance and defense mechanisms
Zinc Excess: causes suppression of T & B cell function, overload of Treg, direct activation of macrophages
Zinc Homeostasis and COVID-19
Zinc Homeostasis and COVID-19
Balanced redox metabolism
Healthy vascular system
Regular glomerular filtration rate, renal blood flow, renal vascular resistance
Regular wound-healing
Regular type I interferons [IFN-𝛼， IFN-𝛽]