Takeaways

• Boost immunity.
  • Activity immunity: vaccines (including annual flu shot)
  • Passive immunity: breastfeed babies.
  • Exercise (not excessively).
  • Diet (zinc, vitamin D).
• Avoid chronic inflammation.
  • Plant-based diets, fermented foods.

Summary

• Identify self from non-self.
• Two systems function in synchrony.
  • Innate immune response.
  • Adaptive immune response.
• Innate immune response:
  • First line of defense: when a pathogen enters.
  • Generic response to non-self, foreign substances.
  • First by trying to block the pathogen from entry (skin, mucus).
  • Next, if entry is gained, inflammatory response and destruction of pathogen (phagocytosis).
  • Involves mostly white blood cells that engulf and digest pathogens.
  • Key immune cells: macrophages, cytokines.
• Adaptive immune response:
  • Second line of defense: when innate response is insufficient.
  • Specific response to antigens, fragments of (digested) pathogens.
  • B cells respond to a specific antigen by turning into plasma cells and releasing antibodies (humoral response).
    • The secreted antibodies bind to pathogens and mark them for further destruction (by other immune cells).
    • Antibodies continue to circulate for some time and respond quickly upon reinfection.
  • T cells respond to specific pathogens that have already entered a cell (cell-mediated response).
    • Sensing the antigen fragments on the surface of an infected cell, T cells bind to the infected cell and drive it to self-destruct (apoptosis).
• Key immune system properties: variation, selection and memory.
  • Variation of immune cells ensures broad coverage of pathogens.
    • Through gene cutting and recombination.
    • Large, varied population of (innate) immune cells.
    • Capable of recognizing virtually any infecting pathogen.
  • Selection (and deletion) processes ensure ability to detect self versus non-self.
    • Non-self-recognizing immune cells proliferate (clonal selection).
    • Self-recognizing immune cells get deleted (clonal deletion).
  • Memory ensures fast future response.
    • Long-term protection from reinfection with the same type of pathogen.
    • On re-exposure, efficient and quick response.

Immune System

• Biological defense system.
  • Structures and processes within an organism that protect against disease.
• Identify self from non-self.
  • Distinguish and detect pathogens.
    • Microbes: viruses, bacteria, fungi and parasites.
  • Isolate and remove nonmicrobial foreign substances.
  • Destroy cancer cells.
• Diverse collection of cells, organs, and tissues.
  • White blood cells (macrophages, B cells, T cells, etc.)
  • Thymus, bone marrow, lymph nodes, spleen, skin.
• Two systems function in synchrony.
  • Innate, non-specific response: no pathogen recognition required.
  • Adaptive, specific response: dependent on pathogen recognition.
• Immune response is costly.
  • Costs energy.
  • May damage host tissue.
• Immune response declines with age.
  • Immunosenescence.
  • Both innate and adaptive immune mechanisms decline.
• (Chronic) Inflammation may increase with age.
  • Ongoing, low-grade, whole-body, systemic inflammation.
  • Due to issues related with stress, nutrition, sleep, physical activity.

Dominant infections

• Developed world.
  • Bacteria.
    • Unicellular organisms.
    • Damage tissue (by replication).
    • Disrupt physiology (by releasing toxins into the bloodstream).
  • Viruses.
    • Nucleic acids surrounded by a protein coat.
    • Lack machinery for metabolism and protein synthesis.
    • Multiply by hijacking machinery of host cell.
    • Replication, kill host cell, move to other cells (common cold).
    • Or, lie dormant before replicating (herpes) or transform host cells into cancer cells.
• Global basis.
  • Parasites (malaria, etc.).

Innate immune response.

• Non-specific response to infection.
  • Recognize some general property marking the invader as foreign.
  • Evolved about 1 billion years ago.
• Defenses include:
  • Body surface, skin.
  • Inflammation.
  • Phagocytosis.
• Consistent sequence of events.
  • Identify pathogen or infected cell.
    • Viruses: replicate inside a cell.
    • Bacteria, parasites: replicate outside a cell.
  • Clear pathogen.
    • Leukocytes stop spread and form barrier (inflammation).
    • Leukocytes engulf and digest (phagocytosis).
    • Cytokines are released.
    • Destruction by NK cells.
    • Aided by complement system.
  • Mobilize adaptive immune response.
    • When innate response is insufficient, activate adaptive immune response.
    • Antigen presentation.

Innate immune response – sequence of events

• First barrier to pathogens: skin.
  • Skin is first impassable barrier to potentially infectious pathogens.
  • Killed or inactivated on the skin by desiccation (drying out) and by the skin’s acidity.
  • In eyes (no skin), tears have the same function.
• If pathogens get through and enter the body: PAMP.
  • Pathogens that enter the body express a signature.
    • Pathogen Associated Molecular Patterns (PAMP).
  • Different from the signature of the host and its cells.
• Pathogens are detected: PRR.
  • Specialized white blood cells, leukocytes, detect the pathogen’s signature.
    • Using Pattern Recognition Receptors (PRR).
  • Leukocytes are recruited to the site of infection.
    • Arrive via blood vessels and lymphatic system.
    • Monocytes, macrophages, neutrophils, natural killers cells, mast cells, etc.
• Triggers: cytokines, inflammation and pathogen engulfment.
  • Triggered by PAMP + PRR, cytokines are released.
    • Cytokines are chemical messengers.
    • Produced by a great variety of cells.
    • Link the components of the immune response together.
    • Signal that a pathogen is present and needs to be destroyed.
    • Release of one cytokine stimulates the release of another (cascades).
    • 40 different types.
  • Cytokine: interferons.
    • Inhibit viral replication.
    • Released by infected cells to warn uninfected cells.
    • Cause uninfected cells to undergo apoptosis, destroy RNA.
    • Regulate innate immune response.
  • Cytokine: interleukins.
    • Growth and differentiation of leukocytes.
    • Bridge the innate and adaptive immune response.
• Starts inflammatory process.
  • More leukocytes move in.
    • Engulf and digest pathogens (macrophages, neutrophils, etc.)
    • Or, produce inflammatory molecules, such as histamines (mast cells).
    • Heat, pain, redness, swelling, and loss of function.
      • Redness: increased blood flow (delivery of leukocites).
      • Swelling: leukocytes are able to reach site of injury.
      • Heat: increased local temperatures.
      • Pain: warning the host.
      • Loss of function: more pressure on the tissue, damage control.
    • Physical barrier to stop spread of infection.
    • Start for repair of damaged tissue.
• Aided by natural killer cells.
  • NK cells constantly patrol and detect viruses.
  • First responder to primarily viruses and tumors (cancer).
  • Identify infections by altered expression of major histocompatibility class (MHC) molecules on cell surface.
    • MHC = cellular identity tag, genetic marker of biological self.
    • No two persons, other than identical twins, have the same MHC.
  • Kill viruses, halt cancer progression.
• Aided by complement system.
  • Complements the adaptive immune system.
    • Attracted to pathogens already bound by antibodies.
  • Consists of a variety of proteins made by the liver that circulate in blood serum.
  • Triggers a cascade.
    • Pathogens rapidly get covered in complement proteins.
  • Marker to attract more leucocytes.

Adaptive immune response

• Slower, second line of defense.
  • Only found in vertebrates (evolved much later than innate immune response).
  • Takes days or even weeks to become established.
• Specific.
  • Recognition/binding of specific antigens via complementary immune cell receptors.
  • Each immune cell only expresses one type of antigen receptor.
• Mutation, variation.
  • Population of immune cells expresses near limitless variety of antigen receptors.
  • Capable of recognizing virtually any infecting pathogen.
• Has memory.
  • Long-term protection from reinfection with the same type of pathogen.
  • On re-exposure, memory will facilitate an efficient and quick response.
• Requires information from the immune response.
  • Activated when the innate immune response is insufficient.
  • Innate immune cells inform adaptive immune cells about presence of antigens.
• Two responses.
  • Cell-mediated: carried out by T cells.
  • Humoral: controlled by activated B cells and antibodies.
• Clonal selection.
  • Rapid increase of T and B cells specific to pathogen from one or a few cells to millions.
  • Each clone has the same antigen receptor as the original and fights the same pathogen.

Adaptive immune response – T cells and B cells

• Response by T cells.
  • APC: antigen presentation.
    • Antigen-presenting cell (APC) detects and engulfs antigen.
      • B cells, macrophages, dendritic cells.
    • Fragments of antigen transported to the surface of the APC.
  • MHC + APC: signal that there is a foreign invader.
    • APC is processed and embedded into the MHC.
    • MHC is the unique identity tag of the self.
  • T cells detection.
    • T cell can only detect the combination of MHP + APC.
    • B cells can detect antigen only.
  • T cells bind to antigen, differentiate and proliferate.
    • Naïve T cell:
      • Inactive, express only CD4 or CD8.
      • Either CD4 or CD8 binds to antigen.
      • CD4 -> T cell becomes helper T cell.
      • CD8 -> T cell becomes cytotoxic T cell.
    • Helper T cell:
      • Activates antibody (B cell).
      • Activates cytotoxic response (T cell).
      • Secretes cytokines.
    • Cytotoxic T cell:
      • Activated by cytokines.
      • Respond to antigens in MHC of infected cells.
      • Also recognize MHC of infected cells without antigen fragments.
      • Induce apoptosis (cell destruction) before virus can replicate and escape the cell.
    • Suppressor (regulatory) T cells:
      • Deactivate T cells and B cells.
    • Memory T cells
      • Hang around to mitigate recurrence.
    • Clonal selection: proliferation of differentiated T cells.
• Response by B cells.
  • B cells bind to antigen.
    • B cells can function as APC: binding intact unprocessed antigens.
    • B cells engulf antigen and display fragmented antigen.
    • Each B cell has receptors with unique antigen binding sites.
      • Determined during maturation in bone marrow.
      • Through unique gene cutting and rejoining process.
      • Resulting in millions of different B cells.
  • Antigen fragments attract helper T cells.
    • Helper T cells promote B cell cloning through release cytokines.
  • B cells proliferate.
    • Cytokines drive accelerated B cell proliferation (clonal selection).
    • Large population of B cells with specific receptors recognizing the pathogen.
  • B cells differentiate into plasma cells.
    • Plasma cells are able to secrete antibodies (in large quantities).
      • Antibody = immunoglobin = Ig.
    • Antibodies have the same recognition patterns as the B cell receptors.
      • Specific to pathogen.
  • Antibodies bind pathogens and mark them for destruction.
    • Antibodies circulate in the blood stream looking to detect specific pathogens.
    • Stop the spread of pathogens that have not yet invaded cells.
    • Recruit phagocytes for destruction of pathogen.
    • Viruses replicating inside host cells are shielded from antibodies.
• Reinfection.
  • Memory cells persist after a primary exposure to a pathogen.
  • Memory cells respond to reinfection without input from the innate immune system.
  • Circulating memory B and T cells rapidly respond to halt pathogen.
  • Vaccination helps to establish immune memory.

Immune cells = white blood cells = leucocytes

• Originate from hematopoietic stem cells in the bone marrow.
  • T cells mature in the thymus.
  • B cells mature in bone marrow.
• Use blood stream and lymphatic system mainly for transportation.
  • Leave circulatory system to enter tissue where they function.
• Lymphatic system:
  • Lymphatic vessels carry lymph throughout the body.
  • Lymph: watery fluid that transports immune cells and gathers antigens as it drains from tissues.
  • Lymph nodes: store large populations of immune cells and filter antigens from lymph.
• Blood stream:
  • About 1% of total blood volume is white blood cells.
  • Rest is red blood cells.
  • Spleen performs same function as lymph nodes, but for blood (storage and filtering).
• Two types of white blood cells.
  • Phagocytes.
  • Lymphocytes.
• White blood cell count (subset of blood count) is often an indicator of disease.

Phagocytes.

• Protect the body by ingesting harmful foreign particles.
  • Essential for fighting infections and for subsequent immunity.
  • Once the pathogen is trapped inside the phagocyte, it is in a compartment called a phagosome.
  • The phagosome merges with a lysosome or granule to form a phagolysosome.
  • The pathogen is killed by toxic materials, such as antimicrobial agents, enzymes, nitrogen oxides or other proteins.
• Types.
  • Neutrophils.
    • Most abundant.
    • First responders.
  • Monocytes.
    • Reside in blood stream.
    • Enter tissue and transform into macrophages.
  • Macrophages.
    • Reside in many tissues.
    • Engulf and digest cellular debris.
  • Mast cells.
    • Connective tissue cells.
    • Play a key role in inflammation, wound healing and allergies.
    • Release histamine.
  • Dendritic cells.
    • Present in tissues in contact with external environment.

Lymphocytes.

• Recognition cells.
  • Small cells, identifiable by their large, darkly staining nuclei.
  • About 80-90% T cells, 10-20% B cells.
• Types:
  • Natural killer cells (innate).
  • T cells (adaptive).
  • B cells (adaptive).

Antibodies

• Protein that is produced by plasma cells after stimulation by an antigen.
  • Plasma cells are differentiated B cells.
• Functional basis of humoral (extra-cellular fluids) immune response.
  • Occur in the blood, in gastric and mucus secretions, and in breast milk.
  • Circulate freely in blood, gastric, mucus sections.
  • Act independently of plasma cells.
  • Can be transferred from one person to another.
• Antibodies inhibit infection by:
  • Neutralizing pathogens: bind and block key sites on the pathogen to reduce infectivity.
    • Prevents pathogens from entering and infecting host cells.
  • Marking pathogens for destruction by phagocytes.
• Five classes.
  • IgM, IgG, IgA, IgD, IgE.
  • Based on physiochemical, structural, and immunological properties.
• Adaptive response:
  • IgM.
    • Early stages of infection.
    • About 10% of antibodies.
    • Binding to antigens not as stable as IgG.
  • IgG.
    • Later stages or reinfection.
    • About 80% of antibodies.
  • IgA.
    • Populates mucous, saliva, tears, breast milk.
  • IgE.
    • Responsible for allergic reactions.

Immune tolerance

• Lack of immune response to self.
  • Huge diversity of lymphocytes.
  • Result of random DNA cutting and recombination process.
  • Includes lymphocytes with receptors that would target self molecules.
• Clonal deletion.
  • During early life, T cells are exposed in the thymus to mix of self proteins.
  • T cells capable of binding to these cells are destroyed by apoptosis.
• Clonal inactivation.
  • Similar process in the periphery.
• B cells can similarly undergo clonal deletion and inactivation.

Insufficient and inappropriate immune responses

• Insufficient response: immunodeficiency
  • Acquired: through pathogens (such as HIV), chemical exposure, stress.
  • Inherited: genetic disorders.
  • Increases susceptibility to infections, cancers.
• Inappropriate response: hypersensitivities
  • Maladaptive immune responses.
    • Toward harmless foreign substances (allergies).
    • Toward self antigens that occur after tissue sensitization (auto-immunity).
  • Allergy:
    • Immediate response to harmless substance.
      • -> B cells produce IgE.
      • -> Mast cells release histamine.
      • -> Variety of allergic responses.
  • Rash, skin irritation.
    • Delayed response to foreign substance (poison ivy).
      • -> cytokines -> T cell response.
  • Autoimmunity
    • Antibodies and T cells may bind self antigens.
    • Self antigens may be structurally similar to pathogen antigens.

Excessive immune response: cytokine storm

• Excessive or uncontrolled release of pro-inflammatory cytokines
  • Associated with a wide variety of infectious and noninfectious diseases.
  • Especially viral respiratory infections (H5N1 influenza, SARS-CoV and SARS-CoV-2).
• Sudden release of cytokines in large quantity.
  • Can cause multi-organ failure, death.

Chronic inflammation

• Key underlying feature for a range of chronic non-communicable diseases.
  • Cardiovascular disease, stroke, and autoimmune disorders such as rheumatoid arthritis.
• Positively correlated with age and co-morbidities.
  • Obesity: “metaflammation”.

Nutrition and immune response

• Generic:
  • Adequate and appropriate nutrition is required for all cells to function optimally.
  • Includes the cells in the immune system.
• Specific.
  • Some micronutrients and dietary components have very specific roles.
    • Development and maintenance of an effective immune system.
    • Reduction of chronic inflammation.
• Zinc.
  • See Zinc write-up.
• Vitamin D.
  • See Vitamin D write-up
• Arginine.
  • Generation of nitric oxide by macrophages.
  • Regulation of cell division.
• Vitamin A.
  • Regulation of cell division.
• Food ingestion.
  • Constant and massive antigenic stimulation.
  • Gut microbiome constantly interacts with immune cells.
  • Plant-based diets may enhance diversity of nutrients reaching microbiome.
  • Leaky gut: acute or chronic gut inflammation due to increased permeability.

Exercise and immune response

• Cytokine release and adaptation.
  • Primarily through cytokine response to exercise.
  • Varies by the type of exercise, intensity, duration and recovery between exercise bouts.
• Endurance training.
  • Release of cytokines due to muscle contractions, lower levels of glycogen.
• Resistance training.
  • Static or dynamic muscle contractions against external resistance of varying intensities.
  • Release of cytokines due to muscle damage.
• Adaptation leads to lower pro-inflammatory cytokines at rest.

Key sources:

• “The Immune System“, Healio.
• “Concepts of Biology“, Charles Molnar and Jane Gair.
• “Diet and Immune Function“, Caroline E. Childs, Philip C. Calder, and Elizabeth A. Miles, Nutrients, 2019 Aug; 11(8).
• Vander’s Human Physiology, Eric P. Widmaier, Hershel Raff, Kevin T. Strang.