Immune System

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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.
  • 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:

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