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.
- Variation of immune cells ensures broad coverage of pathogens.
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.
- Distinguish and detect pathogens.
- 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.
- Bacteria.
- 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.
- Identify pathogen or infected cell.
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 that enter the body express a signature.
- 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.
- Specialized white blood cells, leukocytes, detect the pathogen’s signature.
- 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.
- Triggered by PAMP + PRR, cytokines are released.
- 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.
- More leukocytes move in.
- 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.
- Complements the adaptive immune system.
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.
- Antigen-presenting cell (APC) detects and engulfs antigen.
- 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.
- Naïve T cell:
- APC: antigen presentation.
- 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.
- Plasma cells are able to secrete antibodies (in large quantities).
- 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.
- B cells bind to antigen.
- 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.
- Neutrophils.
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.
- Neutralizing pathogens: bind and block key sites on the pathogen to reduce infectivity.
- 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.
- IgM.
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.
- Immediate response to harmless substance.
- Rash, skin irritation.
- Delayed response to foreign substance (poison ivy).
- -> cytokines -> T cell response.
- Delayed response to foreign substance (poison ivy).
- Autoimmunity
- Antibodies and T cells may bind self antigens.
- Self antigens may be structurally similar to pathogen antigens.
- Maladaptive immune responses.
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.
- Some micronutrients and dietary components have very specific roles.
- 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.