15. Immune System Flashcards
The Immune System
The immune system is a versatile defence system that protects us from pathogenic microbes.
•The body has a layered defence strategy.
First Line
Innate Immunity
• Physical barrier created by the skin and mucous membranes.
Second Line
Innate Immunity
• Non-specific immune response that includes some immune cells, proteins, fever and inflammation.
When pathogens penetrate the physical and chemical barriers of the skin and mucous membranes, they encounter a second line of defence
Third Line
Specific/Adaptive Immunity
• Activated by the innate immune system, producing a response towards a specific pathogen.
Pathogens
A pathogen is an infectious agent that can cause disease in a host.
• The body comes in contact with numerous and various potential pathogens every day, where they interact with the host immune system.
• Pathogens can enter the body and cause disease through openings such as:
- Breaks in the skin.
- The respiratory system.
- The digestive system.
- Male / female reproductive systems.
- Eyes.
Antigens
An antigen is a substance that can be recognised by leukocytes.
• Antigens are usually proteins (hence specific 3D shape).
• Antibodies are proteins that are produced in response to a specific antigen. They combine with these specific antigens.
Types of Antigens
- Foreign antigens (e.g. on microbes, food, drugs).
2. Self-antigens (present on cell membranes).
Types of First Line of Defence
The skin and mucous membranes are the first line of defence against pathogens.
First Line of Defence: Skin
- The skin acts as a physical barrier with layers of tightly-packed epithelial cells. The outer epidermis consist of dead epithelial cells and sheds (to remove microbes).
- The dermis contains accessory structures such as sebaceous glands and sweat glands. These have an immune function:
- Sweat removes microbes from skin and contains IgA.
- Sebum contains fatty acids which inhibit microbial growth.
First Line of Defence: Mucous Membranes
The digestive, respiratory and urogenital tracts are lined with mucous membranes. As is the conjunctiva (in the eyes).
• These barriers and a number of non-specific defences attempt to prevent entry into the membrane.
• Saliva, tears and mucus secretions wash away microbes and also contain anti-microbial substances.
• Mucus traps microbes and foreign particles.
• In the respiratory tract, cilia propel the foreign substances towards the pharynx where they are swallowed = mucociliary escalator.
• Tears and saliva contain IgA and lysozymes. Lysozymes are enzymes that break down bacterial cell walls.
Mucous Membrane: Examples
- Hairs filter air in the nose.
- The vagina (in menstruating women) is acidic making it unfavourable for microbes to inhabit.
- Gastric acid — the acidity destroys many bacteria.
- The microflora generally outcompete pathogens for attachment sites on epithelial cell surfaces (and for essential nutrients).
- Excretion of urine and faeces expels microbes.
- Vomiting and diarrhoea are rapid means of expelling pathogens.
Second Line of Defence: Examples
- Complement system.
- Transferrins.
- Phagocytes.
- Natural killer cells.
- Inflammation.
- Cytokines (e.g. interferons).
- Fever.
Tranferrins
Transferrins are iron-binding proteins in blood.
• They act to inhibit the growth of certain bacteria, by reducing the amount of available iron.
• Bacteria could otherwise use the iron available for their growth.
Complement System
A defensive system made of over 30 proteins produced by the liver.
• Complement proteins are identified by a letter (mostly C) with a number; e.g. C3.
• Proteins are inactive and only become active when split by enzymes into active fragments (a + b); e.g. C3 C3a + C3b.
• When activated these proteins act in a cascade (=amplified)
• The most common mechanism through which complement is activated is via the ‘classical pathway’, whereby antigen-antibody complexes are formed.
• For example, consider what happens in glomerulonephritis.
Complement Systems Process
Collectively, complement proteins destroy microbes by:
- Promoting phagocytosis: The fragment C3b ‘coats’ a microbe in a process called ‘opsonisation’. This promotes the attachment of a phagocyte to a microbe.
- Contributing to inflammation: C3a and C5a bind to mast cells and cause them to release histamine.
- Causing cytolysis: Destroying (bursting) microbes.
Cytokines
Cytokines are small protein hormones that stimulate or inhibit normal cell functions.
• They are a group of non-antibody proteins secreted by leukocytes.
• Cytokines act on cells involved in immunity.
Cytokine Types
Interleukins
Interferons
Tumour necrosis factor (TNF)
Interleukins
These act as mediators between leukocytes. Mostly produced by T-helper cells
Interferons
Interferons comprise a group of proteins produced by virus-infected cells.
• Interferons diffuse to uninfected neighbouring cells, where they induce synthesis of anti-viral proteins that interfere with viral replication.
• Interferons do not stop a virus attaching to and penetrating a host cell, but they prevent it replicating.
• Viruses can only cause disease if they replicate within body cells.
Involved in anti-viral responses.
Tumor necrosis factor (TNF)
Promotes the accumulation of neutrophils and macrophages and causes cell death.
Phagocytosis
Phagocytes perform phagocytosis (‘cell digestion’).
• Phagocytic cells are attracted to sites of inflammation by ‘chemotaxis’.
• The two major types are macrophages (monocytes in blood) and neutrophils, which migrate to an infected area.
• Monocytes migrate to the site of infection and enlarge to form ‘wandering macrophages’. Other macrophages are ‘fixed macrophages’ and stand guard in specific tissues.
• Phagocytes are non-selective in their targets. They engulf and digest foreign materials.
• Macrophages are ‘antigen presenting cells’.
Fixed Macrophages
- Histiocytes (connective tissue macrophages).
- Kupffer cells (liver).
- Alveolar macrophages (lungs).
- Microglia (nervous tissue).
- Langerhans cells (skin).
- Tissue macrophages (spleen, bone marrow, lymph nodes).
Phagocytosis: Stages
- Chemotaxis: Release of chemicals by microbes, leukocytes, damaged tissue and by activated complement that attract phagocytes.
- Adherence: Attachment of phagocyte to target (aided by complement).
- Ingestion: The cell membrane extends projections that engulf the microbe.
- Digestion: The ingested structure merges with lysosomes to form a phagolysosome. Lysozymes and digestive enzymes ‘digest’.
- Excretion: Indigestible material is excreted.
Natural Killer Cells
Natural killer (NK) cells account for 5–10% of lymphocytes. They are ‘non-specific lymphocytes’.
• Present in blood, lymph nodes, spleen and bone marrow.
• NK cells attack anything that they do not recognise, including abnormal body cells (abnormal cell membrane proteins) e.g. cancerous cells.
• NK cells bind to a target cell and release granules containing the protein ‘perforin’.
• Perforin inserts into the cell membrane and creates a channel for tissue fluid to flow into the cell -> cytolysis.
Inflammation
Inflammation is a non-specific defensive response to tissue damage.
• Inflammation can be caused by pathogens, abrasions, chemicals, cell distortion or disturbance and extreme temperatures.
• As the response is non-specific, it means the response to different insults is the same.
Signs of Inflammation
- Redness.
- Heat.
- Pain.
- Swelling.
- Loss of function.
Inflammation: Stages
- Vasodilation and increased permeability:
- Emigration of phagocytes:
- Tissue repair.
Vasodilation and increased permeability
• Vasodilation allows additional blood to the area, bringing oxygen, nutrients,
immune cells and repair substances and removal of toxins and dead cells.
•Increased permeability permits the movement of immune cells, defensive proteins such as antibodies and clotting factors into the tissue.
• Together these create redness, swelling and heat. Pain results from injury to neurons and toxic chemicals released by microbes.
Emigration of phagocytes
Within an hour of the process beginning, phagocytes migrate to the scene (via chemotaxis).
• Neutrophils stick to the endothelium during vasodilation and squeeze through the vessel wall to reach the damaged area (leukocytosis).
• Monocytes quickly follow and transform into wandering macrophages.
• Dead phagocytes accumulate as pus.
Inflammatory Mediators
- Histamine
- Leukotrienes
- Kinins
- Prostaglandins
Histamine
Released by mast cells and basophils. Causes vasodilation and increased permeability.
Leukotrienes
Released by basophils and mast cells. They attract phagocytes and increase vessel permeability.
Kinins
Proteins that induce vasodilation and increased permeability. They also attract phagocytes and induce ‘pain’.
Prostaglandins
Lipids released by damaged cells. Enhance effects of histamine and kinins (and so intensify pain).
Inflammation Benefits
- Promotes phagocytosis (via chemotaxis): The increase in temperature promotes activity.
- Promotes immune response: Vasodilation and increased permeability mean that cells and proteins (e.g. antibodies) can leave the blood and enter the affected site.
- Dilutes toxins
- Fibrin formation: Isolates the affected area and helps to bind wound edges.
Inflammation: Risks
- Swelling: Dangerous if in the cranium.
- Pain: Which can become chronic.
- Adhesions and scar tissue.
- Atherosclerosis: Inflammation is a key feature of this process.
Outcomes of Inflammation
Resolution
Chronic inflammation
Granuloma
Fibrosis
Resolution
•The cause is successfully overcome (complete restoration).
Chronic Inflammation
• If injury-causing agent persists. Can cause chronic pain. Macrophages, plasma cells and lymphocytes become prevalent.
Granuloma
• Cellular attempt to contain foreign body. Aggregation of macrophages surrounded by lymphocytes.
Fibrosis
• Scar tissue formation. Formed by the secretion of collagen by fibroblasts. Occurs often as a result of chronic inflammation.
Non-specific Fever
A fever is an abnormally high body temperature.
• Occurs because the hypothalamus thermostat is reset.
• Commonly occurs in infection and inflammation.
• Many bacterial toxins elevate body temperature, which trigger the release of fever-causing cytokines from macrophages, such as interleukin-1.
• One of the key functions of interleukin-1 is to induce fever.
• Elevated body temperature:
- Makes interferons more effective.
- Inhibits growth of some microbes.
- Speeds up the reactions that aid repair.
Leukocytes
Leukocytes are either granular or agranular.
Granulocytes
Basophils
Eosinophils and Neutrophils:
Basophils and Mast Cells
- In blood are basophils. In tissue are mast cells.
- Release histamine (vasodilates / increases vessel permeability) and heparin (anti-coagulant) -> involved in inflammation.
- Express receptors for IgE and hence involved in allergy / hypersensitivity.
Eosinophils
- Destroy parasitic worms via phagocytosis (less efficient phagocyte).
- Play role in inflammation (central role in asthma).
Neutrophils
- Account for 60% of leukocytes. A phagocytic cell.
* Granules release lysozymes that digest debris.
Agranulocytes
Monocytes
Lymphcytes
Natural Killer Cells
Monocytes and macrophages
- In blood are monocytes, in tissue are macrophages (wandering / fixed).
- Phagocytic and secrete cytokines; e.g. interleukin-1 (fever) and TNF.
Natural Killer Cells
• Target foreign cells and secrete perforin to induce cytolysis.
B- and T- Lymphocytes
Involved in adaptive (specific) immunity and immunological memory.
B- and T- Lymphocytes: Function
- T- and B-lymphocytes possess specificity for antigens. They (usually) recognise self from non-self antigens. Each T- and B-lymphocyte is specific for a particular antigen.
- T- and B-lymphocytes produce immune memory for previously-encountered antigens.
- Immune memory allows them to produce a quicker and more effective attack with the next encounter with the antigen.
Adaptive Immune System
The innate immune system is often sufficient to destroy invading microbes. If it fails to adequately destroy the pathogen, the third line of defence is activated.
• Cytokines (messenger molecules) mediate the connection between the ‘innate’ immune system and the ‘adaptive’ immune system.
• The effector cells of the adaptive immune system are T- and B-lymphocytes.
• T- and B-lymphocytes are normally at rest, but become activated on encountering a foreign antigen (or what they perceive to be foreign).
• A key feature of the adaptive immune system is acting specifically to target certain antigens in the immune response.
Major Histocompatibility Complex (MHC)
MHCs are a group of cell-surface proteins that are required for the immune system to recognise cells that are healthy body cells versus those that are ‘non-self’.
•MHCs are each formed of four polypeptide chains and display a protein produced by the cell on its ‘binding groove’ (this is a ‘self- antigen’ as it is produced by that healthy cell).
•MHC molecules function to present foreign antigens to T-cells.
Class I Major Histocompatibility Complex (MHC-I).
MHC-I is located on all body cells, except erythrocytes.
• When the body cell is cancerous or invaded by a pathogen (i.e. viruses or bacteria replicating in cytosol), the cell starts to produce abnormal proteins.
• These proteins are combined with MHC-I and displayed on the cell membrane (indicating a ‘non-self’ cell) — this flags up to leukocytes (mostly to cytotoxic T-cells / CD8 cells).
• So MHC-I allows our leukocytes to determine healthy body cells from abnormal / infected cells.
Class II Major Histocompatibility Complex (MHC-II)
MHC-II are located only on the cell membrane of ‘antigen presenting cells’ (macrophages and B-lymphocytes).
• The MHC-II displays the ‘foreign antigen’ on its binding groove, having ingested the foreign cell.
• These are used specifically for communication between themselves and T-helper cells.
• MHC-II is used to display the foreign antigen and ‘present’ it to T-helper cells. They are, therefore, vital in the process of ‘antigen presentation’.
T-Lymphocytes
T-lymphocytes (or T-cells) play a central role in cell-mediated immunity.
• Millions of different T-lymphocytes exist, each with a unique T-cell receptor (TCR) that only recognises a specific antigen.
• Produced in bone marrow and mature in the thymus (hence name).
• Most T-cells arise before puberty but continue to mature and leave the thymus throughout life.
• T-cells are divided into: T-helper cells and cytotoxic T-cells.
• T-helper cells are also known as CD4 cells because they express the CD4 protein on their surface. Cytotoxic T-cells are CD8 cells.
Self-Tolerance and Self-Recognition
To function properly, T-cells must have two traits:
1. Must be able to recognise self-antigens (‘self-recognition’)
2. Must lack reactivity to fragments of self-antigens (‘self-tolerance’).
• A loss of self-tolerance leads to autoimmunity.
• T-cells are ‘tested’ against thymus epithelial cells. T-cells should be able to recognise self-antigens. If they do not, these cells undergo apoptosis.
• Only 1–5% of T-cells make it through the process.
• B-cells undergo a similar screening process in the bone marrow.
Adaptive Immunity
Adaptive immunity is the ability of the body to defend itself against specific agents.
•Characterised by specificity for particular foreign antigens and the production of immune memory.
Adaptive Immunity: Types
Cell-mediated
Antibody-mediated
Cell-mediated Immunity
- By T-lymphocytes.
- Cytotoxic T-cells directly attack invading antigens.
- Defence mostly against intra-cellular pathogens.
Antibody-mediated Immunity
- By B-lymphocytes.
- B-cells transform into plasma cells, which synthesise and secrete specific antibodies (Igs).
- Defence mostly against extra-cellular pathogens.
Antibody-mediated Immunity
- B-lymphocytes form and mature in bone marrow and are fixed in lymphoid tissue, where they do not leave.
- An antigen binds to specific B-cell receptors, where it is taken into the cell and broken down into fragments. These are then expressed on the MHC-II.
- Helper T-cells recognise the antigen complex on the B-cell membrane and stimulate it by releasing interleukin-2, which triggers B-cell clonal selection.
- Clonal selection produces two types:
- Plasma cells (secrete antibodies).
- Memory B-cells.
Antigen Presentation
For an immune response to occur, T-cells must recognise that a foreign antigen is present.
• T-cells only recognise protein fragments (antigens) that are processed and presented in a certain way.
• A class of cells called antigen-presenting cells (macrophages and B-cells) are strategically located in places where antigens are likely to penetrate the body.
• Antigen-presenting cells combine the foreign antigen with MHC-II complexes on their cell membrane.
• Antigen-presenting cells migrate into lymphatic tissue, where they ‘present’ the antigen to T-helper cells. This is known as ‘antigen presentation’.
Antigen Presentation: Process
For the T-lymphocytes to get ‘sensitised’ to their antigen, the antigen must be presented to the cell, usually by a macrophage.
• Through the action of phagocytosis, macrophages use lysozymes (enzymes) to break down the antigen into fragments. Some fragments will be combined with MHC molecules.
• When the antigen fragment binds with the T-helper cell, the T-helper cell secretes a cytokine called interleukin-2 (Il-2).
• Interleukin-2 causes the T-helper cell to undergo ‘clonal selection’.
• Interleukin-2 is the prime trigger for T-lymphocyte proliferation and also stimulates clonal selection of B-lymphocytes.
Clonal Selection
- Interleukin-2 binds to receptors on the cell membrane of the T-helper cell that secreted it.
- Interleukin-2 stimulates the division and proliferation of activated T-cells.
Clonal Selection: Products
- Cytotoxic T-lymphocytes:
- Memory T-lymphocytes:
- Helper T-lymphocytes:
Cytotoxic T-Lymphocytes
Bind to target cell and destroy it using protein digesting enzymes called granzymes, and perforin.
Memory T-Lymphocytes
Inactive. Recognise the antigen with any future contact, ready to mount an immune reaction.
Helper T-Lymphocytes
Release cytokines which increase the activity of immune cells such as T-, B- and NK cells.
Regulatory T-cells
Regulatory T-cells were formerly ‘suppressor T-cells’.
• A specialised, sub-population of T-cells which deactivate immune cells (T-helper, B-cells and macrophages) when an immune response is no longer required.
• Thereby maintain immune system homeostasis and tolerance to self-antigens.
• Without the regulatory T-cells, the body would continue trying to fight off a disease that no longer exists (and eventually would end up fighting its own cells).
• Regulatory T-cells prevent excessive reactions.
Antibody Mediated Immunity: Cells
Plasma Cells
Memory B-cells
Plasma Cells
- Secrete antibodies into the blood.
- Only produce one type of antibody.
- A few days after antigen exposure, secrete hundreds of millions of antibodies each day until cells die.
- Short-lived
Memory B-cells
- Long-lived.
* Remember antigen for next time, ready to proliferate and produce more plasma cells for a second immune reaction.
Antibodies
Antibodies belong to a group of glycoproteins called globulins and are hence also known as immunoglobulins.
• Antibodies contain four polypeptide chains (two heavy and two light chains). There is a variable region that is different for each kind of antibody.
• Antibodies generally have two antigen-binding sites.
• Antibodies combine specifically with the antigen that triggered their production. They form antibody-antigen immune complexes.
• Antibodies bind specifically with the antigen that stimulated their production (‘lock and key’).
Inactivation of Antigens
- Neutralising:
- Immobilising:
- Agglutinating and precipitating:
- Activating complement:
- Enhancing phagocytosis:
Neutralising
Neutralise bacterial toxins or prevent viral attachment to cells.
Immobilising
Bind to antigens on bacterial cilia or flagellae.
Agglutinating and precipiting
Antibodies use both their binding sites to cause clumping of cells.
Activating complement
Antigen-antibody complexes activate the complement cascade.
Enhancing phagocytosis
The antibody acts as a flag to attract phagocytes and aids phagocytosis via agglutination and complement.
IgG
Location: Blood, lymph, intestines
How common? •Most abundant (80% of blood antibodies).
Function: Protects against bacteria and viruses.
•Only class of antibody that crosses the placenta.
IgA
Location: Sweat, tears, saliva, breast milk
How common? 10%
Function: •Localised protection of mucous membranes.
•Decreases with stress.
IgM
Location: Blood and Lymph
How common? 10% blood antibodies
Function: Main class of antibody in early immune response
IgE
Location: Blood
How common? <0.1%
Function: •Involved in allergic reactions.
• Binds to mast cells.
Immunological Memory
Based on the presence of long-lasting antibodies and very long-lasting memory B- and memory T-cells.
Immunological Memory: Primary Response
Primary response (first exposure) •A slow response. Antibodies do not appear for several days, then a slow rise in IgM, followed by IgG.
Immunological Memory: Secondary Response
Secondary response (subsequent exposure)
• Memory cells can last decades.
• Much faster response because a full immune response has been developed with thousands of memory cells.
• Often the secondary response is so effective, it kills off the microbe before you exhibit any signs or symptoms.
Vaccination
Immunological memory is the basis for vaccination against certain diseases.
• Vaccines contain weakened (attenuated), whole or partially-killed portions of microbes — microbes are immunogenic but are not supposed to be pathogenic.
• B- and T-cells are activated — primary response. Not many cells have the correct specificity to respond to the antigen, so a response can take several days.
• Subsequent exposure to the living pathogen initiates a far more effective secondary response.
Acquired Immunity
- Naturally-acquired active immunity
- Naturally-acquired passive immunity
- Artificially-acquired active immunity
- Artificially-acquired passive immunity
Naturally-acquired active immunity
•Natural exposure to a disease.
Naturally-acquired passive immunity
- Transfer of IgG antibodies across the placenta from mother to child.
- Transfer of IgA from mother to child via the breast milk.
Artificially-acquired active immunity
• Vaccination.
Artificially-acquired passive immunity
• Injection with immunoglobulins e.g. snake anti-venom.
GALT
- GALT (Gut Associated Lymphoid Tissue) contains immune cells (e.g. macrophages, B- and T-lymphocytes).
- GALT is in the tonsils, oesophagus, small intestine and large intestine.
- The health of the digestive system plays a critical role in a healthy immune system. Leukocytes learn from the microflora.
- Poor function affects immunity, nutritional status and toxic load.
Digestive System Defences
About 70% of the body’s immune system is found in the GIT.
