15. Immune System

Question 1

The Immune System

Answer 1

The immune system is a versatile defence system that protects us from pathogenic microbes.
•The body has a layered defence strategy.

Question 2

First Line

Answer 2

Innate Immunity

• Physical barrier created by the skin and mucous membranes.

Question 3

Second Line

Answer 3

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

Question 4

Third Line

Answer 4

Specific/Adaptive Immunity

• Activated by the innate immune system, producing a response towards a specific pathogen.

Question 5

Pathogens

Answer 5

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.

Question 6

Antigens

Answer 6

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.

Question 7

Types of Antigens

Answer 7

1. Foreign antigens (e.g. on microbes, food, drugs).

2. Self-antigens (present on cell membranes).

Question 8

Types of First Line of Defence

Answer 8

The skin and mucous membranes are the first line of defence against pathogens.

Question 9

First Line of Defence: Skin

Answer 9

• 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.

Question 10

First Line of Defence: Mucous Membranes

Answer 10

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.

Question 11

Mucous Membrane: Examples

Answer 11

• 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.

Question 12

Second Line of Defence: Examples

Answer 12

• Complement system.
• Transferrins.
• Phagocytes.
• Natural killer cells.
• Inflammation.
• Cytokines (e.g. interferons).
• Fever.

Question 13

Tranferrins

Answer 13

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.

Question 14

Complement System

Answer 14

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.

Question 15

Complement Systems Process

Answer 15

Collectively, complement proteins destroy microbes by:

1. Promoting phagocytosis: The fragment C3b ‘coats’ a microbe in a process called ‘opsonisation’. This promotes the attachment of a phagocyte to a microbe.
2. Contributing to inflammation: C3a and C5a bind to mast cells and cause them to release histamine.
3. Causing cytolysis: Destroying (bursting) microbes.

Question 16

Cytokines

Answer 16

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.

Question 17

Cytokine Types

Answer 17

Interleukins
Interferons
Tumour necrosis factor (TNF)

Question 18

Interleukins

Answer 18

These act as mediators between leukocytes. Mostly produced by T-helper cells

Question 19

Interferons

Answer 19

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.

Question 20

Tumor necrosis factor (TNF)

Answer 20

Promotes the accumulation of neutrophils and macrophages and causes cell death.

Question 21

Phagocytosis

Answer 21

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’.

Question 22

Fixed Macrophages

Answer 22

• Histiocytes (connective tissue macrophages).
• Kupffer cells (liver).
• Alveolar macrophages (lungs).
• Microglia (nervous tissue).
• Langerhans cells (skin).
• Tissue macrophages (spleen, bone marrow, lymph nodes).

Question 23

Phagocytosis: Stages

Answer 23

1. Chemotaxis: Release of chemicals by microbes, leukocytes, damaged tissue and by activated complement that attract phagocytes.
2. Adherence: Attachment of phagocyte to target (aided by complement).
3. Ingestion: The cell membrane extends projections that engulf the microbe.
4. Digestion: The ingested structure merges with lysosomes to form a phagolysosome. Lysozymes and digestive enzymes ‘digest’.
5. Excretion: Indigestible material is excreted.

Question 24

Natural Killer Cells

Answer 24

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.

Question 25

Inflammation

Answer 25

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.

Question 26

Signs of Inflammation

Answer 26

* Redness. * Heat. * Pain. * Swelling. * Loss of function.

Question 27

Inflammation: Stages

Answer 27

1. Vasodilation and increased permeability: 2. Emigration of phagocytes: 3. Tissue repair.

Question 28

Vasodilation and increased permeability

Answer 28

• 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.

Question 29

Emigration of phagocytes

Answer 29

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.

Question 30

Inflammatory Mediators

Answer 30

1. Histamine 2. Leukotrienes 3. Kinins 4. Prostaglandins

Question 31

Histamine

Answer 31

Released by mast cells and basophils. Causes vasodilation and increased permeability.

Question 32

Leukotrienes

Answer 32

Released by basophils and mast cells. They attract phagocytes and increase vessel permeability.

Question 33

Kinins

Answer 33

Proteins that induce vasodilation and increased permeability. They also attract phagocytes and induce ‘pain’.

Question 34

Prostaglandins

Answer 34

Lipids released by damaged cells. Enhance effects of histamine and kinins (and so intensify pain).

Question 35

Inflammation Benefits

Answer 35

* 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.

Question 36

Inflammation: Risks

Answer 36

* Swelling: Dangerous if in the cranium. * Pain: Which can become chronic. * Adhesions and scar tissue. * Atherosclerosis: Inflammation is a key feature of this process.

Question 37

Outcomes of Inflammation

Answer 37

Resolution Chronic inflammation Granuloma Fibrosis

Question 38

Resolution

Answer 38

•The cause is successfully overcome (complete restoration).

Question 39

Chronic Inflammation

Answer 39

• If injury-causing agent persists. Can cause chronic pain. Macrophages, plasma cells and lymphocytes become prevalent.

Question 40

Granuloma

Answer 40

• Cellular attempt to contain foreign body. Aggregation of macrophages surrounded by lymphocytes.

Question 41

Fibrosis

Answer 41

• Scar tissue formation. Formed by the secretion of collagen by fibroblasts. Occurs often as a result of chronic inflammation.

Question 42

Non-specific Fever

Answer 42

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.

Question 43

Leukocytes

Answer 43

Leukocytes are either granular or agranular.

Question 44

Granulocytes

Answer 44

Basophils | Eosinophils and Neutrophils:

Question 45

Basophils and Mast Cells

Answer 45

* 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.

Question 46

Eosinophils

Answer 46

* Destroy parasitic worms via phagocytosis (less efficient phagocyte). * Play role in inflammation (central role in asthma).

Question 47

Neutrophils

Answer 47

* Account for 60% of leukocytes. A phagocytic cell. | * Granules release lysozymes that digest debris.

Question 48

Agranulocytes

Answer 48

Monocytes Lymphcytes Natural Killer Cells

Question 49

Monocytes and macrophages

Answer 49

* In blood are monocytes, in tissue are macrophages (wandering / fixed). * Phagocytic and secrete cytokines; e.g. interleukin-1 (fever) and TNF.

Question 50

Natural Killer Cells

Answer 50

• Target foreign cells and secrete perforin to induce cytolysis.

Question 51

B- and T- Lymphocytes

Answer 51

Involved in adaptive (specific) immunity and immunological memory.

Question 52

B- and T- Lymphocytes: Function

Answer 52

* 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.

Question 53

Adaptive Immune System

Answer 53

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.

Question 54

Major Histocompatibility Complex (MHC)

Answer 54

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.

Question 55

Class I Major Histocompatibility Complex (MHC-I).

Answer 55

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.

Question 56

Class II Major Histocompatibility Complex (MHC-II)

Answer 56

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’.

Question 57

T-Lymphocytes

Answer 57

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.

Question 58

Self-Tolerance and Self-Recognition

Answer 58

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.

Question 59

Adaptive Immunity

Answer 59

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.

Question 60

Adaptive Immunity: Types

Answer 60

Cell-mediated | Antibody-mediated

Question 61

Cell-mediated Immunity

Answer 61

* By T-lymphocytes. * Cytotoxic T-cells directly attack invading antigens. * Defence mostly against intra-cellular pathogens.

Question 62

Antibody-mediated Immunity

Answer 62

* By B-lymphocytes. * B-cells transform into plasma cells, which synthesise and secrete specific antibodies (Igs). * Defence mostly against extra-cellular pathogens.

Question 63

Antibody-mediated Immunity

Answer 63

* 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.

Question 64

Antigen Presentation

Answer 64

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’.

Question 65

Antigen Presentation: Process

Answer 65

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.

Question 66

Clonal Selection

Answer 66

* 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.

Question 67

Clonal Selection: Products

Answer 67

1. Cytotoxic T-lymphocytes: 2. Memory T-lymphocytes: 3. Helper T-lymphocytes:

Question 68

Cytotoxic T-Lymphocytes

Answer 68

Bind to target cell and destroy it using protein digesting enzymes called granzymes, and perforin.

Question 69

Memory T-Lymphocytes

Answer 69

Inactive. Recognise the antigen with any future contact, ready to mount an immune reaction.

Question 70

Helper T-Lymphocytes

Answer 70

Release cytokines which increase the activity of immune cells such as T-, B- and NK cells.

Question 71

Regulatory T-cells

Answer 71

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.

Question 72

Antibody Mediated Immunity: Cells

Answer 72

Plasma Cells | Memory B-cells

Question 73

Plasma Cells

Answer 73

* 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

Question 74

Memory B-cells

Answer 74

* Long-lived. | * Remember antigen for next time, ready to proliferate and produce more plasma cells for a second immune reaction.

Question 75

Antibodies

Answer 75

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’).

Question 76

Inactivation of Antigens

Answer 76

1. Neutralising: 2. Immobilising: 3. Agglutinating and precipitating: 4. Activating complement: 5. Enhancing phagocytosis:

Question 77

Neutralising

Answer 77

Neutralise bacterial toxins or prevent viral attachment to cells.

Question 78

Immobilising

Answer 78

Bind to antigens on bacterial cilia or flagellae.

Question 79

Agglutinating and precipiting

Answer 79

Antibodies use both their binding sites to cause clumping of cells.

Question 80

Activating complement

Answer 80

Antigen-antibody complexes activate the complement cascade.

Question 81

Enhancing phagocytosis

Answer 81

The antibody acts as a flag to attract phagocytes and aids phagocytosis via agglutination and complement.

Question 82

IgG

Answer 82

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.

Question 83

IgA

Answer 83

Location: Sweat, tears, saliva, breast milk How common? 10% Function: •Localised protection of mucous membranes. •Decreases with stress.

Question 84

IgM

Answer 84

Location: Blood and Lymph How common? 10% blood antibodies Function: Main class of antibody in early immune response

Question 85

IgE

Answer 85

Location: Blood How common? <0.1% Function: •Involved in allergic reactions. • Binds to mast cells.

Question 86

Immunological Memory

Answer 86

Based on the presence of long-lasting antibodies and very long-lasting memory B- and memory T-cells.

Question 87

Immunological Memory: Primary Response

Answer 87

``` Primary response (first exposure) •A slow response. Antibodies do not appear for several days, then a slow rise in IgM, followed by IgG. ```

Question 88

Immunological Memory: Secondary Response

Answer 88

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.

Question 89

Vaccination

Answer 89

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.

Question 90

Acquired Immunity

Answer 90

* Naturally-acquired active immunity * Naturally-acquired passive immunity * Artificially-acquired active immunity * Artificially-acquired passive immunity

Question 91

Naturally-acquired active immunity

Answer 91

•Natural exposure to a disease.

Question 92

Naturally-acquired passive immunity

Answer 92

* Transfer of IgG antibodies across the placenta from mother to child. * Transfer of IgA from mother to child via the breast milk.

Question 93

Artificially-acquired active immunity

Answer 93

• Vaccination.

Question 94

Artificially-acquired passive immunity

Answer 94

• Injection with immunoglobulins e.g. snake anti-venom.

Question 95

GALT

Answer 95

* 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.

Question 96

Digestive System Defences

Answer 96

About 70% of the body’s immune system is found in the GIT.