The immune system Block 4 Week 2 Flashcards

Question

What are platelets ?

Answer 1

- Platelets are commonly described as cellular fragments – they are not true cells as they do not contain a nucleus or carry nuclear DNA, although they do contain mitochondria. - Platelets have a life span of 7-10 days - The normal platelet count is 150-400 x 109/L - Although they are primarily found in the bloodstream, up to 30% of platelets are transiently sequestered (stored) within the spleen, ready for rapid mobilisation. - Platelets originate from megakaryocytes. Megakaryocytes originate from the common myeloid progenitor - Surface-connected open cannalicular system (SCOCS): The open canalicular system (OCS) is an internal membrane structure found in platelets. And is the way platlets can release all their factors quickly to produce a quick response after injury.

Answer 2

- The key role of platelets is their participation in haemostasis through the formation of blood clots at the site of bleeding. - Platlets contain two types of granules, namely alpha-granules and dense granules - Alpha granules: Alpha-granules contain proteins of high molecular weight, including von Willebrand Factor (vWF), factor V and fibrinogen. - Dense granules: contain low molecular weight molecules such as ATP, ADP, serotonin, and calcium ions. - Platelets have abundant surface receptors, classified into agonist and adhesion receptors - Agonist receptors: recognise stimulatory molecules. These include collagen, thrombin, and ADP amongst others. - Adhesion receptors promote the adhesion of platelets to other platelets, the vessel wall or leucocytes, depending on the receptor stimulated. Examples include the glycoprotein IIb-IIIa receptor, which is targeted by antiplatelets such as tirafiban.

Answer 3

Dense granules are less common

Answer 4

Formation of the platelet plug: -Damage to a blood vessel causes exposure of collagen. Von Willebrand Factor (vWF) binds to collagen which acts as a molecular anchor for platelets to join. - Platelets have VWF receptors. Platelets adhere to the damaged endothelium via vWF. When platelets adhere, they activate and degranulate– their shape changes and they release chemicals that keep the vessel constricted and draw more platelets to the damaged area. This positive feedback loop continues. -The aggregation of platelets results in the formation of a plug that temporarily seals the break in the vessel wall. -Following formation of the platelet plug, coagulation is activated to form a fibrin mesh which stabilises the platelet plug.

Answer 5

-Primary hemostasis is a procoagulation clot forming process associated with the initiation and formation of the platelet plug. - Secondary hemostasis also a procoagulation clot forming process and it is associated with the propagation of the clotting process via the intrinsic and extrinsic coagulation cascades

Answer 6

- The coagulation process is characterised by a cascade of events which lead to the formation of a stable blood clot, made up of fibrin. Proteins called clotting factors initiate reactions which activate more clotting factors. -This process occurs via two pathways which unite downstream to form the common pathway. These are: --The extrinsic pathway: This is triggered by external trauma which causes blood to escape the circulation. The extrinsic pathway takes less time to form a clot than the intrinsic pathway. --The intrinsic pathway: This is triggered by internal damage to the vessel wall. This pathway takes longer to form a clot than the intrinsic pathway. - Both pathways result in the formation of factor Xa. Factor Xa combines with factor Va on the surface of activated platelets (in the presence of calcium ions) to form the prothrombinase complex. - The prothrombinase complex cleaves prothrombin (a zymogen) to thrombin (on the surface of activated platelets)

Answer 7

The extrinsic pathway unfolds as follows: -Damage to the blood vessel means that factor VII exits the circulation into surrounding tissues -Tissue factor (factor III) is released by damaged cells outside the circulation -Factor VII and factor III form a complex, known as the TF-VIIa complex. -TF-VIIa then activates factor X into its active form, factor Xa -In conjunction with factor Va, this triggers the formation of thrombin. Note that the extrinsic pathway is believed to be responsible for the initial generation of activated Factor X (Factor Xa), whereas the intrinsic pathway amplifies its production.

Answer 8

The intrinsic pathway is the longer and more intricate pathway: -Factor XII is activated once it comes into contact with negatively charged collagen on the damaged endothelium, triggering the cascade. -Factor 12 activates Factor 11 -Factor 11 activates Factor 9 -Factor 9a which with its co-factor Factor 8a form the tenase complex which activates Factor 10

Answer 9

-The intrinsic and extrinsic pathways converge to give rise to the common pathway. - The point of the common pathway is to convert prothrombin into thrombin. - The activated factor Xa and Va allow prothrombinase to catalyze this rection -The activated factor X causes a set of reactions resulting in the inactive enzyme prothrombin (also called factor II) being converted to its active form thrombin (factor IIa) by Prothrombinase. -The thrombin then converts soluble fibrinogen (also refereed to as factor I) into insoluble fibrin strands. The fibrin strands which comprise the clot are stabilised by factor XIIIa. Factor I is fibrinogen. Factor II is prothrombin. Factor III is tissue factor (TF in the image above). Factor IV is calcium. EDTA in purple blood tubes binds to calcium to prevent blood from clotting before it has been analysed

Answer 10

- Aswell as coagulants you always have anticoagulants in your bloodstream too. This is too make sure your not making clots everywhere. - There are a few of these such as Tissue Factor Pathway Inhibitor (TFPI). This stops coagulation if it is not required. - Antithrombin is also an anticoagulant. You have lots of anti thrombin going around. Antithrombin is a protease inhibitor that degrades thrombin, factor IXa, factor Xa, factor XIa and factor XIIa. It is constantly active, but can be activated further by a group of common anticoagulants known as heparins. - Calcium ions play a role through their interaction with an activation of several clotting factors. Low levels of calcium are therefore inhibitory to the clotting cascade. - Normally there is a balance between coagulants and anticoaglants. When it is out of balance you have more coagullanta nd you clot

Answer 11

Platelet aggregometry is applied in different clinical settings for: -monitoring response to antiplatelet therapies - the assessment of perioperative bleeding risk -the diagnosis of inherited bleeding disorders - in transfusion medicine -The platelet aggregometry is a test you do on blood to see how well platelets, a part of blood, clump together and cause blood to clot. - A platelet aggregation test requires a blood sample. The sample is initially examined to see how the platelets are distributed through the plasma, the liquid part of the blood. A chemical is then added to your blood sample to test how quickly your platelets clot.

Answer 12

- The prothrombin time (PT) test measures how quickly your blood clots. -Taking the blood thinner warfarin is the most common cause of a prolonged PT. -Generally, the reference range is 10–13 seconds, though it may vary. - PT measures the following coagulation factors: 1,2,5,7,10 -I (fibrinogen), -II (prothrombin), -V (proaccelerin), -VII (proconvertin), -X (Stuart–Prower factor).

Answer 13

The international normalised ratio (INR) is a laboratory measurement of how long it takes blood to form a clot. It is used to determine the effects of oral anticoagulants on the clotting system. Typical target INRs: Important target International Normalised Ratios (INRs) to remember include: -For patients with atrial fibrillation: 2-3 -For patients with metallic valve replacements: 2-3 (aortic valve) 2.5-3.5 (mitral valve) -Following venous thromboembolism (VTE): 2-3 -Note that for patients with a recurrent VTE whilst on Warfarin, the target INR should be increased from 2-3 to 3-4.

Answer 14

- The partial thromboplastin time (PTT) test also measures the speed of clotting. - but is primarily used to determine if heparin therapy is working. It can also help detect bleeding disorders.

Answer 15

Prolonged PT- defective factor 7 Prolonged PTT: defective factor 8,9,11,12 Prolonged PTT and PT: defective factor 1,2,5,10 Normal PTT and PT: thrombocytopenia, factor 13 deficiency, mild form of von wilbrands disease, weak collagen

Answer 16

- Thrombocytopenia is a condition in which you have a low blood platelet count - Thrombocytopenia might occur as a result of a bone marrow disorder such as leukemia or an immune system problem. Or it can be a side effect of taking certain medications. It affects both children and adults. - Immune thrombocytopenia is when antibodies bind to the protein GP2b-3a. These are cleared by Kupffer cells or splenic macrophages. - hematoams - is a bad bruise - cerebral hemorrhage - bleed in the brain

Answer 17

- condition which affects aggregation (clumping) of platelets - autosomal recessive - generally thought to be caused by lack of platelet aggregation. - There is mutation in the glycoprotein 2b and or glycoprotein 3a, which makes it difficult for platelets to aggregate. - Glanzmann thrombasthenia is a bleeding disorder that is characterized by prolonged or spontaneous bleeding starting from birth - People with Glanzmann thrombasthenia tend to bruise easily, have frequent nosebleeds (epistaxis), and may bleed from the gums.

Answer 18

- Hemophilia is usually an inherited bleeding disorder in which the blood does not clot properly. - Hemophilia is a blood disorder characterized by changes in clotting proteins. - Hemophillia is a recessive sex -linked X - chromosome disorder, meaning the vast majority of sufferers are male. - Haemophilia A is due to a deficiency of factor VIII -whilst in Haemophilia B (Christmas disease) there is a lack of factor IX - The severity of hemophilia that a person has is determined by the amount of factor in the blood. The lower the amount of the factor, the more likely it is that bleeding will occur which can lead to serious health problems.

Answer 19

-There are two classes of antithrombotic drugs: anticoagulants and antiplatelet drugs -Anticoagulants slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing. Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.

Answer 20

- Blood platelets are inactive until damage to blood vessels or blood coagulation causes them to explode into sticky irregular cells that clump together and form a thrombus. -The first antiplatelet drug was aspirin, which has been used to relieve pain for more than 100 years. In the mid-1960s, scientists showed that aspirin prevented platelets from clumping, and subsequent clinical trials showed that it reduces the risk of stroke and heart attack. In 1980, researchers showed that aspirin in very low doses (much lower than that required to relieve a headache) blocked the production of a chemical in platelets that is required for platelet clumping. - During that time, better understanding of the process of platelet clumping allowed the development of designer antiplatelet drugs directed at specific targets. We now have more potent drugs, such as clopidogrel, dipyridamole, and abciximab. These drugs are used with aspirin and effectively prevent heart attack and stroke; they also prolong the lives of patients who have already had a heart attack.

Answer 21

- Aspirin causes several different effects in the body, mainly the reduction of inflammation, analgesia (relief of pain), the prevention of clotting, and the reduction of fever -Much of this is believed to be due to decreased production of prostaglandins and TXA2. Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. - Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme.[1] This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors. - Aspirin inhibits platelet cyclooxygenase, a key enzyme in thromboxane A2 (TXA2) generation. - Thromboxane A2 triggers reactions that lead to platelet activation and aggregation, aspirin acts as a potent antiplatelet agent by inhibiting generation of this mediator. -

Answer 22

Aspirin dosing: Aspirin usually comes as 300mg tablets. The usual dose is 1 or 2 tablets, taken every 4 to 6 hours.

Answer 23

- Clopidogrel is an antiplatelet medicine. It prevents platelets (a type of blood cell) from sticking together and forming a dangerous blood clot. - Clopidogrel is a ADP receptor antagonist - clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP- mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible pro-drug: means when you swallow the drug is inactive but when the drug goes through the liver it becomes activated. a biologically inactive compound which can be metabolized in the body to produce a drug. - hepatic CYP2C19 is the enzyme which metabolizes clopidogrel in the liver.

Answer 24

- Clopidogrel can cause Thrombotic Thrombocytopenic Purpura (TTP).

Answer 25

- Anticoagulants that prevent or reduce coagulation of blood, prolonging the clotting time - Their primary goal is to reduce the formation of fibrin - Can be further separated into 2 groups: 1. Direct thrombin inhibitors 2. Direct Factor Xa inhibitors

Answer 26

- Heparin injection is an anticoagulant. It is given intravenously or by injection under the skin. - It does this by activating antithrombin III. - Specifically it is also used in the treatment of heart attacks and unstable angina. -Other uses for its anticoagulant properties include inside blood specimen test tubes and kidney dialysis machines. - Common side effects include bleeding, pain at the injection site, and low blood platelets. -Serious side effects include heparin-induced thrombocytopenia (HIT) -Heparin appears to be relatively safe for use during pregnancy and breastfeeding. - Heparin is produced by basophils and mast cells in all mammals.

Answer 27

- Unfractionated heparin (UFH) - this forms a complex which inhibits thrombin, factors Xa, IXa, XIa and XIIa. -Low molecular weight heparin (LMWH) - this forms a complex that inhibits factor Xa. - LMWH is a less potent anticoagulant than UFH. -In general, the effects of UFH are more unpredictable than LMWH, and so LMWH is preferable in patients with massive pulmonary embolism and for the initial treatment of deep vein thrombosis. -You normally use unfractionated heparin when testing blood clotting. - Heparin Prevents activation factors 2,9,10,11

Answer 28

Heparin is used to treat or prevent clots in conditions where there is a high risk of clot formation and embolism, for example: -in atrial fibrillation - myocardial infarction - deep vein thrombosis -orthopaedic surgery - pulmonary embolism Contraindication: - not used in patients who have had past or present HIT - active bleeding Side effects of heparin are: - HIT (heparin induced thrombocytopenia - Bleeding -osteoporosis - hyperkalaemia. The risk of these side effects is lower with low molecular weight heparin than unfractionated heparin. Heparin overdose is reversed by protamine sulphate. This works better for unfractionated heparin than low molecular weight heparin, so in patients who are at a higher risk of bleeding, unfractionated heparin may be more useful.

Answer 29

- Venous thromboembolism (VTE) is a condition that occurs when a blood clot forms in a vein. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT occurs when a blood clot forms in a deep veins, usually in the lower leg, thigh, or pelvis -All patients admitted to hospital should be assessed to identify risk factors for venous thromboembolism (VTE). Risk factors for VTE include: - significantly reduced mobility - hip and knee replacements - being over the age of 60 - BMI over 30 - use of the combined oral contraceptive pill -active cancer. -Patients at high risk of VTE are started on pharmacological VTE prophylaxis. LMWH e.g. enoxoparin should be used as prophylaxis of venous thromboembolism in patients admitted to hospital. - LMWH cannot be given to patients with chronic kidney disease. -In general, the effects of UFH are more unpredictable than LMWH, and so LMWH is preferable in patients with massive pulmonary embolism and for the initial treatment of deep vein thrombosis. -However, due to its renal clearance, LMWH is contraindicated in patients with kidney disease, with a GFR less than 30. Unfractioned heparin is safe in this group. -UFH may be used as an alternative in patients with chronic kidney disease.

Answer 30

- Pregnancy puts women at a significantly increased risk of developing VTE. An individual risk assessment should be carried out at booking and during any hospital admissions. Risk factors include: - if the woman has had a previous VTE - is more than 35 years of age - has a BMI over 30 - is a smoker - if she has pre-eclampsia. Four or more risk factors is significant, and the woman should be started on LMWH until she is six weeks postnatal. Do not use direct oral anticoagulants (DOACs) and warfarin in pregnancy.

Answer 31

- Warfarin is an oral anticoagulant - Vitamin K anatagonist - That was used first-line for many years in both the management of venous thromboembolism and reducing stroke risk in patients with atrial fibrillation. -

Answer 32

-To produce some of the clotting factors, the liver needs a good supply of vitamin K. Warfarin blocks one of the enzymes (proteins) that uses vitamin K to produce clotting factors - Warfarin competitively inhibits the vitamin K epoxide reductase complex 1 (VKORC1), an essential enzyme for activating the vitamin K available in the body. Through this mechanism, warfarin can deplete functional vitamin K reserves and thereby reduce the synthesis of active clotting factors. - The hepatic synthesis of coagulation factors II, VII, IX, and X, as well as coagulation regulatory factors protein C and protein S, require the presence of vitamin K. -Vitamin K is an essential cofactor for the synthesis of all of these vitamin K-dependent clotting factors. - inhibits epoxide reductase preventing the reduction of vitamin K to its active hydroquinone form this in turn acts as a cofactor in the carboxylation of clotting factor II, VII, IX and X (mnemonic = 1972) and protein C.

Answer 33

- The B lymphocyte (B cell) is one of the most important cells of the body. -These cells form part of the adaptive immune response by producing antibodies and presenting antigens to T cells. -Once activated, they can mature into plasma cells or memory B lymphocytes.

Answer 34

- B cells arise from the common lymphoid progenitor - B - cells progenitors remain in the bone marrow to mature. - After maturation the B cells move into the periphery lymphoid tissue

Answer 35

- Positive selection ensures that only B cells with functional receptors are allowed to develop further. This occurs when the B cell receptor successfully binds its ligand, which induces survival signals. - Negative selection happens when B cells respond to self -antigens in the bone marrow and, as a result, undergo receptor editing, anergy or apoptosis. This promotes central tolerance and minimises the risk of autoimmune reactions when the B cells eventually mature and move to the peripheral circulation. -In immunology, central tolerance (also known as negative selection) is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself

Answer 36

- Once differentiated in the bone marrow, B cells migrate to lymphoid follicles in the spleen. - They also migrate to areas where lymphoid activation and defence is likely to be triggered such as in the mucosal linings. This includes the Peyer’s patches of the colon, which are a type of mucosa-associated lymphoid tissue (MALT). -Other ‘MALTs’ also exist and are named according to their location or organisation e.g. Bronchial (BALT), Nasal (NALT), Organised-mucosa (O-MALT).

Answer 37

- Plasma cells and Memory B-cells - Once activated, B lymphocytes can differentiate into plasma cells. - Plasma cells are large cells with abundant endoplasmic reticulum, which allows them to produce large quantities of antibodies against specific antigens. - They respond to signals from T cells during infection and continue to produce antibodies until the infection is controlled. Plasma cells are often found in chronic inflammation. Memory B - cells: - Some B lymphocytes will differentiate into memory B cells, which are are long-lived cells that remain within the body and allow a more rapid response to future infections. - If the host is re-exposed to the same antigen, these cells rapidly proliferate with assistance from T cells. This produces more cells capable of secreting specific antibodies to the pathogen. This often means that the pathogen can be dealt with before the infection takes hold and becomes symptomatic. T - independent B cells: - B lymphocytes require T cells to produce antibodies. However, a small number can function without T cell help and these are found within sites such as the spleen and peritoneum. -They are particularly important for dealing with encapsulated bacteria. Encapsulated bacteria have a polysaccharide outer layer as opposed to a protein-based one, which allows them to evade T cells. T-independent B cells can recognise these layers and produce antibodies without T cell help.

Answer 38

- Antibodies are also known as immunoglobins - Y - shaped glycoproteins - produced by plasma cells -

Answer 39

- IgA, IgD, IgE, IgG and IgM (ADGEM) - Antibodies are classified according to heavy chain type, which is encoded by a gene on chromosome 14. The different classes are IgG, IgA, IgM, IgD and IgE; in descending order of abundance in serum. (GAMDE) -

Answer 40

- IgG is the most abundant antibody class. - There are four subclasses: IgG1, IgG2, IgG3 and IgG4; in order of serum concentration - IgG is the only antibody to cross the placenta and consequently, it transfers passive immunity from mother to foetus. Newborns, therefore, have high IgG concentrations in the first 3-6 months of life.

Answer 41

- IgA is the most prevalent antibody in secretions, such as saliva and mucous - There are two subclasses, IgA1 and IgA2. - IgA forms a dimer, where a joining chain connects 2 Y-shaped molecules, giving it four antigen-binding sites in total. - IgA antibodies are resistant to enzymatic digestion and act principally as neutralising antibodies. - Breast milk and colostrum have high levels of IgA which coat the aerodigestive tracts; protecting against infections in breast-fed babies. - In adults, IgA forms a barrier layer at mucosal surfaces to prevent pathogenic invasion. Plasma cells in the lamina propria produce excessive amounts of polymeric IgA which then moves by endocytosis through the epithelial layer to be secreted at the luminal side. IgA neutralises pathogens and hinders their attachment to epithelial receptors by binding to their ligands on pathogens or toxins. - IgA molecules can also cross-link polyvalent antigens or pathogens, forming antigen-antibody complexes which are then trapped in the mucus layer and cleared through peristalsis. - IgG and IgA antibodies also have polymorphic variants, referred to as allotypes

Answer 42

IgM antibodies are expressed on the surface of B-cells as monomers but secreted as pentameters. A pentameter has five antibodies connected by a joining chain, with ten antigen-binding sites in total. It is the first immunoglobulin produced during foetal development and the first to be produced by B-cells against a new infection. IgM has high avidity, meaning the antibody-antigen complex is strong, but low affinity, so the strength of a single epitope-antibody interaction is weak.

Answer 43

- IgD is present on the surface of B-cells. It has a role in B-cell and antibody production. All naive B cells express IgD and IgM.

Answer 44

- IgE is mainly found on mast cells but is also present at low levels in the blood and extracellular fluid. It is associated with allergy, particularly type I hypersensitivity reactions, including atopic disease (e.g. asthma and dermatitis) and anaphylaxis. - It triggers histamine release from mast cells and basophils. IgE is also part of the body’s response to parasitic infections.

Answer 45

- Antibody molecules consist of two identical heavy chains and two identical light chains, which consequently give the antibody two antigen-binding sites - Disulphide bonds bind the heavy chains to each other and to the light chains - Each light chain has two domains (one variable and one constant), and each heavy chain has four (one variable and three constant). -

Answer 46

There are five heavy chain types: μ (Mu), γ (Gamma), α (Alpha), ε (Epsilon) and δ (Delta), which classify IgM, IgG, IgA, IgE and IgD respectively.

Answer 47

- There are two light chain types: κ (kappa) and λ (lambda). Each antibody can have either two κ or two λ chains but not one of each. -The ratio of κ and λ is 2:1. However, there are no functional differences between the types.

Answer 48

FAB regions: - The Fab regions (fragment antigen binding) contain the variable domains of the light and heavy chains. The variable domains make up the variable regions of the antibody which give the antibody its antigen specificity. -Therefore, these regions differ between antibodies. Each Fab region also contains two constant domains; one from the heavy chain component and one from the light chain component. Fc region: -The Fc region (fragment crystallisable) consists of the remaining constant domains from the two heavy chains. The Fc region interacts with different immune cells and mediates various functions. For example, opsonisation (see below).

Answer 49

- 10 to the power of 11 different antibody combining sites. Somatic recombination is how we can use such a small amount of genes to form such a large number of different antibody receptor binding site shapes. This happens when a B cell is maturing. Somatic recombination includes: - Germ line diversity of genes - Combinatorial diversity - Junctional diversity -Somatic hypermutation is when the antibody continues to change shape so the ligand fits better. This can continue during the life of the antibody.

Answer 50

The somatic recombination process for generating antibody and TCR diversity is unique among mammalian systems. Antibodies must have enough antigen-binding diversity to recognize every possible pathogen (many V regions) while maintaining the biological effectiveness of their C regions (few C regions).

Answer 51

1. Specificity 2. Amplification

Answer 52

- Somatic hypermutation occurs in germinal centers in lymphoid tissue.

Answer 53

- Opsonization: mainly IgG1 and IgG3 bind to the pathogen, which allows better recognition by phagocytes. - Neutralization: mainly IgG and IgA. Antibodies can prevent pathogens from accessing cells by blocking different parts of the bacterial or viral cell surface. Consequently, this neutralises certain viruses and bacterial toxins. - Complement activation: IgM or IgG. This releases C3b, which acts as an opsonin, and other complement components which make up the membrane attack complex. MAC punches holes in the pathogen plasma membrane which leads to cell lysis and death. - Immune complexes: The binding of multiple antigens and antibodies together can form immune complexes. Complex formation limits the antigens’ diffusing ability, making it easier for phagocytes to find and ingest pathogens through phagocytosis. - Antibody- dependent cell mediated cytotoxicity: Antibodies bind and opsonise target cells. Natural killer cells then recognise the Fc portion of the antibody and release cytotoxic granules (perforin and granzymes) into the target cell which trigger apoptosis. They also release interferons, which attracts phagocytes

Answer 54

- Immunoglobin isotope switching is a biological mechanism that changes a B-cells production of immunoglobin from one type to another, such as from the isotype IgM to the isotype IgG.

Answer 55

- Immunoglobin isotopes appear at different times in our lives. - IgG is passed on from mother before birth from placenta. - Then we start synthesizing our own IgM, IgG and IgA after birth. - Immunoglobin isotopes also have different tissue distribution. - IgA: found around gastrointestinal tract, mucosa, respiratory tract - IgE: protects external epithelium barrier - IgM: around heart

Answer 56

- The constant end of the antibody is called Fc region. Fc receptors found on phagocytes can bind to the Fc region on antibodies. - Image 2 is diplaying Antibody-dependent cellular cytotoxicity

Answer 57

- The type of molecules recognized by T- cell receptors are distinct to what is recognised by a B- cell receptor. - An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope.

Answer 58

- Major Histocompatibility complex (MHC) transport fragments of pathogen protein to the surface membrane of the phagocyte. - The t- cell receptor can then recognize it - Then the t-cell tells the b -cell its okay to produce antibodies - Many autoimmune diseases are caused by MHC picking up the wrong molecules

Answer 59

- Antigens are delivered to the surface of APCs by Major Histocompatibility Complex (MHC) molecules. There are two types: - MHC class I molecules are found on all nucleated cells (not just professional APCs) and typically present intracellular antigens such as viruses. - MHC class II molecules are only found on APCs and typically present extracellular antigens such as bacteria. - The most important APCs are dendritic cells, B cells and macrophages. - This is logical because should a virus be inside a cell of any type, the immune system needs to be able to respond to it. This also explains why pathogens inside human red blood cells (which are non-nucleated) can be difficult for the immune system to find, such as in malaria.

Answer 60

- Before an antigen can be presented, it must first be processed. Processing transforms proteins into antigenic peptides. - ntracellular peptides for MHC class I presentation are made by proteases and the proteasome in the cytosol, then transported into the endoplasmic reticulum via TAP (Transporter associated with Antigen Processing) to be further processed. - Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis -They are then assembled together with MHC I molecules and travel to the cell surface ready for presentation.

Answer 61

-The route of processing for exogenous antigens for MHC class II presentation begins with endocytosis of the antigen. Once inside the cell, they are encased within endosomes that acidify and activate proteases, to degrade the antigen. -MHC class II molecules are transported into endocytic vesicles where they bind peptide antigen, and then travel to the cell surface.

Answer 62

- The antigen presented on MHCs is recognised by T cells using a T cell receptor (TCR). These are antigen-specific. - Each T cell has thousands of TCRs, each with a unique specificity that collectively allows our immune system to recognise a wide array of antigens. - TCR diversity is generated by the random and imprecise rearrangements of the V and J segments of the TCR alpha (TCRA) and V, D, and J segments of the TCR beta (TCRB) genes in the thymus -This diversity in TCRs is achieved through a process called V(D)J recombination during development in the thymus. TCR chains have a variable region where gene segments are randomly rearranged, using the proteins RAG1 and RAG2 to initiate cleavage and non-homologous end joining to rejoin the chains. -The diversity of the TCRs can be further increased by inserting or deleting nucleotides at the junctions of gene segments; together forming the potential to create up to 1015 unique TCRs. -TCRs are specific not only for a particular antigen but also for a specific MHC molecule. T cells will only recognise an antigen if a specific antigen with a specific MHC molecule is present: this phenomenon is called MHC restriction.

Answer 63

-As well as the TCR, another T cell molecule is required for antigen recognition and is known as a co-receptor. These are either a CD4 or CD8 molecule: -CD4 is present on T helper cells and only binds to antigen-MHC II complexes. -CD8 is present on cytotoxic T cells and only binds to antigen-MHC I complexes. -This therefore leads to very different effects. Antigens presented with MHC II will activate T helper cells and antigens presented with MHC I activate cytotoxic T cells. Cytotoxic T cells will kill the cells that they recognise, whereas T helper cells have a broader range of effects on the presenting cell such as activation to produce antibodies (in the case of B cells) or activation of macrophages to kill their intracellular pathogens.

Answer 64

- T lymphocytes originate from haematopoietic stem cells within the bone marrow - Some of these multipotent cells subsequently become lymphoid progenitor cells that leave the bone marrow and travel to the thymus via the blood.

Answer 65

- Once in the thymus, T lymphocytes undergo a selection process in which the majority of developing T cells (called thymocytes) will not survive. During this process, thymocytes with receptors for self-antigens receive negative signals and are removed from the repertoire. - Each T lymphocyte has a T cell receptor (TCR) which is specific to a particular antigen. T lymphocytes that survive thymic selection will mature and leave the thymus. After that, They circulate through peripheral lymphoid organs, ready to encounter their cognate antigens and become activated. The thymus atrophies as we age and so produces fewer naïve T lymphocytes over time.

Answer 66

- Naïve T lymphocytes are cells that have not yet encountered their specific antigen. In peripheral lymphoid organs, naïve T lymphocytes can interact with antigen-presenting cells (APCs), which use MHC molecules to present antigen. Once the T lymphocytes recognise their specific antigens, they proliferate and differentiate into one of several effector T lymphocyte subsets. Effector T lymphocytes interact with host cells (rather than the pathogen) to carry out their immune function. - T lymphocytes use co-receptors to bind to the MHC molecules. Co-receptors can be either CD4 or CD8. CD proteins help to differentiate major groups of effector T lymphocytes. - Naïve CD8+ T lymphocytes will become cytotoxic T lymphocytes. Alternatively, -CD4+ T lymphocytes will become T helper lymphocytes, each of which specialised for particular tasks.

Answer 67

-Cytotoxic T lymphocytes kill their target cells primarily by releasing cytotoxic granules into the target cell. These cells recognise their specific antigen (such as fragments of viruses) only when presented on MHC Class I molecules present on the surface of all nucleated cells. - MHC Class I molecules interact with CD8 on the cytotoxic T cells. Cytotoxic T cells require several signals from other cells like dendritic cells and T helper cells to be activated. -Their main function is to kill virally infected cells, but they also kill cells with intracellular bacteria or tumorous cells.

Answer 68

- T helper cells (Th) have a wide range of effector functions and can differentiate into many different subtypes, such as Th1, Th2, Th17, TfH cells and regulatory T cells. -They become activated when they are presented with peptide antigens on MHC Class II molecules. These are expressed on the surface of APCs. MHC Class II molecules interact with CD4 on the T helper cells, which helps identify this cell type. -CD4+ T cell functions include activating other immune cells, releasing cytokines, and helping B cells to produce antibodies. They help to shape, activate and regulate the adaptive imm

Answer 69

- Antigen-specific, long-lived memory T lymphocytes form following an infection. Memory T lymphocytes are important because they can quickly proliferate into large numbers of effector T lymphocyte upon re-exposure to the antigen and have a low threshold for activation. - They provide the immune system with memory against previously encountered antigens. Memory T lymphocytes may either be CD4+ or CD8+.

Answer 70

- Antigen-specific, long-lived memory T lymphocytes form following an infection. Memory T lymphocytes are important because they can quickly proliferate into large numbers of effector T lymphocyte upon re-exposure to the antigen and have a low threshold for activation. - They provide the immune system with memory against previously encountered antigens. Memory T lymphocytes may either be CD4+ or CD8+.

Answer 71

- T helper cells (Th) have a wide range of effector functions and can differentiate into many different subtypes, such as Th1, Th2, Th17, TfH cells and regulatory T cells.

Answer 72

Tfh ( T follicular helper cells ) CD4+ Cytokines: IL- 21 and IL-6 Function: -Help formation of germinal centres and B cell antibody affinity maturation. Germinal centre formation. -B cell antibody isotype switching. -Antibody affinity maturation. -Enables B cells to develop into plasma cells for Long term humoral immunity Transcription factor: Bcl6

Answer 73

- TH1 (T helper 1 cells ) CD4+ - Cytokines : IL-12, IFN-γ, IL-2 Function: -Activates macrophages. -Helps cytotoxic T-cells. -Provides B-cell help for antibody production -Activation of phagocytes for enhanced killing of intracellular pathogens Target audience: - Intracellular (mycobacteria, listeria, leishmania) -extracellular bacteria. -Fungi Transcription factor: T-bet

Answer 74

- Th2 (T helper 2) cells CD4+ - Cytokines: IL- 4 Function: - Provide help to B cells for antibody production- especially IgE antibodies. - Activates eosinophils and mast cells. Target audience: - Helminth -Extracellular Parasites Transcription factors: -GATA3 -STAT6

Answer 75

Th17 (T helper 17) cells CD4+ Cytokines stimulus : IL-6, IL-21, TGF-β Cytokine production: IL-17 Function: -Enhance neutrophil response. -Improve epithelial barrier function. -Activation of neutrophils / anti-fungal responses / autoimmunity Target audience: Extracellular bacteria (e.g. Salmonella enterica) Transcription factors: ROR-γT STAT3

Answer 76

- Cytotoxic T - helper cells CD8+ Cytokines: IL-12, IL-18 Function: - Kills virus-infected cells -Direct killing of infected “target” cells or cancer cells Target audience: - Viruses Transcription factor: - T-bet Blimp1

Answer 77

Function: - Suppresses other immune cells, particularly CD4+ and CD8+ responses. Cytokines: TGF-β Transcription factor: Foxp3