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HYMS Y1 > Block 4 W2 > Flashcards

Block 4 W2 Flashcards

1
Q

Define antibody.

A

Soluble recognition molecules secreted by B lymphocytes to deliver the effector function.
Fine specificity.

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2
Q

What are the functions of antibodies?

A

Directly kill and neutralise microbes and their toxins.
Clearance of antigens and termination of IR.
Mediate allergic reactions.
Cause immune complex diseases.
Mediate autoimmune cell destruction.

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3
Q

Describe the structure of antibody and draw a diagram.

A

4 polypeptide chains, 2 heavy and 2 light -> held by transmembrane region.
FAB - fragment antigen binding site (variable region)
Fc - fragment crystallisable (constant region)
Hinge - enables flexibility

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4
Q

Define affinity, avidity and valency of immunoglobulins.

A

Affinity - strength of interaction between receptor and ligand e.g. affinity for antigen
Avidity - combined strength of all the interactions e.g. avidity increases with 2 binding sites.
Valency - how many interactions we have that contribute to avidity.

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5
Q

How are infinitely different shapes of antibodies made?

A

Antibodies are encoded for by multiple gene segments.
1. germ line diversity of genes
Somatic recombination:
2. combinatorial diversity - way of combining genes
3. junctional diversity - way of sticking together genes
4. somatic hypermutation - during ongoing IR

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6
Q

List the different classes of immunoglobulins and their functions.

A

IgM - pentameric structure, activates complement system
IgG1 - opsonisation, transport across placenta
IgG3 - (struck to blood) activates complement
IgE - (stuck to tissues) sensitisation of mast cells
IgA - dimeric structure, transport across epithelium
IgG1, 2, 3, 4 - diffusion into extracellular sites.

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7
Q

Which regions of the antibody provides the function?

A

Fc region - interacts with other immune molecules via changes in Fc.

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8
Q

During pregnancy, what are the different types of Ig and where are they found?

A

Whole body - IgG and IgA
Heart - IgM
Respiratory and digestive tracts - IgA
Skin - IgE

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9
Q

How is maternal protection to the foetus provided?

A

Maternal IgG cross placenta as infant produces own IgG.

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10
Q

Define clonal selection.

A

Process of amplification of a specific B cell once recognition of antigen has occurred - allows specificity in IR.
Usually lag period in IR due to clonal selection.

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11
Q

Define class switching.

A

Within life of a B cell clone, the antibody isotope can change but FAB remains constant - B cell responds to immune signals by changing Fc region.

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12
Q

Why is FcR important?

A 
Allows cellular recognition and responses to antibody and enables effector function.
FcR occurs on:
- macrophages 
- NK cells
- mast cells
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13
Q

What factors are required to start B cell antibody production?

A
  • right microenvironment
  • follicular dendritic cells
  • chemokine and cytokines
  • APCs
  • CD4+ T cells
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14
Q

What are the different types of T cells?

A
  • CD8+ cytotoxic T cells -> kill virus infected cells
  • CD4+ Th1 cells -> clearance of intracellular bacteria and viruses
  • CD4+ Th2 cells -> clearance of extracellular parasites i.e. helminths
  • CD4+ Th17 cells -> response to extracellular bacteria and fungi
  • CD4+ Treg cells -> suppresses T cell responses
  • T memory cells
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15
Q

Give examples of professional APCs and their location.

A

Dendritic cells - ubiquitous throughout the body.
Macrophages - lymphoid tissue, connective tissue, body cavities.
B cells - lymphoid tissue and peripheral blood.

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16
Q

Describe thymic education.

A

98% of T cells die in thymus by positive (cortex) and negative (medulla) selection.
Only T cells with TCR able to recognise foreign peptides bound by MHC escape to periphery.

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17
Q

Describe and draw the structure of T cells.

A

2 polypeptide chains (alpha and beta)
1 antigen binding site
Variable, constant and transmembrane regions.

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18
Q

Differentiate how antigen recognition occurs between T and B cells.

A

T cell - use TCR to recognise linear epitopes.

B cell - use Ab to recognise conformation epitopes (tertiary structures).

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19
Q

Describe and draw the structure of MHC class I and II.

A

Class I - One MHC-encoded heavy chain (alpha 1, 2 and 3) + beta-2 microglobulin.
Class II - One MHC-encoded alpha chain + one MHC encoded beta chain.

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20
Q

Describe the function of MHC class I.

A

Expressed on all nucleated cells.
Carry peptides generated in the cytosol or ER.
Present peptides to CD8+ T cells.
Surveillance for virus infection and altered self.

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21
Q

Describe the function of MHC class II.

A

Expressed on specialised APCs.
Carry peptides generated in endosomal compartments.
Present peptides to CD4+ T cells.
Surveillance for exogenous pathogens.

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22
Q

Describe the process of MHC class I antigen presentation to CD8+ T cells.

A
  • virus infects cell
  • viral proteins synthesised in cytoplasm
  • peptide fragments of viral proteins bound by MHC class I in ER.
  • bound protein transported by MHC class I to cell surface
  • cytotoxic T cell recognises complex of viral peptide with MHC class I and kills infected cell.
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23
Q

Describe the process of MHC class II antigen presentation to CD4+ T cells.

A
  • macrophages or B cells engulf bacterium.
  • bacterial peptides bound by MHC class II in vesicles
  • transported to cell surface
  • CD4+ T cell recognises complex of peptide antigen with MHC class II and activates the macrophage or B cell.
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24
Q

Describe T and B cell co-operation.

A

B cell responses require help from CD4+ T cells for activation so these synapse with each other.

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25
Q

What signals are required for T cell activation?

A

Requires both antigen and co-stimulatory signals from the APC for activation.
Antigen - provided by MHC

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26
Q

Do T cells also feature clonal expansion?

A

Yes, ensures continual turnover of T cells so that effector and memory T cells are made with same structure and receptor.

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27
Q

What does somatic hypermutation allow?

A

Greater affinity to antigen by antibodies.

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28
Q

Briefly describe the immune response.

A
  1. pathogen recognition by cells of innate IS, with cytokine release, complement activation and phagocytosis of antigen.
  2. innate IS triggers acute inflammatory response to contain infection.
  3. meanwhile, antigen presentation takes place with activation of specific T helper cells.
  4. CD4+ T helper cells co-ordinate a targeted antigen-specific IR involving two adaptive cell systems:
    - humoral immunity from B cells and antibodies
    - cell-mediated immunity from cytotoxic CD8+ T cells.
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29
Q

What is are the clinical signs of polycythaemia?

A

Breathing difficulties, dizziness, excessive bleeding, splenomegaly, headache, itchiness, red colouring, SOB, phlebitis.

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30
Q

Describe the primary cause of polycythaemia.

A

Genetic defect -> enhanced responsiveness to EPO due to mutations in the EPOR - JAK2 gene.

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31
Q

Describe the secondary cause of polycythaemia.

A

Induced change in cell number due to conditions that promote RBC development:

  • hypoxia i.e. COPD, CHF, kidney transplant
  • EPO secreting tumour i.e. renal cell carcinoma
  • neonatal polycythaemia due to maternal RBC transfusion after delivery.
32
Q

What are the clinical signs of essential thrombocythaemia?

A

Frequently asymptomatic.

Haemorrhage or thrombosis, occasional progression to MF and leukaemia.

33
Q

What are the clinical signs of idiopathic myelofibrosis?

A

Leukoerythroblast blood picture, splenomegaly, bone marrow fibrosis, anaemia, thrombocythaemia or thrombocytopenia.
Progression to acute leukaemia.

34
Q

Describe type I hypersensitivity.

A 
Immediate
IgE
Antigen: recognise soluble antigen
Effector mech: mast cell activation
e.g. allergic, asthmatic reactions and systemic anaphylaxis

Antigen combines with many IgE -> increasing avidity -> degranulation of mast cells.
Secondary response as IgE already primed.

35
Q

What are the consequences of type I hypersensitivity?

A

GIT - increased fluid secretion and peristalsis -> diarrhoea and vomiting.
Airways - decreased diameter and increased mucus secretion -> phlegm and coughing.
Blood vessels - increased blood flow and permeability -> oedema, inflammation.

36
Q

Describe type II hypersensitivity.

A

IgG
Antigen: recognise insoluble matrix or cell bound antigens and cell surface receptors.
Effector mech: complement and phagocytosis.
e.g. drug allergies, chronic urticaria.

37
Q

Describe type III hypersensitivity.

A 
Immune complex diseases
IgG
Antigen: soluble antigens
Effector mech: complement and phagocytosis.
e.g. serum sickness, arthus reaction.
38
Q

Describe type IV hypersensitivity.

A

Delayed due to clonal expansion.
Th1 - soluble antigen - macrophage activation - e.g. contact dermatitis.
Th2 - soluble antigen - eosinophil activation - e.g. chronic asthma.
CTL - cell-associated antigen - cytotoxicity - e.g. contact dermatitis.

39
Q

What is granulomatous inflammation?

A

Most clinically significant type IV hypersensitivity.
Huge no. of schistosome egg granuloma -> portal hypertension -> unable to drain fluid accumulation -> distention of abdomen.

40
Q

Give example of primary immunodeficiency.

A

Chronic granulomatous disease - genetic disorder affecting how phagocytes kill bacteria, fungi and parasites.
4 major forms due to mutation in different proteins that comprise the phagocyte oxidase system.
Recessive sex-linked
Clinical signs: impetigo, skin and rectal abscesses, chronic lymphadenopathy, recurrent pneumonia.

41
Q

Give example of secondary immunodeficiency.

A

HIV/AIDS
Retroviral infection leading to loss of CD4+ T cells.
AIDS diagnosed with stage 3 HIV infection.
CD4 T cell differentiates into many types - more susceptible to infections.

42
Q

Give example of too much IR cancer.

A

Acute lymphoblastic leukaemia of B and T cells.

43
Q

Give example of too little IR in cancer.

A

Insufficient T or B cell response to recognise and kill tumour cells.

44
Q

Define autoinflammation.

A

Prolonged and unwanted innate immunity.
Phagocytes target own tissues.
e.g. familial Mediterranean fever.

45
Q

Define autoimmunity.

A

Loss/failure of self/non-self recognition.
Mediated by lymphocytes.
e.g. Grave’s.

46
Q

What are the triggers for auto-reactive cells?

A
  1. molecular mimicry - pathogen mimics self proteins as antigens.
  2. protein changes and cryptic antigens.
  3. superantigens - bacterial products that broadly stimulate IR i.e. toxic shock
  4. bystander activation
47
Q

What are the therapeutic interventions for auto inflammatory or autoimmunity diseases?

A
  • cytokine therapy e.g. anti-TNF -> generates antibodies that stop cytokine function.
  • reducing lymphocyte activation e.g. interfering with signalling pathways and blocking cell surface receptors.
  • killing the cell causing the disease e.g. anti-B cell antibodies (rituximab) for B cell cancers.
48
Q

What is the function of haemostasis?

A
  • limit blood loss
  • remove damaged tissues
  • repair damaged tissues
49
Q

Define thrombosis.

A

Pathological manifestation of haemostasis, causes blockage of blood vessels -> hypoxia and tissue damage. Dislodge = embolisation.

50
Q

What are the main stages of haemostasis?

A
  1. vascular spasm - damaged blood vessels constrict reducing blood flow in damaged area.
  2. platelet plug formation - platelets bind to damaged vessel wall and form plug.
  3. coagulation - stable blot forms by converting fibrinogen into fibrin.
51
Q

How are platelets destroyed?

A

By Keupfer cells in liver by phagocytosis in spleen.

52
Q

What do alpha-granule consist of?

A
  • adhesive proteins e.g. fibrinogen and vWF
  • platelet specific proteins e.g. PDGF
  • membrane proteins e.g. GPIb
  • alpha-granule-specific proteins e.g. P-selectin
53
Q

What do dense-granule consist of?

A

Vasoconstrictive agents
Platelet agonists e.g. ADP
Ca and Mg

54
Q

What happens in platelet adhesion?

A
  • damage exposes lamina densa, collagen-rich subendothelial connective tissue and vWF to the circulating blood
  • platelet integrin molecule, GPIb adheres to vWF, which in turn adheres to the collagen.
  • platelet rolls until more GPIb/vWF associations occur -> firm adhesion allows platelet activation -> releases granules.
55
Q

What happens in platelet plug formation/primary haemostasis?

A
  • activated platelet monolayer release platelet agonists i.e. ADP, thromboxane A2 and adhesive proteins i.e. fibrinogen, which further recruits more platelets.
  • new platelets change shape and are held together by GPIIb/IIIa, which binds fibrinogen -> fibrinogen cross-bridges.
56
Q

What are the pathways of the coagulation cascade?

A

Extrinsic pathway
Intrinsic pathway
Both leading to the common pathway.

57
Q

Describe the extrinsic pathway.

A
  • rapid onset
  • occurs in response to damaged blood vessels releasing tissue thromboplastin (factor 3)
  • factor 3 complexes with 7 to form 7a.
  • 7a converts 10 to 10a (prothrombinase).

Dependent on intrinsic pathway.

58
Q

Describe the intrinsic pathway.

A
  • slow onset
  • begins with factor 12 interaction with negative membrane layer of platelet plug/collagen converts to 12a
  • 12a converts 11 to 11a
  • 11a converts 9 to 9a
  • 9a combines with 8a(+vWF) to convert 10 to 10a.

Independent of extrinsic factor but dependent on factor 8 + vWF.

59
Q

Describe the common pathway.

A
  • 10a + 5a converts prothrombin (2) to thrombin (2a).
  • thrombin (2a) converts fibrinogen (1) to fibrin monomers (1a)
  • aggregation of fibrin monomers forms fibrin reticulum, aided by factor 13a, to stabilise the clot
60
Q

Describe the final stages of haemostasis.

A
  • Clot retraction and repair -> platelet contraction to close out the wound, PDGF stimulates growth of new connective tissue and smooth muscle and VEGF stimulates growth of new endothelial cells.
  • Fibrinolysis -> tissue plasminogen activator (tPA) activates plasminogen -> plasmin -> dissolves platelet plug and releases D-dimers.
61
Q

What are the normal inhibitors of coagulation?

A
  • NO + prostacyclin -> inhibit platelet aggregation
  • Protein C and protein S -> inhibit factor 5 and 8.
  • Antithrombin III -> inhibits factors 2, 9, 10, 11 and 12.
62
Q

Describe the prothrombin time (PT).

A

Measures time taken for blood plasma to clot.
Evaluates the extrinsic pathway.
Tissue factor is added to plasma and clotting time measured optically.

63
Q

Define INR.

A

International normalised ratio.

64
Q

Describe the activated partial thromboplastin time (APTT).

A

Measures intrinsic pathway. Measures time taken for plasma to clot after Ca2+ and activator is added.

65
Q

Describe thrombin time.

A

Measures the time it takes for fibrinogen to form fibrin.

66
Q

Define D-dimer.

A

Useful predictor of recent clot formation as its the product of fibrinolysis.

67
Q

Define thrombocytopenia.

A

Deficiency of platelets in blood.
Primary thrombocytopenia - unknown reason.
Immune thrombocytopenia- antibodies to GPIIb/IIIa or GPIb/IX.

68
Q

What is the clinical feature of immune thrombocytopenia?

A

Mild ITP - small haemorrhages - petechia (appears as rash).

Severe ITP - extensive haematoma and cerebral haemorrhage.

69
Q

Define Glanzmann’s thrombasthenia.

A

Autosomal recessive bleeding syndrome - affects megakaryocytic lineage.
Lack of platelet aggregation.
Due to nonsense mutations affecting GPIIb/IIIa.

70
Q

What are the clinical features of Glanzmann’s thrombasthenia?

A

Bleeding gums to severe haemorrhage.

71
Q

Define haemophilia.

A

Recessive sex-linked X-chromosome disorder.

Haemophilia A - deficiency in factor 8.
Haemophilia B - deficiency in factor 9.

72
Q

What is the mech of action of aspirin?

A

Inhibits platelet cyclooxygenase - key enzyme in thromboxane A2 generation -> potent anti-platelet agent.
Effects lasts for the life of platelet.

Used in ischaemic stroke, TIA, angina, MI.

73
Q

What is the mech of action of clopidogrel?

A

ADP receptor antagonist.

Prevents blockage of coronary arterial stent.

74
Q

What is the mech of action of heparin?

A

Binds antithrombin III - activating it -> which inhibits thrombin and factor 10a (UFH).
LMW heparin only inactivates factor 10a.

75
Q

What is the mech of action of warfarin?

A

Vitamin K antagonist.
Many clotting factors (3, 7, 9, 10) rely on reduced form of vitamin K (KH2) for carboxylation of glutamic residues.
Warfarin blocks the reformation of KH2 from the oxidised form so reducing clotting factor formation.

76
Q

What is the mech of action of thrombin inhibitors?

A

Directly inhibit thrombin so it can’t be used in coagulation cascade.

HYMS Y1 (25 decks)

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