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IMMUNOLOGY > LECTURE 5 (cells of innate immunity) > Flashcards

LECTURE 5 (cells of innate immunity) Flashcards

1
Q

What are the properties of Neutrophils?

A
  • Circulating phagocytes
  • Short lived
  • Rapid response + not prolonged defense
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2
Q

What are the properties of Monocytes/Macrophages?

A
  • Circulate in blood + become macrophages in the tissues
  • Provide a prolonged defense
  • Produce cytokines that initiate and regulate inflammation
  • Phagocytose pathogens
  • Clear dead tissue and initiate tissue repair
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3
Q

What are the two pathways that Macrophages will develop?

A

CLASSICAL M1
- Induced by innate immunity (TLRs & IFN-y)
- Phagocytosis & initiate inflammatory response

ALTERNATIVE M2
- Induced by IL-4 & IL-13
- Tissue repair & control of inflammation

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4
Q

What are the properties of Dendritic cells?

A
  • Found in all tissues
  • Antigen processing and presentation
  • Initiate inflammatory response & stimulate adaptive response
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5
Q

What are the properties of Mast cells?

A
  • Found on skin & mucosa
  • 2 pathways for activation: innate TLRs and antibody-dependent (IGE)
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6
Q

What are the properties of Natural killer cells?

A
  • Found in blood & periphery
  • Functions by direct lysis of cells & secretion of IFN-y
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7
Q

What is the pathway from Macrophages initiating itself?

A

Macrophages + Dendritic cells -> IL-12 -> Activate NK cells -> IFN-y -> Induce M1 macrophage pathway

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8
Q

What is the Complement system?

A

A set of interacting proteins released into the blood after production in the liver that act together as zymogens activating one another in cascade fashion after initiation from a variety of stimuli

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9
Q

What are the three major steps of the inflammatory response?

A

1) Recruitment of inflammatory cells and Anaphylatoxins
2) Opsonisation of pathogens
(uses opsonins to tag foreign pathogens for elimination)
3) Killing of pathogens
(membrane attack complex -> put holes in membrane)

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10
Q

What are the three pathways for the Inflammatory response?

A
  • Alternative (innate)
  • Lectin-binding/Mannose-binding pathway (innate)
  • Classic (active)
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11
Q

What is the function of the inflammatory response?

A
  • Mediate inflammation
  • Enhance phagocytosis by opsonisation
  • Cause lysis of particles by membrane pore formation
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12
Q

How is the Mannose-binding pathway initiated?

A

When mannose-binding lectin binds to carbohydrates on the pathogen

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13
Q

How is the Alternative pathway initiated?

A

Simple attraction of the early factors to the surfaces of microbes

(bacterial polysaccharides + lipopolysaccharide of the cell envelope of gram-negative bacteria both serve as potent-initiating stimuli)

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14
Q

What is Hereditary Angioedema?

A

PATHOPHYSIOLOGY:
- Autosomal dominant or de novo mutation
- C1 inhibitor deficiency/dysfunction
- Excessive bradykinin -> fluid extravasation into skin & mucosal tissues

SYMPTOMS:
- Cutaneous swelling
- Colicky abdominal pain, vomiting, diarrhoea
- Laryngospasm + airway obstruction

DIAGNOSIS:
- decreased C4 level
- decreased C1 inhibitor protein or function

TREATMENT:
- C1 inhibitor concentrate
- Bradykinin antagonist
- Kallikrein inhibitor

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15
Q

What is the first thing that happens in the acute inflammatory response?

A

Activation of the vascular endothelium in the breached epithelial barrier -> Cytokines + other inflammatory mediators released due to tissue damage induce expression of selectin-type adhesion molecules on the endothelial cells -> Neutrophils first to arrive

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16
Q

What are the steps of Extravasation of phagocytes?

A

1) Rolling phagocytes attach loosely to the endothelium by LOW AFFINITY, SELECTIN-CARBOHYDRATE INTERACTIONS -> E-selectin molecules on endothelium bind to MUCIN-LIKE ADHESION MOLECULES on the phagocyte membrane and bind briefly -> Force of blood flow into area causes cell to detach and reattach repeatedly -> rolls along endothelial surface until stronger binding forces can be found
2) Activation by CHEMO-ATTRACTANTS, Chemokines released in area during inflammation (e.g IL-8, complement split product C5a & N-formyl peptides) bind to receptors on phagocyte surface and trigger a G-PROTEIN-MEDIATED ACTIVATING SIGNAL -> Signal induces a CONFORMATIONAL CHANGE in integrin molecules increasing their affinity for IMMUNOGLOBIN-SUPERFAMILY ADHESION MOLECULES on endothelium
3) Arrest and adhesions interaction between interns and Ig-superfamily cellular adhesion molecules mediate tight binding of phagocyte to endothelial cell + phagocyte movement through extracellular matrix
4) TRANSENDOTHELIAL MIGRATION (phagocyte extends pseudopodia through the vessel wall and extravasates into the tissues)

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16
Q

What happens to Neutrophils whilst in tissues?

A
  • Express increased levels of receptors for chemoattractants
  • Exhibit chemotaxis migrating up a concentration gradient towards the attractant
  • Release chemoattractive factors that call in other phagocytes
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17
Q

What is Leukocyte Adhesion Deficiency?

A

A rare autosomal recessive disease in which there is an absence of CD18, the common B2 chain of a number of integrin molecules -> migration of leukocytes us integrin-mediated cell adhesion -> patient suffer from an inability of their leukocytes to undergo adhesion-dependent migration into sites of inflammation

PATHOPHYSIOLOGY:
- Defect in CD18-containing integrins
- Impaired leukocyte adhesion & endothelial transmigration

SYMPTOMS:
- Skin & mucosal infections without pus formation
- Impaired wound healing
- Delayed umbilical cord separation
- Recurrent chronic bacterial infections

LAB FINDINGS:
- Leukocytosis & Neutrophilia

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18
Q

Where is the origin of Chemokines (IL-8)?

A
  • Tissue mast cells
  • Platelets
  • Neutrophils
  • Monocytes
  • Macrophages
  • Eosinophils
  • Basophils
  • Lymphocytes
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19
Q

Where is the origin of Complement split product C5a?

A

Classical or alternative pathways

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20
Q

Where is the origin of Leukotriene B4?

A

Membrane phospholipids of macrophages, monocytes & mast cells -> Arachidonic acid cascade -> Lipoxygenase pathway

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21
Q

Where is the origin of Formyl Methionyl peptides?

A

Released from microorganisms

22
Q

What is Phagocytosis?

A

When phagocytes ingest and digest particulate debris such as microorganisms, host cellular debris ad activated clotting factors

23
Q

What does Phagocytosis involve?

A
  • Extension of pseudopodia to engulf attached material
  • Fusion of the pseudopodia to trap the material in a phagosome
  • Fusion of the phagosome with a lysosome to create a phagolysosome
  • Digestion
  • Exocytosis of digested contents
24
Q

What is the function of Neutrophils during phagocytosis?

A
  • Release granule contents in which neutrophils die -> forms pus
  • Extrude nuclear contents, histones & neutrophil extracellular traps (NETs) -> Trap + kill pathogens and may damage tissues when enzymes + ROS get released into tissue
25
Q

Which Anaphylatoxins are there?

A
  • C3a
  • C4a
  • C5a
26
Q

Which chemoattractants are there?

A
  • IL-8
  • C5a
  • Leukotriene B4
  • Kallikrein
27
Q

What are the membrane receptors that both macrophages and neutrophils have for antibody and certain complement components?

A
  • Antibody = IgG
  • Certain complement components = C3b
28
Q

What is Opsonisation?

A

When an antigen is coated with opsonins, adherence and phagocytosis is enhanced

[opsonisation = the means by which phagocytosis is enhanced]

29
Q

Describe what happens in Intracellular killing

A

During phagocytosis, “respiratory burst” activates a membrane-bound oxidase that generates oxygen metabolites which are toxic to ingested microorganisms -> two oxygen-dependent mechanisms of intracellular digestion are activated as a result (NADPH oxidase + Myeloperoxidase)

30
Q

Describe what NADPH oxidase does in Intracellular phagocytosis

A

NADPH oxidase reduces oxygen to SUPEROXIDE ANION which generates HYDROXYL RADICALS and HYDROGEN PEROXIDE which are microbicidal

31
Q

Describe what Myeloperoxidase does in Intracellular phagocytosis

A

Myeloperoxidase in the lysosomes acts on HYDROGEN PEROXIDE and CHLORIDE IONS to produce HYPOCHLORITE which is microbicidal -> additionally, NITRIC OXIDE SYNTHASE converted arginine to nitric oxide which as antimicrobial properties

32
Q

Which oxygen-independent degradative materials do the lysosomal contents of phagocytes contain?

A
  • Lysozyme
    [digests bacterial cell walls by cleaving peptidoglycan]
  • Defensins
    [form channels in bacterial cell membranes]
  • Lactoferrin
    [chelates iron]
  • Hydrolytic enzymes
33
Q

During the acute inflammatory response, which pro-inflammatory cytokines are produced?

A
  • IL-1
  • IL-6
  • TNF-alpha

Explanation: These cytokines have systemic effects on the tissues, including fever, production of acute phase proteins and leukocytosis

34
Q

What are the effects of IL-1, IL-6 and TNF-alpha?

A
  • IL-1, IL-6 & TNF-alpha = hypothalamus -> prostaglandins -> fever
  • IL-1, IL-6 & TNF-alpha = Liver -> production of acute-phase proteins (e.g CRP, mannose-binding protein and complement components)
  • IL-1 & TNF-alpha = bone marrow -> leukocytosis
35
Q

What is Chronic Granulomatous Disease?

A

An X-linked recessive deficiency in the production of one of several units of NADPH oxidase which eliminates the phagocyte’s ability to produce many critical oxygen-dependent intracellular metabolites (O2-, -OH, O2 and H2O2). However, the two other intracellular killing mechanisms remain in tact.

PATHOGENESIS
- Impaired respiratory burst & decreased reactive oxygen species -> inhibition of phagocytic intracellular killing

  • Patient infected with Catalase (-ve) organism -> bacteria generate their own H2O2 -> used as a substrate for myeloperoxidase and bacterium is killed
  • Patient infected with Catalase (+ve) organism -> bacteria break down H2O2 -> host cells have no H2O2 to use + myeloperoxidase has no substrate -> RECURRENT INFECTIONS

CLINICAL MANIFESTATIONS
- Recurrent infections with catalase +ve bacteria + fungi
- Lungs, skin, liver, lymph node involvement
- Diffuse granulomas

36
Q

Failure of phagocytic cells to generate oxygen radicals are detected by which tests?

A
  • Nitroblue tetrazolium (NBT) reduction test
    [normal = formazan +ve (purple-blue), abnormal = formazan -ve (yellow)]
  • Neutrophil oxidative index (NOI)
  • Dihydrorhodamine test
37
Q

What is the diagnosis and treatment for Chronic Granulomatous disease (GCD)?

A

DIAGNOSIS
- Measurement of neutrophil superoxide production (DHR flow cytometry + NBT testing)

TREATMENT
- Prophylaxis: TMP-SMX, Itraconazole, Interferon gamma
- Active infection: culture-based, antimicrobial therapy
- Hematopoetic cell transplant is curative

38
Q

What are the 2 major mechanisms for dealing with viral infections?

A
  • IFN-a/b
  • Natural killer cells
39
Q

What are Interferons?

A

A family of eukaryotic cell proteins classified according to the cell of origin. IFN-a and IFN-b are produced by a variety of virus-infected cells.

40
Q

What are the functions of IFN-a and IFN-b?

A
  • Act on target cells to inhibit viral replication (not the virus)
  • Not virus-specific (inhibits viral protein synthesis)
  • Activation of an RNA endonuclease -> digests viral RNA
  • Phosphorylation of protein kinase -> activates elF2 -> inhibits viral protein synthesis
41
Q

What are the functions of interferons collectively?

A
  • Increase in the expression of class I and II MHC molecules and augment NK cell activity
  • Increase the efficiency of presentation of antigens to both cytotoxic and helper cell populations
42
Q

What is the importance of Interferon-a?

A
  • Antiviral activity
  • Used in treatment of hepatitis B and C infections
  • Used to treat hairy B-cell leukaemia, Chronic myelogeous leukaemia and Capos sarcoma
43
Q

What is the importance of Interferon-b?

A

Used to treat multiple sclerosis -> longer periods of remission + reduced severity of relapses

44
Q

What is the importance of Interferon-y?

A

Used to treat Chronic granulomatous disease -> potent inducer of macrophage activation + inflammatory responses -> reverse the CGD patient’s inability to generate toxic oxygen metabolites inside phagocytic cells

45
Q

What are the side effects of IFN therapy?

A
  • Headache
  • Fever
  • Chills
  • Fatigue

Side effects can be managed with ACETAMINOPHEN

46
Q

What are the properties of Natural killer cells?

A
  • Kill virally infected cells and tumour cells
  • Increased in the presence of Interferons a and b and IL-12
  • Share a common early progenitor with T cells but do not develop in the thymus
  • Do not express antigen-specific receptors or CD3
  • Activity doesn’t generate immunologic memory
47
Q

What are the markers used clinically to enumerate NK cells?

A
  • CD16 (FcRg)
  • CD56 (CAM)
48
Q

What are the 2 categories of receptor that NK cells employ?

A
  • Killer activating receptor (KAR)
  • Killer inhibitory receptor (KIR)

Explanation: If only KARs are engaged, the target cells will be killed. If both the KIRs and KARs are ligated, the target cell lives.

49
Q

What is the major KAR expressed by NK cells?

A

NKG2D

50
Q

What are MIC proteins?

A

Stress proteins that are expressed only when cells are infected or undergoing transformation

[Upon binding of KAR to a MIC protein -> NK cells become cytotoxic -> resulting in death of the target cell]

51
Q

How do the KIRs function?

A
  • Activate PROTEIN TYROSINE PHOSPHATASES which inhibit intracellular signalling and activation by removing tyrosine residues from various signalling molecules
  • Bind to HLA-E (specialised type of MHC class I antigens) -> HLA-E bind to HLA-A, B and C -> during viral infections/transformed cells, the amount of class I HLA expression may be decreased, preventing leader sequences from binding to HLA-E -> decrease expression of HLA-E and make cells susceptible to NK mediated killing
52
Q

What happens when NK cells are activated through the FcR (CD16)?

A

Only one signal is required because the antibody signals that there is an active infection -> occur through a mechanism called antibody-dependent cell-mediated cytotoxicity (ADCC)

53
Q
A

IMMUNOLOGY (6 decks)

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