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Flashcards in I3 - Innate Immunity Deck (48):
1

What is a receptor?

a structure on the surface of a cell (or inside a cell) that selectively receives and binds a specific substance

2

What is a ligand?

Any molecule that binds to another, in normal usage a soluble molecule, such as a hormone or neurotransmitter, that binds to a receptor

3

What is an Opsonin?

An antibody or product of complement activation in blood serum that causes bacteria or other foreign cells to become more susceptible to the action of phagocytes.

4

What is phagocytosis?

Endocytosis of particulate material, such as microorganisms or cell fragments

5

What is inflammation?

A response of body tissues to injury or irritation; characterized by pain, swelling, redness and heat

6

What are the immune responses to pathogens?

Innate Immunity Acquired Immunity

7

What is innate immunity?

Immunity that is naturally present and is not due to prior sensitization to an antigen from, for example, an infection or vaccination.

  • Rapid first response to an infection
  • Non-specific
  • Recognition of Pathogen Associated Molecular Patterns (PAMPs)
  • Mediated by natural barriers, soluble and cellular components
  • No immunological memory 

8

What are the natural barriers of the innate immune system?

  • Skin
  • Mucosal epithelium (+/- cilia)
  • Acidic pH in stomach and vagina
  • Lysoyme in tears and other secretions
  • Commensual bacteria in gut, skin etc
  • Cough and sneeze
  • Vomiting and diarrhoea
  • Flushing of bladder

9

What is microbial antagonism?

Normal bacterial flora of the body suppress the growth of potentially pathogenic bacteria and fungi 

•Previous occupancy confers a physical advantage

•Compete for essential nutrients

•Produce inhibitors  eg acid or colicins

10

What are colicins?

Colicins are bactericidins that bind to the negatively charged surface of susceptible bacteria forming a voltage-dep channel in the membrane which kills the cell

11

What are the pathogen recognition receptors?

PRRs include

•Toll-like receptors (TLRs)

•NOD-like receptors (NLRs)

•RIG-I-like receptors (RLRs)

These recognise PAMPs - Pathogen Associated Molecular Patterns

 

12

What is the role of Toll-Like Receptors?

Key part of the innate immune system, recognise PAMPs - Rare or absent in hosts (discriminate self versus non-self). DC activation by TLRs is crucial for APC function

Activation stimulates the innate responses of immune cells to these threats

In vertebrates, also stimulate activation of the adaptive immune system,

Link innate and acquired immune responses

11 family members known in humans

13

Explain the TLR (Toll-Like Receptor) signalling pathway

There is a change in activation status - TLR becomes phosphorylated, linker protein MyD88... (signal transduction pathway)... binds in nucleus, activates

-Interferons and inflammatory cytokines 

14

What are the soluble components of the innate immune system

Cytokines

Chemokines

The Complement System

15

What are CYTOKINES?

A group of low molecular weight regulatory proteins, secreted by white blood cells and various other cells in response to inducing stimuli. 

They regulate the INTENSITY and DURATION of the immune response by:

  • stimulating or inhibiting the activation, proliferation, and/or differentiation of various cells
  • regulating the secretion of antibodies or other cytokines

16

Give examples of Cytokines

INTERFERONS (IFN)

Important in limiting the spread of viral infections (protect uninfected cells)

  • IFN-A and B - produced by virus-infected cells
  • IFN-gamma - produced by activated T cells
  • IFN-lambda - IL-28a and b and IL-29

INTERLEUKINS (IL-)

Large group of cytokines, produced by T CELLS (some produced by macrophages (IL-1), mainly involved in directing other cells to divide and differentiate.

 

17

Discuss cytokine signalling activities

IFNa and b act through a signalling cascade upon virus-infected cells, IFNgamma acts upon infected T Cells to give virus resistant cells. 

(some viruses are treated with interferons - Hep C)

18

What are CHEMOKINES?

A family of structurally related small glycoproteins, involved in potent leukocyte activation and/or chemotactic activity.

4 subgroups, classification based on juxtaposition of amino terminal cysteine residues:

•CXC chemokines (α-chemokines) - Most attract neutrophils

•CC chemokines (β –chemokines) - Attract monocytes, lymphocytes, basophils, and eosinophils

•C chemokine (lymphotactin) - Attracts lymphocytes

•C-X3-C chemokine (fractalkine) - Induces adhesion and migration of leukocytes

(nb. CXC - cysteine, amino acid, cysteine etc)

Chemokines are ligands which bind to chemokine receptors - this is how their activity is mediated. 

19

Give examples of CHEMOKINES

IL-8 - (CXCL8) Neutrophil chemoattraction

RANTES (CCL5) - Regulated upon activation, normal T cell expressed and secreted. Eosinophil and monocyte chemoattraction

MIP-1α (CCL3) - Macrophage inflammatory protein 1α. Monocytes, lymphocyte, eosinophil chemoattraction

20

What is the COMPLEMENT SYSTEM?

A series of proteins (about 26) circulating in the blood and bathing the fluids surrounding tissues. They circulate in an inactive form, and become seqentially activated in response to the recognition of molecular components of microorganisms.

Complement cascade = binding of one protein promotes the binding of the next protein in the cascade. 

21

What are the functions of the complement system?

  • Making bacteria more susceptible to phagocytosis (opsonization)
  • directly lyses some bacteria and foreign cells
  • produces chemotactic substances that mediate inflammation
  • Increases vascular permeability (to get access, cells need to be able to migrate out of blood across epithelium)
  • Causes smooth muscle contraction promoting mast cell degranulation 

22

Briefly, what are the main functions of the complement system?

Lysis 

Chemotaxis

Opsonization

23

What are the complement system pathways?

THREE PATHWAYS

Classical - activated by antigen-antibody complexes

Alternate - activated by C3b binding to microbial surfaces and anitbody molecules

Lectin - Activated by lectin binding to MANNOSE of pathogen surface

24

What activates the CLASSICAL pathway in the complement system?

Antigen-antibody complexes

25

What activates the ALTERNATE pathway in the complement system?

C3b binding to microbial surfaces and antibody molecules

26

What activates the LECTIN pathway in the complement system?

Lectin binding to mannose on the pathogen surface

27

What do the complement pathways lead to?

Production of MAC - Membrane Attack Complex and direct lysis of bacteria.

28

What are the innate immune cells?

Granulocytes -Neutrophil, Eosinophils, Basophils

Natural Killer Cells (NK)

Monocyte/Macrophages

Dendritic Cell (DC)

29

What are neutrophils?

Make up 90% of granulocytes in the blood

Short lived (2-3 days)

Multilobed nucleus

Phagocyte activity associated with granules - attack and destroy microbe or virus infected cells.

Control the inflammation process by up or down regulation (depending on cytokines and chemokines secreted - if proinflammatory will upregulate, if antiinflammatory will down regulate).

30

What are the three types of granules in neutrophils?

Azurophil (myeloperoxidase, lysozyme, defensins)

Specific (lysozyme, lactoferrin, collagenase)

Small Storage (gelatinase, plasminogen activator)

31

What is diapedesis?

Leukocyte extravasation - the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection

 

  • Chemoattraction - Circulating leukocytes are localised towards the site of injury or infection due to the presence of chemokines.
  • Rolling adhesion - Like velcro, carbohydrate ligands on the circulating leukocytes bind to selectin molecules on the inner wall of the vessel, with marginal affinity. This causes the leukocytes to slow down and begin rolling along the inner surface of the vessel wall. During this rolling motion, transitory bonds are formed and broken between selectins and their ligands.
  • Tight adhesion - chemokines released by macrophages activate the rolling leukocytes and cause surface integrin molecules to switch from the default low-affinity state to a high-affinity state. Causes immobilisation of the leukocytes
  • Endothelial transmigration - The cytoskeletons of the leukocytes are reorganised in such a way that the leukocytes are spread out over the endothelial cells. In this form, leukocytes extend pseudopodia and pass through gaps between endothelial cells. Transmigration of the leukocyte occurs as PECAM proteins, found on the leukocyte and endothelial cell surfaces, interact and effectively pull the cell through the endothelium. Once through the endothelium, the leukocyte must penetrate the basement membrane. The mechanism for penetration is disputed, but may involve proteolytic digestion of the membrane, mechanical force, or both.[3] The entire process of blood vessel escape is known as diapedesis. Once in the interstitial fluid, leukocytes migrate along a chemotactic gradient towards the site of injury or infection.

32

What are monocytes?

Specialized migrating phagocytic cells found in the bloodstream

6-16 day lifespan

Differentiate into macrophages upon entry to other tissues.

33

Where are macrophages found?

Brain (microglial cells)

Lungs (dust cells – alveolar macrophages)

Liver (Kupffer cells)

Spleen

Lymph nodes

Joints

Peritoneum

34

What are the functions of macrophages?

  • Phagocytosis and destruction of pathogens and syngeneic tumours
  • Removal of dead cells (homeostasis)
  • Presentation of antigens to lymphocytes (“professional” antigen presenting cells (APCs))
  • Secretion of immune-modulating and effector molecules - a wide range of cytokines and complement proteins

35

What induces phagocytosis?

Receptors on the surface of these cells can recognise and  bind pathogen associated molecular patterns (PAMPS) on bacterial, viral, fungal and parasitic cell surfaces 

36

What are natural killer cells?

Large granular lymphocytes of the innate immune system

Involved in early defenses against

–allogeneic (nonself)

–autologous cells undergoing various forms of stress: infection with viruses, bacteria or parasites and malignant transformation.

•Act by means of …

–direct cytotoxic attack on their targets

–producing a large array of cytokines and chemokines

•contributes to initiation of the antigen-specific immune response

•an important link between innate and adaptive immunity.

37

How to Natural Killer Cells act?

–direct cytotoxic attack on their targets

–producing a large array of cytokines and chemokines

•contributes to initiation of the antigen-specific immune response

•an important link between innate and adaptive immunity.

38

Describe NK cell-mediated lysis

NK receptor engagement facilitates discrimination between targets and non-targets

(important in case of viruses, will want to destroy some self cells)

When viruses attack, down regulate cells like MHC class 1 cells, no longer can inhibit the reaction, destroys self cells

39

How to NKs block infection by viruses?

By producing interferons  which block virus infection

 

 

40

What are Eosinophils?

•2-5% granulocytes in normal blood (higher in allergic or parasitic diseases)

•Bilobed nucleus and many cytoplasmic granules

•Granules stain red with eosin (hence name)

•Granules contain many molecules including,

acid phosphatase, glucuronidase, cathepsins, ribonuclease, arylsulfatase, peroxidase and major basic protein. 

41

What are the functions of Eosinophils?

•Specialized role in immunity to parasites

•Combat antigenic challenges too big to be attacked by phagocytes

–degranulate in presence of opsonised parasites

–external digestion of parasite

•Down-regulate immune responses by destroying histamine

•Phagocytose and kill ingested microorganisms (secondary role)

42

What are Basophils?

<1% white blood cells

•Characterised by deep violet-blue granules

 

43

What are the functions of basophils?

Immune functions poorly understood

–Severe allergy?

–Protection against parasitic infections?

•High affinity Fc receptor for IgE

•Granules contain a number of molecules that are released upon degranulation, e.g.,

–Heparin

–Histamine

44

What are DENDRITIC CELLS?

What are the difference between immature and mature DCs?

•Derived from myeloid and lymphoid progenitor cells

–Myeloid DC

–Plasmocytoid DC

•Immature DCs found at body surfaces and interstitial spaces

–ovoid shape

–active and efficient endocytosis

–no antigen presentation

–migrate to secondary lymphoid tissues where maturation occurs

•Mature DCs

–numerous dendrites

–reduced/loss of antigen capture capacity

–increased surface expression of MHC molecules and co-stimulatory molecules

–maturation completed upon interaction with T cells

45

What are the differences between immature and mature DCs in terms of function?

When in the peripheral, sentinel cells waiting for stimulation by pathogens. In immature state – capable of phagocytotic ingestion. When become activated and ingested, will move to nearest draining lymph node, then will mature into APCs, INDUCE THE ADAPTIVE IMMUNE RESONSE.

When mature, can’t phagocytose, become excellent at antigen presentation.

46

What are the functions of Dendritic Cells?

•Most efficient APCs

•DC maturation is crucial for initiation of immunity

•Present antigens by …

–MHC I complexes to CD8+ T cells

–MHC II complexes to CD4+ T cells

•Major source of many cytokines

–IFN-α, IL-1, IL-6, IL-7, IL-12 and IL-15 

47

How to dendritic cells mature with time?

48

How does a dendritic cell interact with a leukocyte?