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Immunity Flashcards

1
Q

Key milestones in immunology?

A

Edward Jenner - Late 18th Century:
Cowpox conferred protection against smallpox.

Robert Koch - 19th Century:
Infectious disease caused by microorganisms. Hypersensitivity reaction.

Louis Pasteur - 19th Century:
Fowl cholera vaccine and rabies vaccine.

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2
Q

What does an immune system do?

A

Recognise and respond to problems, including infection, invasion or altered self.

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3
Q

Broad outline of what happens in infection?

A
  1. Prevent invasion or colonisation
  2. Limit early proliferation and dissemination
  3. Restrict growth post spread
  4. Kill or control pathogen
  5. Clearance
  6. Offer enhanced resistance to rechallenge
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4
Q

Evidence for anti-microbial mechanisms in bacteria and protozoa?

A
  1. Bacteria
    1. Restriction enzymes
      Target specific non self nucleic acid sequences. Can be induced and may confer resistance to bacteriophages.
    2. CRISPR-Cas systems
      Clustered regularly interspersed short palindromic repeat. Uses RNA guides to target foreign sequences
  2. Protozoa
    1. Induction of intracellular antiviral/bacterial mechanisms
    2. The ability to kill vacuolar organisms by production of reactive oxygen species
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5
Q

Conserved basic requirements of immunity in multi-cellular animals?

A
  1. Allows survival of an individual in the face of loss of cells
  2. Used to develop specialised cellular functions
  3. Development of new sites for pathogen exploitation
  4. As complexity increases, new problems emerge of protection of surfaces and body fluids.
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6
Q

Basic process of immune engagement?

A
  1. Detection
    Pattern recognition (self and microbial)
    Initiates and directs response
  2. Response
    Innate
    Adaptive
  3. Outcome of response
    Pathogen removal/killing
    Control without removal (persistence)
    Pathology (most is self induced)
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7
Q

Which organisms have innate immunity or adaptive immunity?

A

Innate immunity features in all organisms.

Adaptive immunity emerged in the vertebrates.

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8
Q

Key features of adaptive immunity?

A

Adaptive immunity responses are faster the second time around.

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9
Q

Key features of the innate immune system?

A
  1. Barriers
    Mechanical (epithelial cell layers)
    Chemical barriers (mucus, enzymes, pH, oils, antimicrobial peptides)
    Microbiological (enteric microflora)
    *consider induced (part of immune response) vs constitutive (both resistance)*
  2. Tissue fluid systems
    Complement cascades
    Coagulation cascades
    Iron binding molecules
  3. Cellular systems
    Phagocytic cells (macrophages and neutrophils)
    Lytic cells (natural killer cells)
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10
Q

What is the complement cascade?

A

A plasma based enzyme cascade.

  1. Formation of deposits on microbial surface
  2. Lytic membrane attacks complex
  3. Marking surface to assist interaction with immune cells
  4. Elements have chemotactic activity
  5. Used as an effector for both innate and adaptive pathways
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11
Q

What is the coagulation cascade?

A
  1. Traps microbes
  2. Stops blood loss and initiates wound repair to re-establish a barrier
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12
Q

What are iron binding molecules used for in innate immunity?

A

Compete with bacteria for iron, slowing bacterial growth

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13
Q

What are the different complement cascades/pathways?

A

Classical (adaptive), Lectin (innate) and Alternative (innate).

Same results: microbial lysis and enhanced phagocytosis.

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14
Q

What are the receptors used by the innate immune system?

A

Lectins, Toll like receptors and NOD like receptors.

Genomically encoded in their effective configuration. Most animals have 100-200 different receptors. Each expressed at high freq.

Soluble, trans membrane and cytoplasmic location.

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15
Q

What are the receptors used by the adaptive immune response?

A

Antibodies, B and T cell receptors.

They are formed by rearrangement of genomic segments, meaning there is a huge repertoire available (>108 different specificities per person). Each receptor is clonally expressed on very few cells until stimulated.

Soluble or cell surface receptors.

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16
Q

What are the pattern recognition receptors (PRRs)?

A

Respond to Pathogen Associated Molecular Patterns (PAMPs).

Diverse family of PRRs:

  1. Mannose binding lectin in tissue fluid
  2. Toll like receptors which are transmembrane
  3. NOD1 and NOD2 which are cytoplasmic
  4. Cell associated PRR strong inducers of NFkB translocation to the nucleus
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17
Q

Example of a toll like receptor?

A

TLR-5 homodimer agonist is Flagellin (protein in flagellum), which helps the cell to recognise gram negative bacteria.
The activation of this receptor mobilizes the nuclear factor NF-κB (controls DNA transcription) and stimulates tumor necrosis factor-alpha (inflammatory cytokine produced by macrophages/monocytes during acute inflammation and is responsible for a diverse range of signalling events within cells, leading to necrosis or apoptosis) production.

TLR-3 homodimer agonist is dsDNA which helps the cell to recognise viral RNAs/

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18
Q

Describe a macrophage?

A

Innate immune system.

Functions:

  1. Phagocytosis and intracellular killing
  2. Release of proinflammatory cytokines
  3. Antigen presentation
  4. Tissue repair
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19
Q

Describe a dendritic cell?

A

Part of innate immune system.

Antigen uptake in peripheral sites, and presents in lymph nodes.

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20
Q

Describe a neutrophil?

A

Part of innate immunity.

Functions:

  1. Phagocytosis
  2. Intracellular killing
  3. Inflammation and tissue damage
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21
Q

Describe an eosinophil?

A

Part of innate immune system.

Functions:

  1. Killing of antibody coated parasites
  2. Tissue damage
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22
Q

Describe a natural killer cell?

A

Part of adaptive immune system.

Releases lytic granules that kill some virus infected cells.

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23
Q

Comparison of phagocytes?

A
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24
Q

Example of some microbicidal agents produced/released by phagocytes?

A

Competitiors for Iron - Lactoferrin binds Fe

Toxic nitrogen oxides - Nitric oxide

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25
Q

Define cytokine?

A

Soluble mediatior produced by cells.

Any of a number of substances, such as interferon, interleukin, and growth factors, which are secreted by certain cells of the immune system and have an effect on other cells.

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26
Q

Define interleukin?

A

Soluble mediator produced by white blood cells.

Any of a class of glycoproteins produced by leucocytes for regulating immune responses.

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27
Q

Define Interferon?

A

Soluble mediator that can induce a state that interferes with viral replication.

A protein released by animal cells, usually in response to the entry of a virus, which has the property of inhibiting virus replication.

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28
Q

Define tumour necrosis factor?

A

A cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction.

29
Q

Define tumour growth factor?

A

One of several proteins secreted by transformed cells that can stimulate the growth of normal cells.

30
Q

Define chemokine?

A

Small chemotactic molecules.

Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.

31
Q

Define antimicrobial peptide?

A

Small antimicrobial molecule.

Small molecular weight proteins with broad spectrum of anti-microbialactivity against bacteria, viruses, and fungi.

32
Q

Features of adaptive immune systems?

A
  1. Immense diversity afforded by alteration of genomic sequence.
  2. Alterations in repertoire according to circumstance
  3. Memory
  4. Solutions include the TCR and BCR (in jawed vertebrates) and the VLR (jawless fish)
33
Q

Describe antibodies?

A

Have heavy and light chains.

Exist in two forms:

  1. Secreted by B cells
  2. Membrane bound (B cell receptor)

Recognise diverse products - proteins or carbohydrates.

Epitopes can be linear or conformational. A linear or a sequential epitope is an epitope that is recognized by antibodies by its linear sequence of amino acids, or primary structure. In contrast, most antibodiesrecognize a conformational epitope that has a specific three-dimensional shape and its protein structure.

34
Q

Describe T cell receptors?

A

Always a membrane bound heterodimer.

TCRaß and TCRyð

TCRaß recognise linear peptides in context of a presentation complex called MHC

35
Q

What is the MHC?

A

Major Histocompatability Complex.

Set of cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates, which in turn determines histocompatibility. The main function of MHC molecules is to bind to antigens derived from pathogens and display them on the cell surface for recognition by the appropriate T-cells.

36
Q

What is the epitope?

A

The specific part of the antigen involved in recognition.

37
Q

Definition of antigenic or immunogenic?

A

A molecule capable of stimulating a specific adaptive response.

38
Q

How do T cells form such a diverse repertoire?

A

Anticipatory repertoires are generated by rearrangemetn with junctional modification.

In TCRa or TCRy:
One of the V regions, one of the J regions and a C (constant) region. (Gene regions).

In TCRß and TCRð: 
A D (diversity) region inserts between the V & J region.

Nucleotide modification also occurs at the VJ or VDJ junctions. This is known as the CDR3 region (important for peptide/MHC recognition).

39
Q

How does the RAG complex initiate rearrangement of T cell receptor genes?

A

RAG1 and RAG2 and “high mobility group proteins” bind to the RSS motifs (recombination signal sequence).

The two RAG1/RAG2 complexes bind to each other and bring the V region adjacent to the DJ region.

The recombinase complex makes single stranded nicks in the DNA. The nicks are sealed to form a hairpin structure at the end of the V and D regions (effectively closing them off with no end).

DNA-K, Ku, Artemis and DNA ligase are incorporated into a large complex with RAG proteins, forming a signal joint. This closed circle of DNA has no further function.

The hairpin structures are cleaved at the end of V & D regions. TdT is recruited, adding additional nucleotides to the end of the DNA strand. Complementary bases anneal. The other bases are removed, and then DNA polymerases fill in the gaps with complementary nucleotides. Other enzymes in the complex ligate together the ends of the segments, completing the process.

Beta cells also undergo V(D)J recombination.

40
Q

What are the different components of antibodies?

A
  1. The antigen binding Fab fragment (two in each)
  2. The Fc region which recruits other molecules or is bound to cells expressing the Fc receptor
41
Q

Mechanisms of antibodies?

A
  1. Block function (bind to important molecules on the pathogen)
  2. Agglutination (stick pathogens together)
  3. Activate complement
  4. Opsonise (Fc is recognised by receptors on cells)
42
Q

What is antibody dependent cell-mediated cytotoxicity?

A

Mechanism of cell mediated immune defense where an effector cell of the immune system actively lyses a target cell, whose membrane surface antigens have been bound by specific antibodies.

One of the mechanisms which uses antibodies to limit and contain infection.

Requires an effector cell which is classically known to be a nautral killer cell which typically interacts with IgG antibodies. Macrophages, neutrophils and eosinophils can also mediate ADCC.

Part of the adaptive immune response due to its dependence on prior antibody response.

43
Q

What is a TCR co-receptor?

A

The signal from the T-cell complex is enchanced by simultaneous binding of the MHC molecules by a specific co-receptor.

On Helper T cells and Regulatory T cells this co-receptor is CD4 that is specific for MHC class II

On Cytotoxic T cells this co-receptor is CD8 that is specific for MHC class I.

44
Q

How are CD4 and CD8 T Cells divided?

A

By the cytokines that they produce.

Both can perform cytotoxicity but CD8+ T cells are more effective.

CD4 cells help B cells make antibodies and help macrophages become activated. Can also recruit neutrophils to down regulate T cell responses.

45
Q

How are T helper cell subsets defined?

A

By the cytokines that they produce.

46
Q

What are pAPCs?

A

Professional Antigen Presenting Cells. Constitutively express MHC Class I and II.

47
Q

Interactions between dendritic cells and T cells?

A

The only cell to stimulate naïve T cells.

48
Q

Interactions between macrophages and T cells?

A

Macrophages are active scavengers. Their activity is increased by interaction with CD4+ T cells.

49
Q

Interactions between B and T cells?

A

Interactions with CD4+ T cells are needed for efficient maturation and antibody production.

50
Q

Which MHC classes sample where?

A

MHC Class I pathway samples cytoplasm – endogenous. Constitutively expressed by most cells in body.
MHC Class II pathway samples the extracellular compartment – exogenous. Constitutively expressed on restricted set of cells (pAPCs).

51
Q

Antigen presenting pathway for MHC Class I?

A 
Intracellular. MHC Class I molecules are assembled in the ER and consist of two types of chain. The heavy chain is stabilised by the chaperone *calnexin*. Tapsin interacts with the transport protein TAP (associated with antigen presentation) which translocates peptides from the cytoplasm into the ER. These peptides are derived from the degradation of proteins (viral or self-origin). TAP translocates peptides of 8-16 amino acids.
30-70% of proteins are immediately degraded after synthesis (DRiPs – defective ribosomal products as a result of defective transcription or translation). This process allows viral peptides to be presented very quickly.
When peptides bind to MHC Class I molecules, the chaperones are released and peptide-MHC class I complexes leave the ER for presentation at the cell surface.
Sometimes peptides fail to associate with MCH Class I and they are returned to the cytosol for degradation. Some MHC Class I molecules never bind peptides and they are also degraded by the ER associated protein degradation system (ERAD).
On the surface of a single cell, MHC class I molecules provide a readout of the expression level of up to 10,000 proteins.
Interaction occurs between the CD8+ molecule on the surface of the T cell and non-peptide binding regions on the MHC class I molecule. There is also an interaction between the T cell receptor and a peptide bound to the MHC class I molecule.
52
Q

Antigen presenting pathway for MHC Class II?

A

Extracellular. MHC Class II molecules are expressed by APCs such as dendritic cells, macrophages and B cells. MHC Class II complexes consist of a- and b- chains that are assembled in the ER and are stabilised by invariant chain (a polypeptide).
MHC Class II molecules bind to peptides that are derived from proteins degraded in the endocytic pathway.
The complex of MHC Class II and the invariant chain is transported through the Golgi into a compartment – the MHC Class II Compartment (MIIC). Due to the acidic pH, proteases are activated and digest the invariant chain, leaving a residual CLIP in the peptide binding groove of the MHC Class II. The CLIP is later exchanged for an antigenic peptide derived from a protein degraded in the endosomal pathway. This process requires the chaperone HLA-DM.
MHC Class II molecules loaded with foreign peptide are then transported to the cell membrane to present their cargo to CD4+ cells.
The process now follows the same as MHC Class I.

53
Q

Difference between mature and immature dendritic cells?

A
  • Immature: In most tissues, take up and process antigen. Activate PRR.
  • Mature: Don’t take up microbes. Migration to lymphoid organs and present antigen to naïve T cells. MHC I & II high. Cytokine production.
  • After presentation and activation of lymphocytes, cells undergo apoptosis
54
Q

What factors affect the immune protection of an individual?

A
  • Immune capability (genetics, age, sex, health)
  • Nutrition
  • Intercurrent infection (occurs during the progress of another disease)
  • Prior infection or vaccination
55
Q

Which receptors recognise viruses?

A

TLR3 recognises dsDNA
TLR4 recognises RSV surface glycoproteins
TLR7/8 recognises ssRNA
RIG-1 recognises dsRNA and cytoplasm

56
Q

Which receptors recognise bacteria?

A

TLR1/6 with 2 recognise cell wall components
TLR4 recognises Lipopolysaccharides
TLR9 recognises DNA with unmethylated CpG motifs
NODs recognise cytoplasmic cell wall elements

57
Q

Define parasite?

A

An organism which lives in or on another organism (its host) and benefits by deriving nutrients at the other’s expense.

58
Q

Which receptors recognise parasites?

A

TLR2 recognises GPI anchors
TLR4 recognises polymorphisms which may affect the disease outcome

59
Q

What happens in the early induced response of inflammation?

A

Pathogen entry triggers complement activation. Cellular PRR activation with production of cytokines and chemokines. The tissue resident macrophages play a central role. The epithelium of the blood vessels are altered to allow for increased permeability. Proteins and fluids move out of the blood cells (vasodilation).
Redness, heat and swelling occurs. Migration of inflammatory cells into tissue leading to an escalation of the inflammatory response. Pain occurs.
The dendritic cells get activated and leave the tissue, maturing and entering the lymph nodes. Proliferation of lymphocytes leads to swelling of the lymph node.
Migration of the lymphocytes, which leave the node and move to the area of inflammation, which can occur due to signals released.
This full response takes 7-14 days.

60
Q

How do dendritic cells activate T cells?

A

They act as antigen presenting cells in the lymph node. Exogenous antigens enter the MHC Class II pathway. Activate helper T cells and killer T cells as well as B cells by presenting them with antigens derived from the pathogen, alongside non-antigen specific costimulatory signals.
Only pAPCs are able to activate a resting helper T cell when the matching antigen is presented.
In non-lymphoid organs, macrophages and B cells can only activate memory T cells whereas dendritic cells can activate both memory and naïve T cells (most potent of all the APCs).
In lymphoid organs, all three cell types can activate naïve T cells.
Formation of CD8+ memory T cells requires the interaction of dendritic cells with CD4+ helper T cells. This help from CD4+ T cells licenses the matured dendritic cells to efficiently induce CD8+ memory T cells, as have taken up antigens exogenously in the MHC Class II pathway. For this activation of dendritic cells, concurrent interaction of all three cell types, namely CD4+ T helper cells, CD8+ T cells and dendritic cells, seems to be required.

61
Q

What is the cognate interaction?

A

Cell interaction that is specific for the same antigen. Can be a relationship between antibody and T cell specificity. The CD4 T cell can trigger antibody production.

62
Q

How do CD4 T cells and macrophages interact?

A

Macrophages can kill pathogens and then present antigens directly to CD4+ T cells. The T cells can release IFNy which activates macrophages to kill more efficiently and produce TNFa.

63
Q

Key facts of the immunological memory?

A

The population of specific cells is larger.
Easier to activate – there is an earlier commitment to effector status. Migration patterns also differ – the immune cells are less focussed on lymph nodes and migrate through tissues. Produced by different tissues in the body so changes the chemokine receptors to recognise those expressed in non-lymphoid tissues.

64
Q

Example of immunological memory?

A

Measles in the Faroe Islands. In 1781 there was a measles outbreak. 1782-1845 there was a measles free period of 63 years. In 1846 there was a 2nd outbreak of measles with 70% incidence.
Of all those living on the Faroes who had measles in 1781 were immune to measles in the 2nd outbreak.
Long term immune memory without continuous exposure.

65
Q

What is the quick hit strategy?

A

Avoiding the adaptive immune response by getting in and out of the host quickly.

66
Q

Integration of immune mechanisms in pathogen killing?

A

Plasmodium falciparum.
Different immune mechanisms target different parts of the life cycle. Innate and adaptive responses are both important.
Has a complex life cycle with both invertebrate and vertebrate host. Causes cerebral malaria.

In the mosquito…
Immune responses – PRR, production of nitric oxide, enzymes, antimicrobial peptides. Mosquitos are most effective with their immune systems at disrupting malaria development during ookinete invasion of the midgut.

In the human…
Mosquito infects and triggers PRR. Sporozoites travel through the blood to the liver in a matter of hours, meaning antibodies don’t have long enough to develop.
Over 2 weeks, the Sporozoites develop into schizonts. During this time Natural Killer cells have a minor effect. By entering the hepatocytes, the Sporozoites are protected against antibodies.
Hepatocytes express MHC Class I. This is because the parasite exists in a specialist vacuole but some molecules get translocated into the cytoplasm.
Exit the liver (as merozoites) when the CD8+ response is becoming effective. These are antigenically distinct from Sporozoites, so the anti-sporozoite antibody doesn’t react.
Parasite enters Red Blood Cells and replicates. The RBC hasn’t got MHCs on its surface so no direct recognition from T cells or antibody.
Damaged cells give a brief exposure to extracellular environment when the schizont ruptures so antibodies could attack. These damaged red blood cells are cleared efficiently in the spleen by macrophages! CD4+ T cells help antibodies and activated splenic macrophages.
Malaria expresses proteins on the surface of the RBC – Pf-EMPs. These stop the sick RBCs from circulating through the spleen, avoiding removal. However, these Pf-EMPs can be targeted by antibodies. To avoid clearance, there are lots of copies of these in the parasite genome which it switches between – antigenic variation.
Subsequent infections are less severe as all of the life cycle can be targeted by adaptive immune mechanisms: Anti-sporozoite antibody, CD8+ T cells, CD4+ T cells and Anti-Pf-EMP antibodies.

67
Q

How do vaccinations work?

A

Antigen from the pathogen stimulate T and B cells, and induce memory.
An adjuvant is a substance that is added to a vaccine to increase the body’s immune response to the vaccine. Stimulates PRRs.

68
Q

Types of vaccine?

A 
Live vaccines: attenuated pathogen or related pathogen
Dead vaccines (need adjuvant): whole killed pathogen or subunit
Vectored vaccines: sub unit delivery using a live carrier or DNA
69
Q

Consequences of immune deficiency:

A

Red – lacks innate response
Green – lacks T and B cells
Yellow – normal response

Cells & Genes (25 decks)

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