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MICI 2100 > Lec 17-Humoral Immunity: Cytokines, Antibodies, And Complement > Flashcards

Lec 17-Humoral Immunity: Cytokines, Antibodies, And Complement Flashcards

1
Q

What is humoral immunity?

A
  • Part of immune sys—B lymphocytes
  • Mediated by macromolecs in blood or lymphatic system in extracellular fluids i.e. antibodies, complement proteins, antimicrobial peptides
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2
Q

Humoral immunity as a line of defence can be compared to:

A

Can be compared to weapons that innate and adaptive immunity use

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3
Q

Antibodies are specific to what kind of immunity?

A

Adaptive

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4
Q

Complement are specific to what kind of immunity?

A

Innate

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5
Q

Cytokines and chemokines are specific to what kind of immunity?

A

Innate AND adaptive

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6
Q

What are cytokines?

A
  • Molecules of WBCs (leukocytes)
  • The ligand of immune cells
  • Small protein
  • Allow immune sys cells to communicate
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7
Q

Job of cytokines is to

A

Connects immune sys cells so they can communicate

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8
Q

What are chemokines?

A
  • Similar to cytokines
  • A bit smaller, a bit more evolutionarily ancient
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9
Q

Differences between cytokines and chemokines (2)

A
  • Cytokines are bigger than chemokines
  • Each family of cytokines has a specific receptor, whereas chemokines only have one type of receptor
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10
Q

Cytokines interacting with receptor induces what responses (3):

A
  • Can induce signalling—intracellular cascade causes an immune outcome
  • Can induce migration of immune cell
  • Can cause changes in expression of adhesion molecules and chemokines receptors on target membrane
  • Can signal cell to proliferate, differentiate, survive, or die
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11
Q

Sensitivity of target cell to a specific cytokine is determined by:

A

Presence of certain cytokine receptors

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12
Q

How big are cytokines?

A

Small, 5-20 kDa

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13
Q

Where are cytokines?

A

Cytokines are mainly secreted, but some of them are membrane bound so they require cell-to-cell interaction to activate

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14
Q

3 actions of cytokines:

A

Endocrine, paracrine, autocrine

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15
Q

Endocrine action of cytokines

A

Cytokine is produced by immune cells and is released into bloodstream to reach cells throughout the body (distal effect)

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16
Q

Paracrine action of cytokines

A

Molecule that is secreted has a short effect, can only produce signal in a neighbouring cell

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17
Q

Autocrine action of cytokines

A

Cells produce ligand for itself, the molecule is released but then binds to the cell that secreted it

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18
Q

Are most cytokines soluble proteins?

A

Yes

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19
Q

How does solubility impact cytokines?

A

Cytokines that are soluble can travel long distances, and stop on the cell with their specific receptor to induce signal. Cytokines that are not soluble are membrane bound (eg. TNF family)

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20
Q

Pleiotropic cytokines

A
  • Can have multiple effects
  • One cytokine can act on diff cells, and in each cell triggers a specific signal with a defined immune outcome
  • Eg. Active T-helper cells secrete IL-4 which goes to multiple cells to result in diff outcome in each cell
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21
Q

Redundant cytokines

A
  • One cell producing more than one type of cytokines that all bind to the same target cell to produce the same effect in that cell
  • Eg. CD4 T-helper cell secretes IL-2, 4, and 5 all to go to the same B cell
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22
Q

Antagonist cytokines

A
  • Antagonistic effect
  • One cell produces 2 cytokines, one with an activating function and the other with an inhibitory function
  • Eg. Activated T-helper cell produces IL-4 and IFN which both bind to B cell with opposite effects
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23
Q

Synergy cytokines

A
  • Two or more cytokines work together to bind to the same target cell to induce an effect
  • Eg. Activated T-helper secretes IL-4 and 5 work together to impact B cell
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24
Q

Difference between redundancy and synergy

A

Redundancy: 1+ cytokines all secrete and bind to target, each one induces identical effect
Synergy: 2+ cytokines secrete and bind to target, need eachother/work together to produce an effect

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25
Q

Cytokine grouping based on?

A
  • Cytokines are grouped based on their target receptors
  • When they target these receptors, they trigger specific signalling
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26
Q

6 major cytokine families:

A

Interleukin (IL)-1 family, hematopoletin family, interferon family, tumor necrosis family, interleukin (IL)-17 family, chemokines

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27
Q

Why is variability in antennae of receptor important?

A

Variability in receptor allows us to modulate signalling—diff target can respond in diff way. Receptors need to have dimers/multi dimers which gives the cell time to respond gradually to a signal

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28
Q

Chemokines structure

A
  • Small, 7.5-12.5 kDa
  • One type of receptor only—they are GPCR receptors
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29
Q

GPCR structure

A

Transmembrane proteins, span it many times. Have intracellular signalling with a/b/Y subunits (you know about this already)

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30
Q

One major function of chemokines:

A

Call immune cells to infection site

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31
Q

How do other immune cells respond to cytokines being made?

A

Other immune cells move toward places where chemokines are highly concentrated

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32
Q

Examples of cytokine-related diseases

A

Septic shock, bacterial toxic shock, rheumatoid arthritis, T2 diabetes, lymphoid and myeloid cancer, H1N1, SARS and SARS-CoV-2

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33
Q

How do cytokines result in increased disease states

A

Increase in inflammatory cytokine levels

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34
Q

What is cytokine-based therapy for?

A

If cytokine levels are related to disease, therapies can reduce cytokine levels to treat disease

35
Q

Therapy for rheumatoid arthritis

A
  • Arthritis is an autoimmune inflammatory disease
  • TNF (an inflammatory cytokine) causes it
  • Injection of Enbrel, a soluble TNF receptor, absorbs the circulating TNF, reducing the levels
36
Q

Therapy for MS

A
  • Injecting IFN receptors takes up INF to reduce levels
37
Q

Therapy to prevent transplant rejection

A
  • Monoclonal antibodies act against chain of IL-2
  • Blocks receptors so cytokine cannot bind and there is no immune response induced against foreign organ
38
Q

Signal transduction in immune cells

A
  • Cytokines and chemokines are mostly soluble
  • Cytokines need to dimerize to activate signalling, chemokines only are one type of receptor
  • Once the cytokine reaches the receptor, intracellular signalling is activated
  • This allows immune signalling so immune cells can do what cytokines are signalling for it to do
39
Q

What are antigens?

A

Substances that react with antibodies or T-cell receptors (TCRs)

40
Q

What is an immunogen?

A

Substances that induce an immune response, can trigger activation of immune cell

41
Q

Are all antigens immunogens?

A

No

42
Q

How do B cells activate antibodies?

A

B-cell receptors activate antibodies. Every BCR is unique, and can recognize a different antigen

43
Q

What INTRINSIC factors determine immunogenicity/affect ability to trigger immune response?

A
  1. Size—small molecs i.e. haptens, are not immunogens
  2. Complexity—complex proteins/carbs are good immunogens, ones with simple repeating units i.e. DNA are not
  3. Physical form—insoluble molecules or aggregates are usually better immunogens
44
Q

What EXTRINSIC factors determine immunogenicity/affect ability to trigger immune response?

A
  1. Dose—larger doses (mg/g) are better than small, but note that if dose is too large it may cause immunotolerance
  2. Route—injection is typically more effective than oral exposure
45
Q

What does activation of BCR do?

A

Activates B cell, B cell makes antibodies

46
Q

What is an epitope/their significance?

A

Antibodies and BCRs struggle to interact with the large size of antigenic molecules, so they interact with small portions of it called epitopes. An antibody is specific to an the epitope of an antigen.

47
Q

Where can antibodies recognize epitopes?

A

Antibodies can recognize epitopes on sugars, AAs, or other orgo molecules (anywhere with a large complex structure)

48
Q

What does antigen need to be associated with?

A

MHC 2

49
Q

Difference between T-cell and B-cell recognition (MHC)

A

Because antigens need to be associated with MHC to be recognized by T-cell receptors, TCRs can only recognize short peptide sequences

T-cells and B-cells can recognize the same antigen/epitope but T-cells need the MHC2

50
Q

BCR vs TCR

A
  • BCRs are Y shaped, TCRs are straight
  • Bubbles on the sides of BCRs are immunoglobulins (IgM), which are important for interaction of antibody with antigen. They are flexible structures, allowing the antigen to fit onto the receptor
  • TCRs also have some IgM domains but not as many as BCRs. They are heterodimers with alpha and beta domains
51
Q

What helps with efficiency of neutralization?

A

Groove of BCR is able to recognize diff epitopes on the same antigen due to its flexibility—important for neutralization, able to get rid of antigens faster

52
Q

How does B-cell activation work?

A

B-cells are interacting with multiple BCRs at the same time (each BCR on a diff epitope), triggering a signal transduction that activates the B-cell to produce antibodies

53
Q

Affinity and avidity

A
  • Affinity: Measures strength of interaction between epitope and an antibody’s antigen binding site
  • Avidity: Gives measure of overall strength of an antibody-antigen complex, depends on: affinity of antibody for epitope, valency of antibody and antigen, and structural arrangement of parts that interact.
  • High avidity is better than high affinity bc how long antibody stays and how well it can fit into the space (valency) are also taken into account
54
Q

What characterizes efficacy/specificity of an antibody?

A

Affinity and avidity

55
Q

Describe valency—which type is better?

A

A receptor with only one binding site is univalent. The structure of most antibodies we produce has 2 binding sites (bivalent), so interaction of these with epitope has more chances for antibody to bind

56
Q

Hydrophilic/hydrophobic domains of BCR

A

BCRs all have 2 chains joined together.
- Memb-bound form of BCR: Need hydrophobic domain that sticks it in PM
- Secreted form of BCR (antibody): Can’t be hydrophobic or it won’t be soluble in circulation, is fully hydrophilic
BCR common feature is a groove compatible with a specific antigen, allows B cell to produce antibodies

57
Q

2 effects of BCR binding to epitope

A

BCR binds to epitope of antigen. BCR-antigen complex is internalized, phagosome gets processed, activating intracellular signalling which causes 2 things:
1. BCR divide to become plasma cells that will make proteins to target antibody
2. Antigen chewed up in phagosome get presented as MHCII on surface of active B cell, active B cell will activate T cell to initiate cellular response and also form memory B cell

58
Q

Structure of BCR

A

Shape is formed by 2 chains—heavy and light.

N-terminus (Fab) part is variable, forms the groove for interaction. Has a heavy and a light chain. N-terminus on the same cell can change in sequence and structure over time to recognize antigen with more avidity/affinity.

C-terminus (Fc) has effector function, bc the heavy chains can be recognized by receptors on innate immune cells. It then activates adaptive immunity to produce antibodies that coat pathogen. Coating enhances innate immunity (pos feedback)

59
Q

5 antibody classes that B cells can produce

A
  • All are encoded in heavy chain constant region
    IgG: Bivalent, similar structure to D and E. Have 2 exposed groups, heavy chains bind to eachother to make antibody more soluble
    IgM: 5 repeating units joined by C-terminus of endchains, very balanced but so big that it can cause transient interactions which can be problematic in neutralizing antigen. First antibody that B-cells produce when theyre activated!!!!! Its just not as efficient so it needs the others
    IgA: More balanced, is dimerized through J-chains, therefore has 4 grooves
    IgE: Refer IgG
    IgD: Refer IgG
60
Q

What is antibody type determined by?

A

Type of antibody is mainly determined by sequence of constant region. Constant region can trigger activation of other immune receptors, stimulating more innate immunity

61
Q

Antibody function against parasites

A

Antibody can be triggered against parasites, when they stick onto parasites it flags the parasite. This allows other cells to see the heavy chain and prepare for elimination of parasite

62
Q
  1. Opsonization for phagocytosis
A

Macrophage has FC receptors. When bacteria is surrounded by antibody, its constant region is sticking out which is a target for FC. Macrophages can see bacteria due to sugar coat on outside, and they bind to heavy chain which triggers phagocytosis and elimination of pathogen

63
Q
  1. Fix complement
A

Complement is a protein on the wall of protein. When antibody binds to pathogen and interacts thru heavy chain to complement, it stabilizes the complement allowing for a MAC (membrane attack complex) attack and fast lysis of pathogen

64
Q
  1. Block attachment
A

Viruses like to enter using natural pore/receptor of cell body. When antibody is surrounding a target viral molec, it prevents attachment and invasion of virus to target

65
Q
  1. Neutralize toxins
A

Pathogens i.e. bacteria can produce toxins. If antibodies recognize these toxins as an epitope, they surround molec and let toxin precipitate so it cant enter our cell

66
Q

IgG

A
  • 70-75% of total Ig pool
  • FIRST RELEASED DURING SECOND INFECTION—cell now knows that IgM is not the most efficient and this one has been trained to be better during first infection
  • Gamma (Y) gene
  • Monomer
  • Most efficient
  • Fixes complement, opsonizes, blocks attachment
  • Can pass thru placenta to provide immunity to developing fetus
  • Without, IgG, we would be severely immune compromised with agammaglobulinemia
67
Q

IgM

A
  • 10% of gene pool
  • mu (u) gene
  • FIRST ONE TO BE RELEASED IN FIRST TIME ENCOUNTERING
  • Pentamer—good valency, not great effinity
  • Can fix complement, block attachment
  • Not good at opsonization
  • Don’t last long
68
Q

IgA

A
  • Dimer
  • Alpha (a) gene
  • 15% of total Ig pool
  • Secretory (mucus, tears, milk)
  • Good at blocking attachment
  • Not good at fixing complement or opsonizing
69
Q

IgE

A
  • Very low levels
  • Epsilon (E) gene
  • Produced during allergic rxn
  • Bind to FC receptors on mast cell—>can bind to allergen to produce mast cell rxn
  • No good for 4 main functions
70
Q

IgD

A
  • Monomer
  • Delta (d) gene
  • Surface attachment
  • Enhance B cell activation
  • No info on other functions
71
Q

Gene organization for antibodies

A

5 antibody classes are each encoded by a specific gene. Genes to encode them are clustered in the same region of the genome. The gene sequence allows for variability so we can respond to all possible antigens

72
Q

4 functions of antibody

A
  1. Opsonization for phagocytosis
  2. Fix complement
  3. Block attachment
  4. Neutralize toxins

**Antibodies DO NOT kill

73
Q

Somatic recombination process

A
  • Happens in BCR and TCR
    For BCR:
  • Different genes encode Variable region, Diversity region, Joining region, and Constant region
  • Heavy chain has VDJC, light chain has VJC
  • When B cell is activated, genomic region where these 4 genes are sitting is chopped. Cell chooses which V, D, J, C genes they want to get rid of/keep
  • Genomic region now has less DNA, only keeps what the cell wants to make the antibody
  • Once gene has been reorganized, transcription starts to make antibody with a particular polypeptide chain to make the best possible antibody for that specific antigen
74
Q

Number of genes for light chain and heavy chain of BCR

A

Light chain is encoded by K and lambda genes
- Variable: 40 K genes, 30 lambda genes
- Diversity: 0 K genes, 0 lambda genes
- Joining: 5 K genes, 4 lambda genes

Heavy chain made by H genes
- Variable: 40 H genes
- Diversity: 25 H genes
- Joining: 6 H genes

Gives cell a lot of possibilities for gene

75
Q

Somatic hypermutation

A
  • In B cells only
  • FDJC region has high rate of mutation
  • Differences in polymorphism occur when cell divides bc this is the region that determines intensity of interaction between epitope and BCR. Mutations make groove a different shape, increasing diversity of epitopes that can bind
  • Affects D region ONLY
76
Q

Modifications that B cell makes when it makes an antibody

A
  1. Class switch (Ig’s): by choosing gene that encodes constant region of heavy chain
  2. Somatic recombination
  3. Somatic hypermutation
77
Q

TCR gene regions

A
  • TCR has alpha and beta chain with immunoglobulin receptors. A and B chain have a Variable and Constant region
  • V region shapes groove so TCR can recognize antigen with best affinity so it can quickly create memory T cell and go clean up infection
78
Q

Number of genes for immunoglobulin and TCRs

A

Immunoglobulin made of H and K+lambda genes
- Variable segments: 40 H genes, 70 K+lambda genes
- Diversity segments: 25 H genes, 0 K+lambda genes

TCRS made of B and A genes
- Variable segments: 52 B genes, -70 A genes
- Diversity segments: 2 B genes, 0 A genes

79
Q

What is the complement system?

A
  • Bind to surface of microbes to induce death
  • Circulate inactive—activate in reponse to pathogen
  • In vertebrates
  • Consists of 11 proteins (A, C1-9, and D) that are secreted by liver into circulation
  • 3 cascades for complement activation: Classical, mannose-binding lectin-mediated, and alternative
80
Q

Classical pathway

A
  • Complement protein C1 recognizes antibody on pathogen and binds to antibody
  • C1 calls C2 and C4. C2 and C4 are cleaved and form C3 convertase complex
  • C3 convertase calls C3 to complex and breaks it into C3A and C3B. C3B joins C3 convertase to make C5 convertase complex
  • Once C3B joins, it promotes opsonization and clearance of pathogen. C3A acts as cytokine, has inflammatory function, recruits immune cells
  • C5 complex calls C5 proteins to start formation of MEK complex (formation of pore on pathogen wall so water can enter pathogenic cell and kill it)
81
Q

Lectin pathway

A
  • MBL protein recognizes lectin on yeast and binds
  • Binding calls C2 and C4. C2 and C4 are cleaved and form C3 convertase complex
  • C3 convertase calls C3 to complex and breaks it into C3A and C3B. C3B joins C3 convertase to make C5 convertase complex
  • Once C3B joins, it promotes opsonization and clearance of pathogen. C3A acts as cytokine, has inflammatory property, recruits immune cells
  • C5 complex calls C5 proteins to start formation of MEK complex (formation of pore on pathogen wall so water can enter pathogenic cell and kill it)
82
Q

Alternative pathway

A
  • Spontaneous C3 hydrolysis into C3A and C3B
  • C3B joins C3 convertase to make C5 convertase complex
  • Once C3B joins, it promotes opsonization and clearance of pathogen. C3A acts as cytokine, has inflammatory property, recruits immune cells
  • C5 complex calls C5 proteins to start formation of MEK complex (formation of pore on pathogen wall so water can enter pathogenic cell and kill it).
83
Q

Humoral vs cell-mediated immunity

A

Humoral:
- Activated by B-cells
- Produces antigen-specific antibodies

Cell-mediated:
- Activated by T-cells
- Does not involve antibodies. Instead is activation of phagocytes, cytotoxic T cells, and cytokine release

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