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BS32009 > Cytokine Concepts and the Complement Pathway > Flashcards

Cytokine Concepts and the Complement Pathway Flashcards

1
Q

What are cells of the innate immune system?

A

Neutrophils, macrophages, dendritic cells, natural killer (NK) cells, eosinophils, complement system

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2
Q

Cells of the adaptive immune system?

A

T cells: T helper cells (Th) and Cytotoxic T lymphocytes (CTL)
B cells (produce antibodies)

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3
Q

Main role of the adaptive immune system?

A

Differentiates between self and non-self
Slow, highly specific response
Memory to previously encountered antigens

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4
Q

Main role of the innate immune system?

A

Detects danger
Rapid, generic response
Communicates danger to adaptive immune system

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5
Q

What are the 2 types of danger signals for the innate system?

A

PAMPs and DAMPs (recognised by PRRs)

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6
Q

What is ‘negative selection’?

A

Developing adaptive immune cells that react to ‘self’ molecules will be deleted, so that only functioning mature adaptive immune cells remain

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7
Q

How many complement pathways are there, and what are they?

A

3:
Classical
Mannose-binding lectin
Alternative

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8
Q

What is the complement system?

A

Series of soluble proteins in the blood: C1-C9

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9
Q

What are the 3 possible outcomes of the complement pathway?

A

Anaphylotoxins (inflammation)
Membrane attack complex (lysis)
Opsonisation

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10
Q

What is the classical pathway?

A

Only occurs when there are antibodies present specific to a foreign antigen.
Antibody complexes on bacteria are bound by complement component C1q > activates component C3

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11
Q

What is the mannose-binding lectin pathway?

A

Activation through mannose-binding lectin (mannose isn’t present on the surface of host cells)
Activates complement component C3

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12
Q

What is the alternative pathway?

A

Complement component C3 suddenly activates and binds to nearby membranes
Host cells have control proteins that prevent further compliment activation - bacteria do not
C3 is activated by hydrolysis
Alternative pathway can amplify other already active pathways

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13
Q

What is complement lysis?

A

Membrane attack complex (MAC) forms in the membrane of bacteria - a barrel-like structure formed from multiple complement components (C6/C9)
This allows water to rush in, ions out, the bacteria swells and bursts

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14
Q

What is opsonisation?

A

Marks cells for phagocytosis
Membrane bound complement components (ie C3b) bind to the surface of bacteria
Phagocytes have Complement Receptors which bind membrane-bound complement
Encourages phagocytosis and killing (ie macrophage engulfs the membrane bound bacterium > lysosome fuses with phagosome to create a phagolysosome and destroy bacteria)

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15
Q

What is complement anaphylotoxins?

A

Fragments of complement components (C5a, C3a) are released on complement activation
Anaphylotoxins are toxins that can cause anaphylaxis
Fragments can act on epithelium to cause oedema (makes blood vessels leaky) > recruitment of immune cells > activation of mast cells (release histamine)

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16
Q

5 different classes of cytokines

A

Chemokines (cause cells to move)
Interleukins
Interferons
TNF family
TGF superfamily

17
Q

What are the 4 chemokine groups and what are they based on?

A

Can have homeostatic or inflammatory effects on leukocyte migration
4 groups based on position of cysteine residues that mediate disulphide bridge formation in 3D structure:
XCL - binds to XCR receptors
2 genes (lymphotactin-1 and -2)

CCL - binds to CCR receptors
27 genes (CCL1-CCL28, CCL9=CCL10)

CXCL - binds to CXCR receptors
17 genes (CXCL1-17)

CX3CL - binds to CX3CR receptors
1 gene (fractalkine)

The chemokine-receptor cell moves up the chemokine gradient to the chemokine producing cell

18
Q

Chemokines in the lymph node

A

T cells express CCR7 > mediates migration to T cell area > secrete ligands CCL19 and CCL21
B cells express CCR7 + CXCR5 > migrate to B cell area > secrete ligand CXCL13

19
Q

Inflammatory cytokine IL-1beta and TNF-alpha

A

Induce blood vessels to become more permeable, enabling effector cells and fluid containing soluble effector molecules enter infected tissue > inflammation at site of infection

20
Q

Inflammatory cytokine IL-6

A

Induces fat and muscle cells to metabolise, make heat and raise the temperature in the infected tissue > inflammation

21
Q

Inflammatory cytokine CXCL8

A

Recruits neutrophils from blood and guides them to infected tissue > inflammation

22
Q

Inflammatory cytokine IL-12

A

Recruits and activates natural killer (NK) cells that secrete cytokines that strengthen the macrophages response to infection > inflammation

23
Q

Cytokine receptor families

A

Type 1 Cytokine Receptor
IL-2, IL-6, IL-12
Dimeric
JAK/STAT signalling

Type 2 cytokine receptor
IL-10, IFNs
Dimeric
JAK/STAT signalling

TNF receptor family
TNF
Trimeric
NFkappaB/MAPK signalling

IL-1 receptor family
IL-1, IL-33
Has Ig domains
NFKB/MAPK signalling

TGF receptor family
TGF-beta
SMAD signalling

Chemokine receptors
7 transmembrane domains
G protein coupled signalling

24
Q

Which two interleukins can bind to and signal through the same receptor?

A

IL-4 and IL-13 (thus, both have to be blocked to generate an effect)

25
Q

IL2Rgammac receptor (common gamma chain) subunit is required for which interleukin receptors?

A

IL-2, IL-4 IL-7, IL-9, IL-13, IL-15, IL-21

26
Q

What is the process of cytokine release? Any exceptions?

A

In the moment transcription and translation of cytokine genes
Closely regulated at transcription, mRNA stability and translation
Cytokines are made with a pro-sequence (signal peptide) that allows their transport to the ER and their subsequent secretion via secretory vesicles

Exceptions: IL-1beta and TNF
IL-1beta requires inflammasome
TNF is initially expressed as a plasma membrane protein, but requires cleavage by the protease TACE (Adam17) to release the mature TNF cytokine

27
Q

Systemic effects of cytokine release on the hypothalamus, liver, and bone marrow?

A

IL-1, IL-6, TNF
Hypothalamus: fever
Liver: actute phase protein production (complement components, c-reactive protein, etc)

IL-6, TNF, G-CSF
Bone marrow: increased production of immune cells

28
Q

What are the 3 signals required to activate and differentiate a CD4+ T helper cell response?

A

Signal 1: Antigen presentation on MHC class II molecules on antigen presenting cells (APC), recognised by T cell receptor (TCR) of naive CD4 T cell

Signal 2: Costimulation - dendritic cells activated through PRRs upregulate surface receptors which ligate T cell surface receptors

Signal 3: Polarisation - in response to cytokines secreted by APC or other nearby immune cells, the Th cell will polarise to take on specific characteristics

29
Q

What effect do the following cytokines have on a naive CD4 T cell: IL-12, TGFbeta + IL-6, IL-4, TGF-beta?

A

IL-12: Th1
TGFbeta + IL-6: Th17
IL-4: Th2
TGF-beta: Treg immunosuppressive

30
Q

What is the effect of the following T helper cells: Th1, Th2, Th17, Treg?

A

Th1 > produces IFNgamma > activates macrophages > phagocytose and kill bacteria

Th2 > produces IL-4, IL-5, IL-13 > B cell IgE production (allergies), mucous secretion, eosinophilia

Th17 > produces IL-17, GM-CSF > highly inflammatory, recruit/stimulate production of neutrophils

Treg > produces TGF-beta, IL-10 > immunosuppressive (anti-inflammatory)

31
Q

Result of mutations in Th2 cytokines (eg IL-13)?

A

Increased risk of asthma
Anti IL-4 and IL-13 therapies don’t work
Anti IL-4-Ra (the receptor subunit) does work

32
Q

Result of mutations in Th1/Th17 cytokines?

A

Increased risk of inflammatory bowel disease

33
Q

Development of anti-TNF therapy?

A

Binds to TNF and blocks its ability to stimulate cells
First: Infleximab, used human IgG1 constant region but mouse variable region (body would eventually recognise mouse as non-self)
Second: Adamilumab, fully human IgG1 antibody
Third: Etanercept, human IgG1 Fc + human TNFR2 ectodomain

Approved for rheumatoid arthritis, psoriasis, Psoriatic Arthritis, Crohn’s disease, ulcerative colitis

BS32009 (8 decks)

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