Cytokine Concepts and the Complement Pathway Flashcards
What are cells of the innate immune system?
Neutrophils, macrophages, dendritic cells, natural killer (NK) cells, eosinophils, complement system
Cells of the adaptive immune system?
T cells: T helper cells (Th) and Cytotoxic T lymphocytes (CTL)
B cells (produce antibodies)
Main role of the adaptive immune system?
Differentiates between self and non-self
Slow, highly specific response
Memory to previously encountered antigens
Main role of the innate immune system?
Detects danger
Rapid, generic response
Communicates danger to adaptive immune system
What are the 2 types of danger signals for the innate system?
PAMPs and DAMPs (recognised by PRRs)
What is ‘negative selection’?
Developing adaptive immune cells that react to ‘self’ molecules will be deleted, so that only functioning mature adaptive immune cells remain
How many complement pathways are there, and what are they?
3:
Classical
Mannose-binding lectin
Alternative
What is the complement system?
Series of soluble proteins in the blood: C1-C9
What are the 3 possible outcomes of the complement pathway?
Anaphylotoxins (inflammation)
Membrane attack complex (lysis)
Opsonisation
What is the classical pathway?
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
What is the mannose-binding lectin pathway?
Activation through mannose-binding lectin (mannose isn’t present on the surface of host cells)
Activates complement component C3
What is the alternative pathway?
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
What is complement lysis?
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
What is opsonisation?
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)
What is complement anaphylotoxins?
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)
5 different classes of cytokines
Chemokines (cause cells to move)
Interleukins
Interferons
TNF family
TGF superfamily
What are the 4 chemokine groups and what are they based on?
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
Chemokines in the lymph node
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
Inflammatory cytokine IL-1beta and TNF-alpha
Induce blood vessels to become more permeable, enabling effector cells and fluid containing soluble effector molecules enter infected tissue > inflammation at site of infection
Inflammatory cytokine IL-6
Induces fat and muscle cells to metabolise, make heat and raise the temperature in the infected tissue > inflammation
Inflammatory cytokine CXCL8
Recruits neutrophils from blood and guides them to infected tissue > inflammation
Inflammatory cytokine IL-12
Recruits and activates natural killer (NK) cells that secrete cytokines that strengthen the macrophages response to infection > inflammation
Cytokine receptor families
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
Which two interleukins can bind to and signal through the same receptor?
IL-4 and IL-13 (thus, both have to be blocked to generate an effect)
IL2Rgammac receptor (common gamma chain) subunit is required for which interleukin receptors?
IL-2, IL-4 IL-7, IL-9, IL-13, IL-15, IL-21
What is the process of cytokine release? Any exceptions?
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
Systemic effects of cytokine release on the hypothalamus, liver, and bone marrow?
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
What are the 3 signals required to activate and differentiate a CD4+ T helper cell response?
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
What effect do the following cytokines have on a naive CD4 T cell: IL-12, TGFbeta + IL-6, IL-4, TGF-beta?
IL-12: Th1
TGFbeta + IL-6: Th17
IL-4: Th2
TGF-beta: Treg immunosuppressive
What is the effect of the following T helper cells: Th1, Th2, Th17, Treg?
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)
Result of mutations in Th2 cytokines (eg IL-13)?
Increased risk of asthma
Anti IL-4 and IL-13 therapies don’t work
Anti IL-4-Ra (the receptor subunit) does work
Result of mutations in Th1/Th17 cytokines?
Increased risk of inflammatory bowel disease
Development of anti-TNF therapy?
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
