Epithelial barriers, phagocytes, dendritic cells, NKs and the complement system
How fast does the innate immune system react?
In 12hrs after infection.
What are the main differences between innate and adaptive immune system?
The innate immune system only reacts to a few conserved structures (PAMPs) because the receptors are limited and germline encoded. Furthermore, it does not have a memory.
What are acute phase proteins?
Complement activating opsonins that are induced by TNFa, IL1 and IL6. Examples are C-reactive protein and mannose-binding lectin
Which of the cytokines has a direct antiviral effect?
IFN alpha and beta (type 1 interferons)
Which pathways are there for complement activation?
The classical pathway, in which an antibody binds an antigen, the alternative pathway, working without previous antigen-binding and the lectin-pathway, which requires mannose-binding lectin
How does complement activation work?
If either one of the three pathways takes place, C3 dissembles into C3a (causing inflammation) and C3b (opsonizing the microbe). This causes C5 to dissemble. In final steps, this leads to formation of the membrane-attack complex from C9.
What effects have type 1 interferons, next to being antiviral?
degrade viral mRNA, increase MHC1 expression and increase toxicity of NKs and CTLs
Which actions can the three polymorphonuclear granulocytes carry out?
Neutrophils kill phagocytosed and extracellular microbes, eosinophils kill large extracellular microbes and basophils recruit immune cells.
What is required for degranulation of eosinophils?
IgE-Ag complex and C5a
Which of the three polymorphonuclear granulocytes are important in allergy?
Which cytokines can be produced by Macrophages and DCs?
TNFa, IL1, IL6, IL8, IL12
How does killing of microbes by phagocytosis take place?
The microbe binds to receptors and is taken up. Then a phagolysosome is formed, killing the microbes by NO and ROS formation.
How does opsonisation work?
Phagocytes contain receptors for antibodies and C3b. When encountered, phagocytosis is much more efficient.
Which cytokines are produced by NK cells?
IFNy in response to IL12
What effects do MHC1 receptors have on NK cells?
If there are MHC1 receptors on a cell, killing by NKs is inhibited.
Which compounds are found in granules of NKs and what effects do they have?
Perforin, causing lysis
granzymes, causing apoptosis
How can cells be killed by NKs when they are stressed?
Usually, MHC1 leads to phosphate removal on activating ligands like MIC-A, but if a cell is stressed, expression of activating ligands may be upregulated, resulting in inefficient inhibition
How does leukocyte recruitment take place?
TNFa and IL1 cause the expression of E-selectin on endothelial cells, causing leukocytes to start rolling on the membrane. They are then activated by IL8 and TNFa, IL1 and IFNy cause firm attachment by integrins.
Name examples for PRRs.
TLRs, NLRs, RLRs
Name examples for PAMPs and receptors that recognize them.
LPS (TLR4 using CD14 and MD2)
LTA (TLR2+TLR6, also using CD14 and CD36)
dsRNA (TLR3 with CD14)
bacterial DNA (TLR9 via granulin)
Which cytokines are typical for a Th1 immune response?
IFNy for activation and secretion
Which cytokines are typical for a Th17 immune response?
IL6 and TGFb for activation
IL17A, IL17F and IL22 upon secretion
Which cytokines are typical for a Th2 immune response?
IL4 for activation
IL4, IL5 and IL13 upon secretion
Which cytokines are typical for a Treg immune response?
TGFb for activation
What are the structural differences between MHC1 and MHC2?
MHC 1 has a much longer alpha strand (1-3) and only one small beta, while MHC2 has one alpha and one beta. Also only the alpha strand of MHC1 is in contact with the membrane, while both are at MHC2
What does HLA stand for?
Human Leukocyte Antigen
What is encoded by "MHCIII"?
Some complement proteins and cytokines
How many different MHC molecules are there?
6 for MHC1 and 12 for MHC2
What is the difference between the MHC1 and MHC2 pathway?
MHC2 presents molecules that have been endocytosed, while MHC1 does so with peptides in the cytosol. MHC2 is assembled in an endosome, MHC1 goes via the ER and golgi
What are CLIPs?
MHCII associated invariant peptides
Peptides in the MHCs that need to be removed by HLA-DM before antigens can bind
What is unique about DCs?
They can present foreign antigens on MHC1 for CD8+ recognition
Which molecules are expressed by DCs when mature?
IL12, B7, ICAM-1
Which receptors are involved in activation of T-cells by DCs?
MHC1, B7 and CD28
Which cytokine is important in self-activation of CD4+ cells?
What is CD40 important for?
T-cell activation induces CD40L, which binds CD40 on an APC, leading to B7 expression on the APC
What happens during the different stages of lymphocyte maturation?
Pro-lymphocate: initiation of antigen receptor rearrangement
Pre-lymphocyte: selection of cells with antigen receptors
Immature lymphocyte: selection of functional competence
Mature lymphocyte: initial responders
Differentiated effector cell
Which mechanisms are important for receptor diversity?
Multiple germline V genes
Recombination of VJ and VDJ
Recombination of Heavy and Light Chains
N and P nucleotide addition
What is unique in BCR diversity?
It is also influenced by somatic hypermutation
Which enzyme causes somatic hypermutation?
Activation induced cytidine deaminase
Which cells promote isotype switching?
Th cells (CD40L-CD40)
Which cytokines cause isotype switching?
IFNy causes IgG
IL4 causes IgE
TGFb causes IgA
Which hypersensitivity reactions are there?
Immune complex deposition
How can Mastcells be triggered?
Via complement or IgE cross-linking
How does signal transduction in mastcells take place?
IgE activates protein tyrosine kinases and then the MAP cascade.
Name immediate symptoms of allergy.
What is typical for the inflammation of a late phase allergic response?
Many eosinophils can be found.
What is BAT?
Basophil activation test: free antibodies are removed from blood and allergen is added. Then measure release of histamine by basophils.
What is IBH?
Insect bite hypersensitivity, a disease of horses
When is an anaphylactic shock probable?
When the allergen enters the blood stream.
Which types of desensibilisation are there?
Standard and lymphatic injection (faster)
How does desensibilisation work?
Tregs are induced that produce IL10, which leads to more production of IgG4 by By4 instead of IgE by Be
How does selection in the thymus take place?
Does the cell bind MHC? If yes -> selected
Does the cell bind a self antigen? If no -> selected
Which cells are selected to be Tregs?
The ones displaying a relatively high avidity for MHC and self peptide
What are the mechanisms for B cell tolerance?
Receptor editing if too strong binding for self antigen in bone marrow
If the binding is still too strong, deletion takes place
Cells that bind self antigens weakly undergo anergy
What happens when anergy is induced?
CTLA-4 or another inhibiting peptide is upregulated
Signals are blocked
How does CTLA-4 work?
It binds to B7 in a stronger manner than CD28, thus inactivating signals
With which mechanisms can Tregs suppress the immune system?
Secretion of IL10, TGFb and IL35, causing cell cycle arrest
Consumption of IL2, causing apoptosis
Galectin-mediated cell cycle arrest
How can Tregs suppress DCs?
Decrease costimulation with CD39 and CTLA4
Decrease antigen presentation with Nrp1 and LAG3
Which cytokines cause suppression of Treg function?
IL2 and IL6
Which factor is important in DC activation?
NF kappa b
Which are the most important accessory proteins for TLR4?
CD14 and MD2
How can C-type lectins bind molecules?
Sugars in a Ca2+ dependent manner (Type 1) and proteins and lipids in a Ca2+ independent manner (Type 2)
Name examples for Type 1 and Type 2 C-type lectins.
MMR and DEC-205 are Type 1
Dectin 1 (with ITAM motif) and DC-SIGN are Type 2
Which C-type lectins are important in endocytosis?
DC-SIGN and MMR
Which role do C-type lectins play in tolerance?
If a CTL is triggered without costimulation of a TLR, tolerance is induced. This may also happen if the antigens trigger the CTL so much that the signal overrules the TLR signal
Which CTLs have an effect on TLR signalling?
Dectin-1 (together with TLR2) has a enhancing effect, DC-SIGN has a suppressing effect
What is special about the CTLs DC-SIGN and MMR?
They can also be present as soluble "antibodies"
What is the difference between canonical and non-canonical pathway in NF kappa b signalling (in short)?
The canonical pathway works via RELA and p50, the non-canonical works via RELB, p100 and p52
What causes different gene activation patterns?
Acetylation and phosphorilation of both RELA and histones
What is Raf-1?
A MAP-kinase that modulates TLR signalling via DC-SIGN
Which compounds can inhibit NF kappa b?
Aspirin inhibits binding of p50/RELA to S26
PS341 cyclosporin inhibits p52/RELB complex
FK506 inhibits p50/RELA movement to the nucleus
What are effects of Bcl-2?
Which intracellular factors are typical for Th1 cells?
STAT4, STAT1 and Tbet
Which intracellular factors are typical for Th2 cells?
STAT 6 and GATA-3
Which intracellular factors are typical for Th17 cells?
STAT3 and RORyt
What effect has schistosoma mansoni on naive T cells?
it shifts them to a Th2 phenotype via omega-1
What are Tfh cells?
Follicular helpercells that reside in lymph nodes and induce antibody production via IL-4 and IFNy
How does the Th9 pathway work?
In the presence of TGFb and IL4, Th2 cells may switch to Th9, producing IL9. This induces antigen independent proliferation and IgG and IgE production, stimulate mast cells and eosinophils.
Which cytokines are characteristic for a Th22 response?
IL6 and TNFa upon activation, then IL22, IL13 and TNFa
What happens if GATA-1 is activated?
IL4, IL5 and IL13 production, leading to immunity against extracellular pathogens
This takes place when encountering IL4 and IL33
What happens if Tbet is activated?
TNFy production, leading to immunity against intracellular pathogens
This happens when IL12 and IFNy are encountered
What happens when FoxP is activated?
IL10 and TGFb production, leading to tolerance and immunosuppression
This happens when encountering TGFb
What happens if Bcl6 is activated?
IL21 and antibody production
This happens when IL6 and IL21 are encountered
What happens if AHR is activated?
IL22 production, leading to tissue regeneration
This happens when encountering IL6 and TNFa
What happens if RORyt is activated?
IL17A, IL17F and IL22 are produced, leading to extracellular immunity
IL23, IL6 and TGFb trigger this response
What happens if PU1 is activated?
Production of IL9, causing allergy
IL4 and TGFb trigger this response
Which immune cells are most important in tumor immunity?
What are tumor antigens?
Antigens mainly present on tumor cells. They can be
- products of mutated genes
- overexpressed proteins
- specific for differentiated tissues
- peptides of oncogenic virusses
How can tumor cells escape the immune system?
Which sorts of immunotherapy are there for cancer?
Passive: treatment with tumor secretions
Active: treatment with tumor infiltrating lymphocytes
Which role does CTLA4 play in tumor immunity?
It suppresses immunity by interacting with B7. An anti-CTLA-4-antibody can reduce this effect
What is PD-L1?
A receptor upregulated in inflamed tissue, which in combination with PD-1 in tumor cells induces T-cell inhibition
What are CAR Tcells?
Chimeric antigen receptor T cells, which express an epitope for the NY-ESO-1 antigen (commonly found in breast/testis tumors)
Which types of anti-tumor-vaccines exist?
purified tumor antigens
professional APC-based vaccines
cytokine/costimulator enhanced vaccines
In which ways can antigens be presented to the immune system by the gut?
By MHC on epithelial cells
By DCs and Macrophages that reach into the gut lumen
Via M cells
What is special about DCs in the gut?
They can drive Treg differentiation from FoxP- cells
Which cells play a role in inducing Tregs in the gut?
Which forms of tolerance can be induced in the gut?
Tolerance via Tregs in low doses
Tolerance via anergy/depletion in high doses
What effect does retinoic acid have?
It promotes tolerance via CD103 DCs
It enhances TGF driven formation of FoxP cells
It synergizes with IL5 and 6 to promote class switching to IgA
It induces expression of the gut homing receptor CCR9
What is AhR important for?
Arylhydrocarbon receptors are important for a working immune system in the gut. It is activated by e.g. dietary compounds which leads to IL22 production in the cryptopatches.
Which cells are most dependent on AhR activation?
intraepithelial lymphocytes and CD4+ RORyt cells.
Which Th cells need AhR?
Th17 and Th22
How can polysaccharides help the immune system?
They interact with Bcells and as polysaccharide-protein conjugate may interact with T cells.
They also cause upregulation of MHCII and costimulating factors in APCs
Which part of bacteria serves as a Vita-PAMP?
Which receptor is important in determining invasiveness?
What are Th17 cells for?
Protection against extracellulars and fungi
How are macrophages activated by CD4+ cells?
Which cytokines are important for mucus secretion?
IL4 and IL13 from Th2 cells
How does immunity against helminths work?
Epithelial cells secrete IL25 and IL33, leading to IL13 production of Nuocytes, which causes mucus secretion by goblet cells.
Which cytokines activate fibroblasts?
IL4 and IL13 from nuocytes
How is tissue repair induced by Th2 cells?
they produce IL4 and 13 to activate macrophages, which cause encapsulation of the pathogen and tissue repair.
Which cytokines cause secretion of antimicrobial peptides in the gut?
IL22 and IL17 from Th17 cells
What determines if a naive T cell becomes a Treg or Th17 cell?
If homeostatic DCs produce RA, Tregs are induced. If mature DCs produce IL6, Th17s are induced
Which states of tolerance are there?
Immunological tolerance (anergy of Th2 cells)
Physiological tolerance via the gut
Modified Type 2 response (IgG4 production and blocking of eosinophils
What is the effect of ES-62?
It disrupts BCR and TLR4 mediated signalling
Which kinds of macrophages are there?
Classical, activated by TNFa and IFNy (Th1), secreting IL10
Wound healing, activated by IL4 (Th2), secreting IL10/IL12
Regulatory, activated by IL10 (Treg), secreting IL12
What may be targets for a vaccine against hookworms?
The enzymes for haemoglobin degradation
Which pathway is important in the antiviral pathway?
On what is the influenza immune escape based?
surface protein change
How can the herpes virus inhibit immune response?
It can bind IgG
What are GP120 and GP40?
Fusion proteins of HIV
In short, which mechanisms are there for virusses to escape the immune system?
antiviral state inhibition
host protein shut off
infection of immune cells
suppress antigen presentation
What is the problem with PSA vaccines against pneumonia?
They only stimulate B-cells to produce mainly IgM, so frequent boosters are necessary
What kinds of vaccines are there?
baculovirus expression system
recombinant carrier vaccines
What happens if Tregs encounter IL6?
They can become Th17 cells
What happens if you trigger Th17 cells with TGFb, IL6 and IL23?
They secrete IL10 and IL17 and become immunoregulatory
What happens if you trigger Th17 cells with IL23?
They secrete IL22 and IL17 and become immunopathologic