27/03 Flashcards
Where can we find and structure of TLR
TLR are homodimer or heterodimer receptor expressed on innate cells, T and B lymphocytes
How can a TLR bind the molecule present on the pathogen?
1- MyD88 bind the IL1 receptor associated kinase (IRAK)
2- The phosphorylation of IRAK lead to the binding of TRAF6
3- MyD88-IRAK-TRAF6 bind the TIR domain on TLR
4- TLR dimerize
How can a dendritic cell be activated?
1- A barrier has been broken and the bacteria enter the cell
2- The TLRs recognition induce the production of cytokines (TNF and interferon type 1)
3- A positive feedback mechanism activates macrophages
4- NK and T cells are recruited and activated
5- IL12 and IFN-γ are produced and act on dendritic cells
6- Dendritic cells start to phagocytise, change their shape increasing the expression of MHC (became mature dendritic cell) and move to the lymphoid organ and activate the active immunity by secreting factors that increases the expression of chemokine’s secretion
What’s imiquimod?
A drug that contrast the misfunction of TLR, it’s used to stimulate an inflammatory response against HPV infection
Which kind of cytosolic receptors exist?
- NLR (nod like receptors): recognize some peptidoglycans
- RLR (rig like receptors): recognize viral DNA
- CDS (cytosolic DNA sensor): recognize bacterial DNA
What does the inflammasome do?
The inflammasome activates the caspase 1 that cleaves the pro-IL1 allowing the release of the active form.
IL1 may activate the NFkB pathway leading to an inflammatory response
Which are the PRR that are usually present on immune cells’ surface? What do they do?
Scavenger receptor:
* Phagocytosis,
* Secretion of pro-inflammatory cytokines and reactive oxygen intermediates (ROI)
* Antigen presentation
C-type lectins:
* Phagocytosis
* Release of pro-inflammatory cytokines
* ROI productions
* Increase of cell adhesion and migration
* Activate complement
Toll like receptor:
* Anti-viral and anti-microbial activities
* Secretion of pro-inflammatory cytokines
* Production of ROI
NOD like receptors: Inflammasome assembly and release of IL1 and IL18
RIG like receptors: Production of interferons and other pro-inflammatory cytokines
Cytosolic DNA sensor:
* Release of interferons and other cytokines
* Destruction of viral DNA
* Inhibition of protein synthesis
Which are the main features of cytokines?
- Small dimension (17-20kDa)
- They work in dimers
- Short half-life
- Redundant: there are more cytokine for the same job
- Pleiotropic: they can affect different cells and have different effect on the same cell
- Synergic: they can initiate the same function together or antagonize with other cytokines
- Polarized: cytokines are secreted just in specific point (polarized manner) in order to avoid the dispersion of the cytokines produced
With which general mechanism can a cytokine work?
Autocrine: on the same cell that release it
Paracrine: on close cells with the right receptor
Endocrine: blood circulation
Which kind of cytokine receptor can we have and which structure do they have?
IFN: heterodimers
common gamma chain: heterodimers/trimers
common beta chain: heterotrimers
IL1: homodimers
IL2: heterodimers/trimers
TNF: homotrimers
IL2 receptor: structure
2 or 3 chains (alfa, beta and gamma), beta and gamma transduce the signal.
A cell can be pre-activated in order to have the chain already expressed on the membrane before the arrive of the signal.
Effect of IL2
activation and proliferation of T, B and NK cells
Which are the main function of chemokines
Constitutive chemokines: physiological extravasation of immune cells: CXCL12 (B cells), CCL19 and CCL21 (T cells)
Inflammatory cytokines: CCL2
Which chemokines receptor has an impact on HIV
CCR5: it’s receptor is used by HIV viruses to enter the cells and infect them
Which structure can activate the classical pathway of the complement?
The binding between 2 glomerular head of C1q and two antibodies with the consequent autocleavage
How can we activate the lectinic pathway?
Mannose binding protein (MBP) and ficolins must recognize foreign sugars on microbe surfaces
How can the complement actually defend the organism from the bacteria?
Each pathway terminate with the assembly of the MAC (Membrane attack complex) which can open a pore in the membrane of the pathogen
How does the alternative pathway start?
The factor B stabilize C3b, then the complex is cleaved by factor D into Ba and Bb. Bb can bind C3b acquiring a convertase activity stabilized then by properdin.
It’s a spontaneus C3 cleavage
Which biological functions are mediated by the complement?
Cell killing
Opsonization
Induction or amplification of local inflammatory response
Immunocomplex removal
What’s the opsonization?
The components of the complement (especially C3b) cover the antibodies on the cell surface of many bacteria, virion and infected cells. In this way the cell can be phagocytize by macrophage.
How can the complement modulate a inflammatory response?
all the soluble complement fragment that get released after the cleavage cause:
- a local inflammatory reaction
- an increase of size and permeability of local blood vessels
- cause the oxidative burst
How can the complement mediate the immunocomplex removal?
C3b bind the antibody and it’s recognized by C1 receptor on erythrocytes, then they’re carried towards the spleen or the liver
How can we inhibit the classical pathway?
Using C1inh, a soluble molecule that binds C1r and C1s mimiking C4
Which are the characteristics of the genes of both MHC class 1 and 2?
o Polygenic: there are multiple genes involved in the phenotype (multiple loci)
o Polymorphic: for each gene there are different isoforms in a population due to single nucleotide polymorphisms (SNPs) or polymorphism of hundreds of base pairs
o Co-dominant
Structure of MHC class I
They have an α chain (polymorphic) with 3 globular domains (α1, α2, α3) and they’re associated with a β2 microglobulin chain with a glomerular domain.
How can MHC class I present the peptide
α1 and α2 generate what we call pocket in which there has to be a peptide. The peptide has to be 8-10 amino acids long and with anchor residues necessary for the correct binding to MHC class I.
Structure of MHC class II
It’s a heterodimer with an α and a β chain, each with 2 globular domains (α1, α2, β1, β2). There’s a pocket between the α1 and the β1 domain which can contain a peptide of 13-20 amino acids. The presence of anchor amino acids is not needed.
In which cells can we find MHC class II?
dendritic cells, Langerhans cells, B cells and thymic epithelial cells.
With class II trans activators (CIITA) it can be induced also in other cells
Which kind of peptides show the MHC class I and II?
class I: peptides created by the LMP2-LMP7 modified proteasome (endogenous)
class II: residues of phagocytized and lysed pathogens (exogenous)
Describe the process that lead to the presentation of the peptide by the MHC class I
1- Infection -> production of cytokines such as INFγ
2- The immunoproteasome (LMP2 and LMP7) cut the proteins (not necessary ubiquitinated)
3- Formation of peptides
4- Entrance of peptides in the ER thanks to TAP1 and TAP2 while the MHC chains are hold in place by calnexin and careticulin
5- Presentation on the surface of the cell on the groove of the MHC thanks to the tapasin
What’s the role of the invariant chain in the MHC?
It maintain the structure of the pocket of MHC class II complex
What is the cross presentation of an antigen?
is performed by dendritic cells and allow the presentation of exogenous proteins and peptides coming from phagocytized pathogen in MHC class I molecules.
Dendritic cells are able to express Sec61 which is a protein that form a pore channel in the phagosomes and allows some of the peptides present inside the phagolysosome to reach the cytosol
How can a cell present non-proteic antigens?
other antigens like lipidic antigens can be presented by non-classical HLA molecules. They’re then recognized by gamma-delta T cells and invariant NK cells
