First Midterm Flashcards
what is an ideal PRR?
An ideal PRR should be:
- ubiquitous
- able to detect non-self antigen
- rapid and potent
An ideal PAMP is:
- has bacterial lypopolysacc present on many bacteria
- Has mannose glycoproteins
- double stranded RNA
- in methylated cpG RNA
What happens during an inflammation?
Vasodilation
Dec in blood flow velocity
Inc in capillary permeability
Influx of immune cells to appeared tissues
Four signs of inflammation
Redness
Heat
Edema
Pain
Steps in inflammation
Epithelium is breached
Microbe invasion
Resident phagocytes detect microbes
Steps in phagocytosis:
- Expression of surface PRRs
- PRRs detect/engage invading microbes
- Cytoskeleton rearrangement
- Microbe internalization in the phagosomes
- Lysozyme destroy microbes
- Reactive o2/n2 destroy microbe proteins etc
What are cytokines?
Secreted proteins by the macrophages and natural killer cells
Drives the immune and inflammatory response
What is the effect of the cytokines?
Induce protein in the endothelium, inc its adherrence to passing leukocytes
Difference of chemokines from cytokines?
Low molecular weight
What are the effects of chemokines?
Stimulate leukocyte movement and regulate the migration of leuk to the tissues from blood
How does inflammation causes cancer?
Tumor is seen as unhealed wound and inflammation can promote growth through supply of nutrients
Toll like receptor (TLR) cause the release of what?
Release of anti-microbe peptide
Inflammatory cytokines
Other molecules that drive immune response
What is NF-kB?
Nuclear factor-kB: activated in response to TLR + PAMP
- transcription factors that regulate genes involved in immune response
What is I-kB?
Inhibitory of kB: cytoplasmic protein which binds and retains NF-kB in the cytoplasm
Process of transcription of immune genes by the NF-kB?
- I-kB is still bound to NF-kB, retaining it in the cytoplasm in a resting cell
PAMP+TLR = intracell signaling
Proteolytic destrctionof I-kB
nF-kB–>nucleus –> transcription of immune genes
What are adaptor proteins?
Non-enzymatic proteins that assist assembly of signalling complexes which are recruited by PRR upon its PAMP detection
What does TIR mean and what does it do?
Intracellular Toll Interleukin-1 Receptor-1 motif: structural motif that converts pathogen detection to intracellular signalling cascade found at the base of TLR
What does NLS do?
NF-kB in a resting cell is not active (i.e. Inert in the cytosol). NLS allows it to move inside the nucleus to be activated
What critical cellular processes does NF-kB regulate?
Inflammation
Adaptive immunity
Proliferation
Survival
TLR signalling consequences involve what?
Cytokine production
Production of enzymes involved in immune responses
Growth factor production (promotes healing)
Activation of adaptive immune cells
What are the advantages of TLR signalling?
Speed (fast signalling system after PAMP detection)
Economy (limited no of tlr but they detect large # of pathogens)
Amplification (activation of large, systemic responses after a localized detection of microbes)
What is an “oxidative burst”?
Production of ROIs and RNI which digest the microbes after the detection of PAMP by the PRR
What are the multiple contributions of PRR to immune response?
Induction of phagocytosis
Activation of oxidative burst
Recruitment and activation of additional leukocytes
Distinct characteristics of Adaptive Immune Response which differentiate it from the innate?
- Detects vast repertoire of molecules
- Receptors generated by somatic recombination
- Improved “adapted” response after repeat exposure
State the main difference between B cells and T cells:
T cells require antigen presentation by dedicated antigen presenting cells (APCs), while BCR can directly recognize its cognate antigen
What is humoral immunity?
It is directed against EXTRACELLULAR microbes and is mediated by B cells which secretes antibodies that neutralize and eliminate microbes and microbial toxins
What is cellular immunity?
It is directed against intracellular microbes and is mediated by T lymphocytes which activates phagocytes and lymphocytes or kill infected host directly
To activate naive lymphocytes what 2 signals are required?
- Antigen receptor binds to antigen
2. Microbial/innates immune signals
What happens after microbial elimination and once the signal for lymphocyte activation disappears?
They undergo programmed cell death (apoptosis)
What are antibodies?
A secreted BCR after activation of b cells which is released into the circulation and mucosal fluids upon infection. They neutralizes microbes and microbial toxins.
Stop microbes from entering/colonizing host cells.
What are MHCs?
APCs present antigens to T cells on major histocompatibility complex (MHC) class i and class ii molecules
Structure of Class I MHC consists of:
An alpha chain, non covalently bonded to a beta2-microglobulin chain
Where is the polymorphic residues of the Class I MHC located?
Alpha1 and alpha2 domains
Why is it that only CD8+ T lymphocytes respond to Class I MHC?
Because of alpha3 domain which is invariant and contacts only T cell CD8 receptor
What is a TAP?
A cellular pump that drives transport of cytoplasmic proteins into the ER where they assoc with Class I MHC molecules.
What are CTLs?
Cytotoxic T lymphocytes. When T lymphocytes gets triggered after TCR activation, it differentiates to CTLs which kills infected cells, thereby eradicating the infection.
In Class II MHC where is can you find the binding groove?
Alpha1 and beta1 domains form a peptide binding groove that hold 10-3- amino acids.
What is an invariant chain and what does it do?
Invariant chains are proteins that blocks the peptide binding groove of MHCII, preventing peptides from associating with MHCII in the ER.
What are the means of APCs in ingesting microbes?
- PRR bind microbes
- Receptors bind antibodies bound to the microbes
- APCs sample their environment through pinocytosis
Explain co-dominance property of MHC.
Both parental alleles are equally expressed which means each individual can express 6 different Class I molecules and 10-2- different Class II molecules
Explainhe polymorphism property od MHC.
Many different alleles are present in the population which ensures that different individuals can respond to different microbial peptides.
What are the features of peptide binding to MHC?
- Each molecule displays one peptide at a time.
- Broad specificity
- Very slow off-rate
- Stable expression requires peptides
- MHC molecules bind only to peptides
What are antibodies?
Antibodies are a type of glycoprotein produced by B lymphocytes. Antibodies bind antigen with a high degree of specificity and affinity. They can recognize a variety of 3D shapes.
The structure of an antibody is composed of:
Four polypep: 2 identical light chains ans 2 identical heavy chains forming a Y-shaped molecule. They are both connected by disulfide bonds.
State the difference between the structure of the light chains and the heavy chains.
Each light chain contains one V domain and one C domain.
Each heavy chain contains one V chain and at least three C domain
True or false.
Each BCR has its own unique variable region and unique constant region.
False. Each BCR has a unique variable region and SHARE SIMILAR constant region.
State the difference between the functional domains of BCRs.
V region = varies between clones and involved in antigen recognition
C region = conserved among clones and is required for structural integrity and effector functions.
What is an epitope?
Part of the antigen recognized by an antibody and this can be recognized on the basis of sequence or shape
State the difference between affinity and avidity.
Affinity: strength with which one antigen-binding surface binds an antigen.
Avidity = greater strength in binding of the antibody to several epitopes
What part of an immunoglobulin allows it to be transported across a mucosal epithelium?
J chain
What is the function of the IgA?
Found across the mucosal epithelia and confer neonatal passive immunity
What is the function of IGE?
Triggers mast cell degranulation and allergic response by binding to the FcE receptors of mast cells.
What is opsonization? Explain.
The binding of IgG to antigen which promotes microbe internalization.
Ig-Ag binds the FcY receptor of macrophages
Ag internalized through phagocytosis
Microbe is degraded
Microbial peptides are presented on Class II MHC molecules which activates CD4 t cells.
What is Antibody-Dependent Cellular Cytotoxicity (ADCC)?
- IgG binds on the Ag found on the surface of target cells.
- FcY receptos or NK cells bind to the Fc of Ig
- Cross-linking of Fc receptors signals to the NK cell to kill the target
- Target cell dies by apoptosis.
What does the immunoglobulin heavy chain composed of?
It contains variable (V) region, diversity (D) and joining (J) gene segment. VDJ segments are follwed by sequentially arranged constant gene segment.
What is the difference between light and heavy chain?
The light chain loci displays a similar organization to the heavy chain except it lacks D gene segment.
How is diversity in V(D)J somatic recombination achieved in b cells?
V, D and J segment are in tandem. Random recombination of D with J, then V with D-J segment happens and a new gene is transcribe, and the resulting mRNA is translated to new IgM heavy chain. While each VDJ recombination yields a unique antigen specificity, the constant region remains fixed, thereby ensuring conserved effector functions.
What are the two fates of b cells after differentiation occur?
Some b cells differentiate into antibody secreting plasma cells while others become memory cells.
What are memory lymphocytes?
They are produced from naive lymphocytes as a result of antigen exposure. They persists for years in a quiescent state. Rapidly reactivated by the repeat exposure to antigen and mediate faster, more potent immune response.
What is class switching?
A new class of Ig is made when cytokine signals induce rearrangements at the heavy chain locus. This switch only affects the constant region. New constant region = new effector functions.
After migrating to the thymus, what happens to the t cell precursor?
Somatic recombination occurs which generates a naive T cell with unique TCR.
What is the difference between the alpha chain and the beta chain of t lymphocytes?
Alpha chain locus has no D segment (similar to light chain in BCR), while Beta chain locus has a D segment (similar to heavy chain in BCR).
What is allelic exclusion?
If the recombination reaction in one of the alpha chain gene, recombinase is shut off at the other alpha chain locus. This leads to having only a single receptor on the cell surface to preserve specificity.
What happens after the somatic recombination in the thymus?
Thymic epithelial cells present self antigen on MHC I and MHC II, which determines the thymocyte specificity.
What is positive selection of T cells?
After being presented with self antigen by MHC I and MHC II, the naive, mature T cell retains expression of CD4, and ceases the expression of the CD8, if it binds to a specific-MHC II complex.
What happens after a failure in positive selection?
Non-reactive T cells are removed from the thymus through apoptosis.
What is negative selection?
Auto-reactive, high affinity anti-self TCR expressing T cells is removed from the thymus through apoptosis.
What are the similarities and differences between the structure of TCR and BCR?
Both are composed of two chains that combine to form a variable and constant domains and both have flexible hinge regions.
Unlike BCR, the TCR is directly and permanently anchored in the plasma membrane, thus the C-terminus has no effector functions and only needed for signalling.
Why are CD4 and CD8 considered as co-receptor?
CD4 and CD8 do not directly interact with the antigenic peptide. They only interact with invariant residues on MHC class II and I.
In order for T cells to be fully activated what does it need?
After encountering antigen in the lymph nodes, T cell received “second” signals, which trigger its full activation. This signals are passed through CD28 + B7 interaction on APCs.
What are accessory molecules?
Several other proteins involved in the TCR-MHC-peptide interactions. They have three functions: recognition, signalling, and adhesion.
What is LFA-1 and how does it function?
It is the major integrin which stabilizes and strengthens the T cell-APC interaction. It binds ICAM-1 on APCs. Typically, it is found in its resting (low-affinity) state, but exposure to chemokines converts it to a high affinity state.
What is the importance of receiving the second signal in T cell activation and how does T cell receive it?
In the absence of antigens, only self-peptides are presented to T cells. No full activation happens as no signal is coming from APC (B7). Only upon infection, does the costimulator on APCs gets stimulated by microbial PAMPs, generating the second signal needed for T cells to be activated.
What happens after T cell activation?
T cell responds to antigens and costimulators with the production of cytokines. Cytokines are mainly produced by macrphages and T cells (CD4+ T cells). The production is transient to regulate immune response. They act in paracrine (nearby) or autocrine (self) manners to stimulate multiple arms of the immune response.
How does the number of T cells decrease after immune response?
As T cells diminish the number of microbes, the number of antigens, costimulators and cytokines decreases as well. As a consequence, T cell numbers drop.
What are the effector functions of the CD4+?
CD4+ effector cells produce surface molecules and cytokines that mainly activate macrophages and B cells. Active CD4+ T cells express the surface molecule CD40L which binds CD40 on macrophages, B cells and dendritic cells and activates them. Dendritic cells increase expression of costimulators, further stimulating CD4+.
What is interferon-Y (IFN-Y)?
H
Interferon-Y is the most important cytokine produced by type-1 helper cells. It is a potent activator of macrophages, thereby enhancing microbial killing. It also stimulates B cells to produce antibody isotypes that promote phagocytosis of microbes.
What is the genus of the causative agent of malaria?
Genus Plasmodium
What is the genus of the mosquito carrier of malaria?
Genus Anopheles
What does injecting saliva of the mosquito do to its host?
The saliva contains anti-hemostatic and anti-inflammatory agents which stops clotting and blocks pain response.
What is the life cycle of the plasmodium?
Sporozoite (bloodstream)–>merozoite –> trophozoite –> gametocytes
Parasite replicates in the hepatocytes and matures into merozoites which burst out the hepatocyte and enter the bloodstream.
How does sickle cell anemia prevents infection of malaria?
Hemoglobin mutations (inc sickle cell trait) cause the RBC to lyse faster after infection , disrupting the parasite growth.
Why can’t CD8 T cell and NKC target infected RBCs?
RBCs lack nuclei, therefore do not express MHC I. They also do not express stress-induced ligands for NK cell activating receptors.
How does hypersensitive reactions work in some individuals?
Hypersensitivity is mediated by IgE-coated mast cells, seconds exposures to antigen trigger Mast cell activation and degranulation. Degranulation then induces inflammatory responses characteristic of hypersensitivity.
What mechanism does sporozoite have to evade host immune system?
IgM assembles on the surface of the parasite and poke holes in it. Sporozoites are capable of shedding their coat which prevents Ig-mediated complement fixation or opsonization.
How does opsonization work in Plasmodium-infected cells?
- Anti-var IgG opsonizes (coats) microbes.
- Phagocyte Fc receptors bind opsonized microbes.
- Signals from Fcγ receptors activate phagocytosis.
- Phagocytes internalizes IgG-coated microbe.
- Phagocyte destroys internalized microbe. Peptides may be displayed on MHC II for CD4 activation.
How does Plasmodium avoid immune response using var genes?
The Plasmodium genome encodes 50-60 copies of var genes.
Var genes cause infected RBC to adhere to endothelium.
Every day or so, var gene expression switches and an entirely new surface antigen is formed.
These ‘new’ plasmodium replicate in RBC and escape both T and B cell-dependent immunity.
Eventually by adulthood there are memory cells to all variants of var and relatively good immunity is in place.
