immunology Flashcards
how are good bacteria beneficial in immunology?
they act as competition for ‘bad’ bacteria
if pathogens enter the body, how are they identified?
Toll-like receptors (TLRs) expressed on dendritic cells and macrophages, detect PAMPs
PAMPs are pathogen-associated molecular patterns - certain properties the body uses to identify potentially harmful things, for example gram -ve bacteria have LPS in cell wall
what are DAMPs?
damage-associated molecular patterns - certain features of damaged or dying host cells that need to be destroyed/are potentially harmful, also detected by TLRs
explain the events of the innate inflammatory response, initiated by activation of TLRs via PAMPs
blood vessels - dilate, become permeable and endothelial cells become sticky (by expressing certain receptors?) so ‘catching’ white blood cells and facilitating their access.
pro-inflammatory cytokines are released e.g. prostaglandins, histamines and cytokines
Fever - induced as part of a ‘complement cascade’ when PAMPs are identified. inhibits pathogen proliferation and speeds chemical reactions used by antimicrobial peptides
what do dendritic cells/macrophages do when TLRs are activated?
activate inflammatory actions to eliminate the pathogens AND they also recruit other immune cells.
Responsible for dendritic cells presenting pathogen components
how is response to infection potentially dangerous?
a response that might be appropriate locally, could be dangerous systemically - for example in sepsis you get loss of plasma volume, crash of blood pressure, clotting, a cytokine storm etc…
what links the innate and adaptive immune response?
dendritic cells - phagocytic, express TLRs…
they present fragments of digested pathogen to activate other immune cells
and they migrate to lymphoid tissues to activate and stimulate T-cells of the active immune system
multipotent hematopoietic stem cells (form immune and blood cells) have two lineages. which is involved in adaptive immunity?
the lymphoid lineage -
T cells, B cells and plasma cells
also gives rise to natural killer cells but these are an exception as they are not considered adaptive
which lineage of the multipotent hematopoietic stem cells gives rise to cells in the innate immune response?
myeloid lineage - gives rise to neutrophils, eosinophils, macrophages, megakaryocytes, basophils, mast cells etc…
(also erythrocytes)
what are neutrophils
eosinophils?
macrophages?
Neutrophils = short lived, respond and migrate to the site of detection, present in at-risk areas. These phagocytose
Eosinophils target molecules too large to engulf e.g. splinter/parasite
Macrophages - long-lived phagocytes abundant in areas likely exposed to pathogens
where are B-cells and T-cells made?
B-cells = bone marrow
T cells = thymus
they migrate to lymph tissue in order to be exposed to foreign antigens
what kind of T cells are there, including their roles?
Cytotoxic - kill infected host cells
Helper - activate B cells, cytotoxic T cells etc…
Regulatory - opposite of helper T cells and tell immune cells to ‘stand down’
how is the best antibody selected in clonal selection?
Body accumulates a library of ‘random’ lymphocytes
If Th cell/dendritic cell presents an antigen one of these dormant lymphocytes have some affinity for, the lymphocyte is activated
The stronger the fit between antigen and lymphocyte = the stronger the activation, in order to get the best lymphocyte producing the most effective antibody. Plasma cells then produced
why are transplants in newborns less likely to be rejected?
the immune system hasn’t had a chance to learn what ‘self’ is in order to distinguish the transplanted organ from the others
explain a simple experiment that shows the immune system can forget something it had originally learnt to be ‘self’
If you knock out a protein, then introduce it to the organism after a while, they will attack it despite it technically being a ‘self protein’ - they never learnt to recognise it. Immune system can ‘forget’ as well if something isn’t seen for a while
explain four ways the immune system develops ‘self tolerance’
Receptor editing developing lymphocytes that recognise self molecules (self-reactive lymphocytes) change their antigen receptors so that they no longer recognise self antigens
Clonal deletion, self-reactive lymphocytes die by apoptosis when they bind their self antigen
Clonal inactivation (also called clonal anergy), self-reactive lymphocytes become functionally inactivated when they encounter their self antigen
Clonal suppression, regulatory T cells suppress the activity of self-reactive lymphocytes
antibodies - how many are there?
also known as immunoglobulins, they make up 20% of the protein in plasma
5 classes - IgG/M/A/D/E
explain the structure of antibodies
IgGs are the classic two light chain two heavy chain disulfide bridge kind
Variable region changes between IgGs obvi
Variable region has 3 hypervariable regions, making up the surfaces to which the antigens are binding
what are the light chain variable region gene, and heavy chain variable region gene, made up of?
Light chain gene (variable region) = x40 V domains, x5 J domains, x1 C domain
Heavy chain gene (variable region) = x40 V domains, x25 D domains, x6 J domains and x5 C domains
these are seen in the germ line DNA.
as the B cell develops these are recombined, a V exon/segment is joined to a J one (and often a few extra Js removed from the mRNA)
(also D segments if heavy chain) and a C
explain how V(D)J recombination is used to develop a range of B cells that produce different antibodies
In developing B-cells, these exons^ present in the germ-line are recombined via splicing of DNA in V(D)J recombination to form a functional VL (as in light) or VH coding sequence
The developing B-cell joins a V segment to a J segment (on the gene level, chooses just one allele - allelic exclusion)
Transcription will then start at the V segment, continuing onto the now fused J segment (and often transcribes a few extra J segments removed from the mRNA later) and onto the C segment etc… (don’t forget the D segment if a heavy chain)
so chopping and choosing different combos for these (variable splicing) and then being able to do different heavy and light chain combos = high variability
what is junction diversification?
VDJ - junction diversification is when nucleotides are lost/gained in recombining gene segments
what is the primary antibody repertoire?
new, unchallenged human immune system contains around 1x10^12 different antibody molecules
what is antigen-driven somatic hypermutation?
this is how our immune system can produce any antibody -
Several ‘resting’ B cells in the primary repertoire
B cells with closest fit to the antigen present receive stimulation to divide
These cells divide again and often mutate in the process, at which point the new closest fit is selected
Most mutations have little effect, some will make the antibody ‘worse’ (stopping antigen binding and removing stimulus)
Mutations that increase infinity bind more antigen = ‘more’ stimulation = divide more
describes as ‘in vivo evolution’
what is affinity maturation?
a result of somatic hypermutation ^ (over time after initial immunisation there is a progressive increase in affinity of the antibodies
Accumulation of point mutations in both heavy and light chain V-region coding sequences)
what are germinal centres?
what enzyme drives the mutations in B-cells?
clusters of B cells in secondary lymphoid tissue
- it’s where B cells proliferate super fast - site of somatic hypermutation and affinity maturation
The mutations are driven by the activation induced deaminase expressed in these GCs (AID)
how can so many mutations - 1 mil x faster than typical background rate - be tolerated?
Too much mutation - hypersomatic mutation - and double stranded breaks (like in V(D)J recombination) both signal p53 pathway to apoptosis
BCL-6 expressed in germinal centres (where B cells are, and are hyper mutating)
binds to p53 promoter to turn off expression to prevent destruction of B cells
is BCL-6 dangerous?
can be, while B cell mutations are necessary and beneficial, they can still become harmful so lack of self-destruction ability/detection of mutations can cause issues. Reward outweighs risk tho
explain the three step process used by dendritic cells to activate T cells
three membrane interactions
material presented by dendritic cells that have phagocytose the pathogen.
Use MHC protein to bind the foreign peptide fragments and carry them
Dendritic cells also have stimulatory ligands to say ‘take us seriously’
Cell-cell adhesion molecules to hold the T-cells in place long enough for them to ‘get the message’
how can dendritic cells tolerise T-cells?
by presenting self antigens on their MHCs. this interaction is essentially the same as with pathogenic material but does not include stimulatory ligand/protein
explain what TCR structure is like
T-cell receptors are immunoglobulins, therefore they have b=variable regions and hypervariable loops, similar to antibodies
TCR variability is generated by V(D)J recombination and junctional diversification
produced in the thymus, giving around 1x10^8 but this decreases with age
what is immunosenescence?
progressive decline of immune competence with age
what are tumour specific antigens?
their existence is suggested by the fact that tumour transplants are always rejected when healthy tissue isn’t
what is the cancer immunoediting model?
Suggests immune cells control/manage cancer/tumours in three stages:
- Elimination = tumours killed by natural killer cells etc…
- Equilibrium = balanced state between immune and tumour cells (being ‘managed’)
- Escape = Immune system can’t deal with it anymore, tumour cells escape and become ‘clinically detectable’
what are some methods of using the body’s immune system to fight cancer that are under development?
checkpoint inhibitors (to take the brakes off of the immune system)
vaccines - e.g. HPV
oncolytic viruses
mAbs
CAR-T therapy, which genetically modifies T-cells to recognise tumour antigens
what is GVHD disease?
this is a common-ish side effect of heterogenous hematopoietic stem cell/bone marrow transplant in which the transplanted T-cells will attack and kill the new host
don’t exactly get the point but what’s some basic info about candida albicans?
a yeast, normally exists with no issue in skin, mouth, gut, vagina
can become pathogenic, and when phagocytosed it can bursts out of macrophages and form hyphae
show does taphylococcus aureus hide from the immune system?
Has protein A in cell wall
Its active site binds to constant region of igGs
igGs are 20% of blood serum, so staph covers itself in a ‘coat’ of IgGs, avoiding detection from immune system
HIV?
Infects T-h cells, dendritic cells, macrophages (anything with CD4 receptor)
Surviving aspects of immune system recognise these infected cells ^^^, phagocytose and present their parts, telling the immune system to target its own cells
result = immune deficiency and susceptibility to normally manageable pathogens. chances of getting cancer is much higher, showing immune system is normally constantly protecting us from cancer
what is the general cause of autoimmune disease?
defects in delf-tolerance - immune system attacks ‘self’, causing production of inflammatory responses and leading to fibrosis
what kind of cell is thought to be involved in the immune system ‘managing’ tumours?
TILs - tumour infiltrating lymphocytes
