immunology

Question 1

how are good bacteria beneficial in immunology?

Answer 1

they act as competition for ‘bad’ bacteria

Question 2

if pathogens enter the body, how are they identified?

Answer 2

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

Question 3

what are DAMPs?

Answer 3

damage-associated molecular patterns - certain features of damaged or dying host cells that need to be destroyed/are potentially harmful, also detected by TLRs

Question 4

explain the events of the innate inflammatory response, initiated by activation of TLRs via PAMPs

Answer 4

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

Question 4

what do dendritic cells/macrophages do when TLRs are activated?

Answer 4

activate inflammatory actions to eliminate the pathogens AND they also recruit other immune cells.
Responsible for dendritic cells presenting pathogen components

Question 5

how is response to infection potentially dangerous?

Answer 5

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…

Question 6

what links the innate and adaptive immune response?

Answer 6

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

Question 7

multipotent hematopoietic stem cells (form immune and blood cells) have two lineages. which is involved in adaptive immunity?

Answer 7

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

Question 8

which lineage of the multipotent hematopoietic stem cells gives rise to cells in the innate immune response?

Answer 8

myeloid lineage - gives rise to neutrophils, eosinophils, macrophages, megakaryocytes, basophils, mast cells etc…

(also erythrocytes)

Question 9

what are neutrophils
eosinophils?
macrophages?

Answer 9

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

Question 10

where are B-cells and T-cells made?

Answer 10

B-cells = bone marrow
T cells = thymus

they migrate to lymph tissue in order to be exposed to foreign antigens

Question 11

what kind of T cells are there, including their roles?

Answer 11

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’

Question 12

how is the best antibody selected in clonal selection?

Answer 12

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

Question 13

why are transplants in newborns less likely to be rejected?

Answer 13

the immune system hasn’t had a chance to learn what ‘self’ is in order to distinguish the transplanted organ from the others

Question 14

explain a simple experiment that shows the immune system can forget something it had originally learnt to be ‘self’

Answer 14

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

Question 15

explain four ways the immune system develops ‘self tolerance’

Answer 15

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

Question 16

antibodies - how many are there?

Answer 16

also known as immunoglobulins, they make up 20% of the protein in plasma

5 classes - IgG/M/A/D/E

Question 17

explain the structure of antibodies

Answer 17

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

Question 18

what are the light chain variable region gene, and heavy chain variable region gene, made up of?

Answer 18

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

Question 19

explain how V(D)J recombination is used to develop a range of B cells that produce different antibodies

Answer 19

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

Question 20

what is junction diversification?

Answer 20

VDJ - junction diversification is when nucleotides are lost/gained in recombining gene segments

Question 21

what is the primary antibody repertoire?

Answer 21

new, unchallenged human immune system contains around 1x10^12 different antibody molecules

Question 22

what is antigen-driven somatic hypermutation?

Answer 22

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’

Question 23

what is affinity maturation?

Answer 23

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)

Question 24

what are germinal centres?

what enzyme drives the mutations in B-cells?

Answer 24

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)

Question 25

how can so many mutations - 1 mil x faster than typical background rate - be tolerated?

Answer 25

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

Question 26

is BCL-6 dangerous?

Answer 26

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

Question 27

explain the three step process used by dendritic cells to activate T cells

Answer 27

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’

Question 28

how can dendritic cells tolerise T-cells?

Answer 28

by presenting self antigens on their MHCs. this interaction is essentially the same as with pathogenic material but does not include stimulatory ligand/protein

Question 29

explain what TCR structure is like

Answer 29

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

Question 30

what is immunosenescence?

Answer 30

progressive decline of immune competence with age

Question 31

what are tumour specific antigens?

Answer 31

their existence is suggested by the fact that tumour transplants are always rejected when healthy tissue isn’t

Question 32

what is the cancer immunoediting model?

Answer 32

Suggests immune cells control/manage cancer/tumours in three stages:

1. Elimination = tumours killed by natural killer cells etc…
2. Equilibrium = balanced state between immune and tumour cells (being ‘managed’)
3. Escape = Immune system can’t deal with it anymore, tumour cells escape and become ‘clinically detectable’

Question 33

what are some methods of using the body’s immune system to fight cancer that are under development?

Answer 33

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

Question 34

what is GVHD disease?

Answer 34

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

Question 35

don’t exactly get the point but what’s some basic info about candida albicans?

Answer 35

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

Question 36

show does taphylococcus aureus hide from the immune system?

Answer 36

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

Question 37

HIV?

Answer 37

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

Question 38

what is the general cause of autoimmune disease?

Answer 38

defects in delf-tolerance - immune system attacks ‘self’, causing production of inflammatory responses and leading to fibrosis

Question 39

what kind of cell is thought to be involved in the immune system ‘managing’ tumours?

Answer 39

TILs - tumour infiltrating lymphocytes