Immunity

Question 1

What structures do respiratory diseases affect

Answer 1

Nasal cavities, pharynx (throat), larynx (voice box), trachea, bronchi, bronchioles, alveoli

Question 2

What are the classes of respiratory disease

Answer 2

Obstructive

Restrictive

Infectious

Vascular

Question 3

Obstructive Lung disease

What, why, example

Answer 3

Reduction in airflow and hard to exhale air so air will remain in the lungs after full expansion.
Bigger lungs.

Can be due to inflammation, excess mucus, airway narrowing because of smooth muscle tightening

A common example is asthma.

Question 4

Restrictive lung disease

What, why, example

Answer 4

Smaller lungs

Reduction in lung volume because it’s hard to inhale air and they cannot fully expand lungs.

Due to lung scarring, fibrosis, extra parenchyma problems.

Interstitial lung disease.

Question 5

What do both restrictive and obstructive lung disease cause

Answer 5

Difficulty catching breath

Question 6

Three examples of obstructive

Answer 6

COPD
(Chronic obstructive)

Asthma

Bronchitis.

Question 7

Two examples of restrictive

Answer 7

ILD

Sarcoidosis

Question 8

Examples of infectious respiratory disease

Answer 8

Viral and bacterial infection

Rhinovirus is cold.

Tuberculosis

Pneumonia

Asbestos

Pollutants

Question 9

Examples of vascular respiratory disease

Answer 9

Pulmonary oedema

Pulmonary hypertension

Question 10

What can respiratory disease be caused by in general

Answer 10

Environmental and genetic.

Pollen and dust mites.

Affects vulnerable people with other illnesses or the elderly or malnutritioned.

Question 11

How genes cause respiratory disease

Answer 11

Monogenic disease caused by single genes are rare.

Polygenic diseases are caused by the contribution of many genes.

Mono- CF

Poly- asthma, lung cancer, COPD

Question 12

How the environment can affect genes causing respiratory disease

Answer 12

Smoking during pregnancy can cause epigentic changes where the baby will be asthmatic.

Question 13

What causes polygenic disease

How is asthma caused

How is COPD caused

Similarity ?

Answer 13

Caused by 2 or more genes at different loci on different chromosomes.

Asthma- TLR2 TLR4 CDI4 are some of the many genes causing many problems in pathogen recognition, innate immunity and mucus production, IgE production and airway remodelling.

COPD- SERPINA1 TNFA cause serine protease inhibitor and are pro inflammatory.

A lot of the same genes are faulty in asthma and COPD.

Question 14

How is smoking linked to COPD and how does it affect genetic causes

Answer 14

90% of patients are smokers.
But only 10-20% of smokers get COPD.

This is due to genetic risk factors.
Alpha 1 antitrypsin deficiency is monogenic so if you smoke it is likely to progress to polygenic COPD.

Antioxidant genes are associated with COPD and we need them to block that bad things that occur due to smoking.

Some people have genes more likely to cause a smoking addiction.

Question 15

How do stem cells form immune cells

Answer 15

They can make lymphoid stem cells. Which can either become B cells, T cells or killer cells. This is adaptive immunity.

Or they can make myeloid progenitors. Which can be neutrophils, eosinophils, basophils, mast cells, monocytes (dendritic cells or macrophages). Which is innate immunity.

Question 16

Three levels of the human immune system.

Answer 16

Physiological barriers prevent pathogens gaining access to the body.

Innate immunity can be cellular (macrophages and neutrophils) or it can be humoral (antimicrobial peptides)

Adaptive can be cellular (b and T cells) or it can be humoral (antibodies).

Question 17

What sits on the boundary between innate and adaptive immunity

Answer 17

Dendritic cells

Natural killer T cells

Question 18

Summary of innate immunity

5

Answer 18

Rapid and happens in minutes.

Born with it and it remains unchanged and has no memory.

Evolutionarily conserved. Plants have it too.

Recognise pathogen and activate antimicrobial response.

When it goes wrong it can cause disease.

Question 19

How does innate immunity recognise pathogens

Why can’t pathogens avoid this

Answer 19

Relies on a limited number of genetically predetermined receptors called PRRs. Pattern recognition receptors.

They recognise highly conserved structured expressed by large groups of pathogens. These structures are important for survival so the pathogen cannot change them to avoid detection. PAMPs pathogen associated molecular patterns

Or DAMPS damage associated molecular patterns which are consequences of injury.

Common biological consequences of infection are also recognised.

Question 20

missing self

Answer 20

molecules expressed on normal healthy cells which have an inhibitory function, if the cells is infected it loses these molecules and the immune system recognises this.

Question 21

where are PAMPs found

how do they bind

Answer 21

found on bacteria, viruses, protozoa and fungus

PRRs can directly bind to PAMPs or interact with other receptors bound to PAMPs

PRRs can bind to many ligands. There are many toll like receptors which can each bind to many different ligands.

Question 22

what are DAMPs and what do they do

what does the cell do in response to injury

Answer 22

molecules created to alert the host to tissue injury and initiate repair

intracellular molecules are sometimes released during cell necrosis or activation following injury, eg mRNA should not be outside the cell so if it is there must be cell damage.

ECM molecule fragments released or upregulated in response to tissue injury eg fibronectin, fibrinogen.

Question 23

what is the damage chain reaction

what are high levels of DAMPs associated with

Answer 23

harmful stimulus causes tissue damage which releases DAMPs and these will activate TLRs which will release pro inflammatory mediators which could go onto cause further tissue damage.
this will cause more DAMPs release and cause more damage.
high levels of DAMPs are associated with many inflammatory disorders such as atherosclerosis and cancer.

Question 24

how many TLRs do humans have.

what is TLR10

what do different TLRs in different places do?

which TLRs are which

Answer 24

10 members

TLR10 is cell surface and the ligand is undetermined

the ones on the cell surface recognise bacterial proteins and the ones in endosomes recognise viruses.

TLR 1, 2, 4, 5, 6 are cell surface and do extracellular detection.
TLR 3, 7, 8, 9 are endosomal and detect viruses inside the endosome.

Question 25

what part of the TLR interacts with the adapter what are the different adaptors and where are they found

Answer 25

the toll interleukin receptor domain TIR of the TLR interacts with the TIR domain of the adapter protein. there are four TIR adapters and MyD88 is the main one which is found on all TLRs except TLR3. The other ones are called TRIF, TIRAP/MAL, TRAM. TLR2 + 4 require TIRAP. TLR3 has TRIF. TLR 4 is the only one that uses all four adapter proteins

Question 26

how do TLRs signal and what do they activate and cause CELL SURFACE AND ENDOSOMAL SEPARATELY

Answer 26

CELL SURFACE- TLRs signal via a phosphorylation cascade and activate the TFs NFKB and MAPK. this causes the release of pro inflammatory cytokines and chemokine. ENDOSOMAL- the endosomal TLRs activate interferon regulatory factors 3+ 7 and cause the release of type 1 interferons which control viral infections. endosomal can also activate NFKB sometimes with TLR3 and this leads to the same thing as the cell surface TLRs.

Question 27

what happens when TLR4 detects a bacteria and how is this different to when it detects a virus LPS?

Answer 27

when TLR4 recognises LPS (bacteria) it will activate MyD88 and cause cytokine release. when TLR4 recognises a virus the receptor will translocate to the endosome and lose MyD88 and pick up TRAM and TRIF and then this will activate the interferons but also the NFKB.

Question 28

what do NOD like receptors do and how many of them do humans and mice have what are these receptors characterised by

Answer 28

recognise bacteria and DAMPs in the cytoplasm 22 NLR genes in humans and 34 in mice characterised by the presence of a conserved nucleotide binding and oligermerisation domain (NOD) also known as NACHT.

Question 29

what is the structure of the NOD like receptor and how are they split into families

Answer 29

the C terminal has leucine rich repeats which are for detecting bacteria the N terminal has pyrin domains or CARD domains (caspase activation and recruitment domains) they are divided into four families based on N terminal effector domains.

Question 30

what do NOD1 and 2 recognise

Answer 30

bacterial peptidoglycans NOD1 recognises gram negative bacteria in the periplasmic space NOD2 recognises gram positive bacteria in the cell wall.

Question 31

what are NOD1 and 2 activated by

Answer 31

recognition of specific motifs called muropeptides in peptidoglycans. 1 recognises meso diaminopimelic acid containing PGN fragments 2 recognises muramyl dipeptide found in the PGN of nearly all gram positive and negative organisms.

Question 32

what happens to NODs when they are activated

Answer 32

they traffic to intracellular membranes to trigger signalling NOD1 and 2 are originally cytoplasmic proteins and they will activate NFKB and MAPK to make cytokines and chemokine.

Question 33

what is NLRP for and how is it activated why is this important in the TLR cascade

Answer 33

for inflammasome assembly and activation, which then goes on to activate caspase1. it can be activated by PAMPs or DAMPs. you need the caspase 1 from the inflammasome activation to finish the job of the TLR cascade and change pro interleukins into interleukins. notes make sense.

Question 34

where are RIGI like receptors found and what do they do what are the different members and what do they recognise

Answer 34

they are in the cytoplasm and they detect viral pathogens RIGI- recognise short double stranded RNA, retinoic acid inducible gene 1, 5 triphosphate caps, influenza a and RSV. MDA5- recognise long double stranded RNA with no end specificity, rhinovirus, melanoma differentiated gene 5, replication intermediates LGP2- very high affinity for any double stranded RNA.

Question 35

what are the replication intermediates detected by MDA5 type RIGI receptors

Answer 35

viruses are single stranded but when they replicate they make double strands which can be detected by MDA5.

Question 36

what is the RLR signalling pathway which does it apply to of the RLR members and what does each of them do

Answer 36

receptor binding to double stranded RNA causes a conformational change allowing it to interact with the adapter protein IPS1 on mitochondrial membrane. this will activate NFKB and IRF3+7 to make cytokines and type1 interferons (only RIGI and MDA5) LGP2 functions as a positive regulator for RIGI and MDA5 mediated virus recognition.

Question 37

does every cell express all of the receptors we have learnt about

Answer 37

no

Question 38

what is the main job of cytokines what do they do as a whole in a general view.

Answer 38

recruitment of innate immune cells to the site of injury and lymphocyte activation. this causes systemic effects such as fever and production of IL6. they allow immediate defence against the pathogen but they also direct adaptive immunity.

Question 39

what is leukocyte recruitment and how does it happen what are selectins and integrins

Answer 39

adhesion molecules are induced on circulating immune cells and endothelial cells. this allows the neutrophil to roll along the endothelium and squeeze through to travel to the site of infection. selectins are adhesion molecules on endothelium and platelets integrins are on monocytes and neutrophils etc there is also immunoglobulin ICAM1 used as an adhesion molecule.

Question 40

what do cytokines activate describe this response

Answer 40

the acute phase response (systemic) activation of hepatocytes in liver causing the release of acute phase proteins bone marrow to cause neutrophil mobilisation hypothalamus increases temperature and this stops the replication of pathogens due to the high temperature and the adaptive immune response works better at high temperatures. dendritic cells migration to lymph nodes to initiate adaptive immune response (TNF alpha cytokine)

Question 41

how many people get sepsis and how many survive why is this

Answer 41

200,000 people get it a year 44,000 die it is difficult to diagnose and it is a cascade of cytokines caused by spreading infection and causing death

Question 42

what is the anti viral response following the activation of type 1 interferons 5 things

Answer 42

they can induce the resistance to viral replication, by activating genes that cause the destruction of mRNA and inhibit the translation of viral proteins but this will also stop some of the host proteins too. can increase the MHC 1 expression and antigen presentation of viral proteins, this facilitates recognition and susceptibility to cytotoxic T cells activate natural killer cells to kill infected cells induced chemokine to recruit lymphocytes activates dendritic cells and macrophages

Question 43

what are some therapeutic targets of PRRs and what are the two effects it can have on immunity what are some of the molecules that are used for this any side effects? what is the main challenge here

Answer 43

to stop overstimulation of immune system we can use antagonists to block the binding of ligands. we use small molecules, proteins, oligonucleotides, peptides and antibodies. a side effect could be that we may repress some protective mechanisms. we could also use agonists to promote the immune response such as interferons and vaccines. a side effect would be that it may cause too much inflammation. so the main challenge is to reduce excessive inflammation without affecting innate immunity.

Question 44

two examples of TLR targeting drugs why do many of these drugs not make it to human trials

Answer 44

agonists for TLRs can be used as vaccines (imiquimod) antagonists can be used for sepsis (eritoran) complexity

Question 45

what is innate immunity compared to acquired

Answer 45

innate- rapid response to a broad range of microbes and uses external physical defences and internal cellular defences. it is not varied aquired- slower responses to specific microbes, humeral (antibodies) or cellular (lymphocytes)

Question 46

what percentage of all human disease is respiratory how can adaptive immunity cause problems what is adaptive immunity

Answer 46

6% underactive or overactive adaptive immunity can cause problems with respiration a protective response to antigens from pathogens

Question 47

what is an antigen

Answer 47

a molecule capable of inducing an adaptive immune response | proteins, lipids, polysaccharides

Question 48

what are the first cells to encounter antigens and what are some examples of them

Answer 48

cells that sit at the interface between innate immunity and adaptive immunity such as alveolar macrophages and dendritic cells.

Question 49

what is antigen presentation

Answer 49

alveolar macrophages and dendritic cells send out processes to taste the environment and eat and breakdown any pathogens they then present the foreign antigens on themselves to interact with lymphocytes.

Question 50

what are lymphocytes and where does each type come from

Answer 50

adaptive effector cells T lymphocytes come from the thymus and B lymphocytes come from the Bone marrow.

Question 51

what are the types of T cells what do B cells do

Answer 51

cytotoxic T cells which are killer cells. T helper cells which help other immune cells. make antibodies

Question 52

what are the three properties of adaptive immunity

Answer 52

ability to mount specific responses to a huge range of pathogen derived antigens (diversity) avoid reacting to self antigens (self tolerance) development of immunological memory by long lived b and T cells, enables a more rapid and effective second response.

Question 53

what is the structure of lymphocyte receptors

Answer 53

both b and T cell receptors have a constant region which is the same for all cells and is embedded into the cell membrane. the variable region is attached to the constant region and each cell will have a different variable region. this is what binds the antigen and the variable region determines the receptor specificity estimates 10^8 different receptors.

Question 54

why can't the human body code for all the lymphocyte receptors and how is the problem removed

Answer 54

we don't have enough DNA to code for that many receptors much diversity is generated early in development via DNA rearrangements (VDJ recombination) this occurs in the absence of infection and there is random splicing to make every receptor unique. then when an antigen is detected it will cause rapid lymphocyte replication which gives room for many mistakes which will generate further diversity and this is called somatic hyper mutation.

Question 55

what is affinity maturation

Answer 55

If you generate a lymphocyte receptor that reacts better with the antigen than the original, this will be selected to continue and the worse one dies out (affinity maturation)

Question 56

what is VDJ recombination and how does it cause diversity need checking

Answer 56

we all have many variable regions, diversity regions and joining regions. in every B to T cell all but one of each region is randomly deleted. the remaining regions are joined together to form the mature variable region of the receptor. recombination is not precise and this will increase diversity. further mutations occur on pathogen exposure (somatic hypermutation).

Question 57

what is tolerance and when can it occur what happens if we don't have tolerance

Answer 57

a state of unresponsiveness of the immune system to antigens that normally have the capacity to elicit an adaptive immune response can be to own antigens or fetus during pregnancy, or it can develop to pathogens or cancers failure to establish tolerance leads to an autoimmune disease where the immune system will attack its own antigens. (thyroid, arthritis, systemic lupus erythematous)

Question 58

what is central/early tolerance how do tregs form (peripheral tolerance)

Answer 58

in the thymus or bone marrow there are specialist cells that express all of the bodies proteins on their surface. cells that are able to bind to the bodies own antigens are deleted. the only surviving b and T cells cannot recognise antigens already in our bodies. However some of the T cells in the thymus that react more audibly with the bodies antigens are developed in regulatory or suppressor T cells. (Tregs) they migrate to the lymph nodes and watch out for any cells that evolve receptors that can react to self antigens and delete them.

Question 59

how does immunological memory happen how are they differentiated from normal cells

Answer 59

following activation a small proportion of high affinity b and T cells differentiate into long lived quiescent memory cells which reside in lymph nodes or tissues. they are ready for second infection and to rapidly release antibodies. memory cells are distinguished from naive cells by having an increased lifespan.

Question 60

in detail process of antigen presentation what is the MHC what are CD4+ and CD8+ and what happens when they interact with the antigen

Answer 60

the cell ingests the bug and presents the foreign antigens on its surface. it combines the foreign antigen with its own molecule called MHC (major histocompatibility complex) which is what will interact with the lymphocyte receptor. when a cytotoxic T cell expressing the antigen CD8+ interacts, it will become activated to produce a killer cytotoxic T cell that pumps holes into infected cells. when a precursor helper CD4+ cell interacts with the antigen and MHC it will produce a range of cytokines. the cytokines made depends on the interaction of other receptors on the lymphocyte surface.

Question 61

what do CD4+ cells do in response to cytokines

Answer 61

differentiates into a wide range of T helper cells which can help many different immune cells

Question 62

what do cytotoxic T cells do when they are activated what happens if they are defective

Answer 62

they patrol the body for other cells expressing the particular antigen and dock onto them. they then secrete the contents from granules which are preformed within the cell, they contain proteins such as perforin which punches holes into the target cell until it explodes. defective cytotoxic T cells increase viral infections and may promote the progression of cancer.

Question 63

what determines the type of T helper cell produced after pathogen detection and how

Answer 63

the cytokines released following CD4+ binding to antigen will activate different T cell TFs. this will cause the production of a certain set of proteins and affect the behaviour of the T cell and what helper cell subset it will differentiate into.

Question 64

what are the different types of t helper cell what can T cell defects cause and example of how

Answer 64

Th1 cells fight viral infections because they activate macrophages. Th17 cells activate neutrophils and help to kill fungi. Th2 and Tfh help B cells to function. a range of opportunistic infections which wouldnt normally infect healthy people (HIV- helper T cells are depleted)

Question 65

how do B and T cells interact and do they always have to? what are antibodies how do T cells help the formation of memory cells

Answer 65

B cells can respond to some antigens on their own but they respond better with the help of T cells. with help from T cell the B cells develop into plasma cells which secrete many antibodies antibodies are secreted versions of the B cell receptors which bind to antigens on pathogens if the t helper cell is a Tfh (follicular) it may encourage the development of a long term memory B cell.

Question 66

what are the different classes of antibodies

Answer 66

IgM- the first antibody made. it is bound by its constant region together so it forms a complex of five antibody molecules which all have the same variable region. this will allow more effective binding. IgG- is secreted next by the plasma cell and this is the most common antibody (80%) IgA- it is produced at mucosal surfaces in the lungs and it doesn't get broken down easily by other proteins made in the lungs to fight bacteria, it is a dimer. IgD- B cell receptor IgE- binds mast cells and mediates allergic reactions.

Question 67

how is IgM binding made to be more effective what is a disadvantage of IgM

Answer 67

they have a low affinity at the start of the immune response so the complex of five helps to increase binding rates. however it can't get out of the bloodstream so it only has a localised response

Question 68

what are some different antibody functions

Answer 68

neutralisation- bind to antigen and cover it to prevent the virus recognising its receptor on the cell surface to stop it from infecting other cells. compliment fixation- antibodies can bind other effector molecules of the innate immune system and bring it close to the bacteria to help kill the bacteria directly. opsonisation- they can bind the bacteria to cells of the innate immune system (neutrophils) by acting like Velcro and making it easier for neutrophils to injest bacteria. aggulation- sticking many antibodies and bacteria together

Question 69

what do the two parts of the antibody interact with

Answer 69

variable regions binds to target antigen constant region interacts with effectors

Question 70

what are IgM and IgG and A good at

Answer 70

IgM is good at neutralising and agglutinating IgG and A are good at opsonisation and fixing compliment

Question 71

what does defective antibody production cause

Answer 71

bacterial respiratory infections

Question 72

how can we manipulate the immune system

Answer 72

vaccination- fool it into thinking its seen a pathogen before so when we get infected we go straight to the rapid secondary response. immune supression- to stop an overactive immune system in autoimmune disease or transplantation. monoclonal antibodies- can be generated for many targets so have many functions, can set infections, can suppress immune system or treat cancer. (magic bullets)

Question 73

what can be used as a vaccine and what do they do examples of vaccines used for certain diseases what is also put into a vaccine and why

Answer 73

uses immune memory to enhance adaptive response. dead or weak bacteria, viral proteins, capsular polysaccharides influenza vaccine uses a dead pathogen BCG uses genetically modified weak pathogen tetanus uses a toxin these are combined with adjuvants which evoke the immune response to enhance the immunogenicity

Question 74

why do we give booster dose vaccines how do vaccines help the individual but also the whole world how many vaccines are there and how can they be given

Answer 74

to generate higher affinity antibodies herd immunity- the disease cannot spread if 75-95% of the population are vaccinated. 25, injection, nasally or orally.

Question 75

why aren't vaccines more successful

Answer 75

Logistics- not enough people are vaccinated due to side effects or money target selection- the vaccine must not cause disease but must stimulate long lived immunity dangerous or poorly understood pathogens some have a high mutation rate such as HIV or the flu and so the surface antigens change regularly

Question 76

what are the major antigens for the flu vaccine what is antigenic shift and drift

Answer 76

neuraminidase and hemagluttnin antigen shift- one virus can interact with others that affect other animals and exchange genetic material and can become completely different so the vaccine no longer works antigen drift- replication causes errors and mutations which alters the antigens structure

Question 77

what is the difference between influenza a and b

Answer 77

influenza a expresses n and h and can affect other species by antigen shift influenza b causes less severe disease and is less variable.

Question 78

why would you want to suppress the immune system what is a side effect

Answer 78

``` stop autoimmunity (rheumatoid arthritis) inflammatory disease (inflammatory bowel disease) organ transplantation ``` easily infected because they have no immune system.

Question 79

what are some ways of stopping the immune system and how do they work examples of the drugs names

Answer 79

Corticosteroids- treat asthma short term by targeting innate immunity cells. also used long term to stop inflammatory diseases such as hypersensitivity pneumonitis due to inhaling allergens. antimetabolites- stop replication of T cells by stopping DNA synthesis. Methotrexate prevents folic acid production which is needed for DNA synthesis. caclineurin inhibitors- stops T cell replication, only used for transplants and it is very toxic but effective. it prevents the G0 to G1 in the cell cycle. (cyclosporin and tacrolimus) monoclonal antibodies- can target B cells and prevent it making antibodies (rituximab)

Question 80

what are monoclonal antibodies \ how are they made

Answer 80

clonal antibodies engineered to specific targets for scientific and medical applications they are given repeatedly immunising a mouse and removing the antibody producing cells and fusing them with cancer cells. but this will make foreign mouse antibodies. recombinant technology using viruses or Yeast allows humanised antibodies to be made.

Question 81

omalizumab targets....... pembrolizumab and nivolumab targets....

Answer 81

targets IgE for asthma PD1 for lung cancer

Question 82

how to tumour cells avoid the immune system how can monoclonal antibodies help this why is this better than chemotherapy

Answer 82

tumour antigens should cause a T cell response but the tumour expresses PDL1 which turns off T cells by engaging inhibitory checkpoints. monoclonal antibodies can stop t cell repression by cancer cells but this can cause inflammatory side effects. but this is better than chemotherapy because it is more specific and doesn't stop all replicating cells. the monoclonal antibody blocks PD1 receptor on the T cells so the tutor PDL1 cannot bind.