Week 10 Flashcards

Question

Severe combined immunodeficiency (X-linked SCID most common; Yc deficiency)

Answer 1

T cell precursor——> naive T cell Thymic T cell development T cell receptor produced Positive selection Negative selection

Answer 2

C- cardiac abnormalities A- abnormal faces: small face, smooth philtrum, underdeveloped jaw, thin upper lip, small eye openings, low nasal bridge T-thymic aplasia/hypoplasia C-cleft palate H- hypocalcaemia 22-chromosomal abnormality

Answer 3

SLE and systemic vasculitis: -10 year survival approximately 90% -infection 20-55% of deaths Dialysis: -yearly mortality 20% -infection 30% Rituximab (anti-CD20 treatment) -after 5 cycles 1/3 will have low immunoglobulins iatrogenic combined immunodeficiency

Answer 4

Vaccines are artificial ways of introducing memory to a pathogen Memory normally develops during/after infection Memory is important for generating a faster, adaptive immune response Vaccines work before pathogen can proliferate and cause disease

Answer 5

Vaccines work through antibody High affinity class switched antibody. Not IgM, at end immune response Need antibody that targets epitopes or proteins that are protective

Answer 6

IgG antibody: as germinal centres develop Less IgM antibody

Answer 7

Immunised donor secondary response: -higher frequency of antigen-specific B cells than unimmunised donor primary response -IgG, IgA instead of IgM>IgG Affinity of antibody higher Somatic hypermutation higher

Answer 8

Vaccination is the single most cost effective health care intervention Huge impact on childhood morbidity and mortality

Answer 9

Safe: must not cause illness and death Protective: efficacy must be high Sustained protection: protection should last several years Induce neutralising antibody : some pathogens infect cells that cannot be replaced so need neutralising antibodies to prevent such infection (polio/neurones) Practical: low cost, stable, easy to administer, no side effects

Answer 10

Passive: donating immunity Active: activating the host to develop immunity

Answer 11

Giving someone antibodies: Human serum: -rabies -rhesus D -VZV Animal serum: -tetanus Monoclonal antibodies: -anti RSV- palivizumab -anti sars CoV2-regeneron Pros: immediate protection, no 2 week lag generating a germinal centre, specific antibody to disease Cons: short lasting, half life IgG 14-21 days

Answer 12

Whole microorganism: -live attenuated (BCG, yellow fever, VZV, MMR) -dead (whole cell pertussis, rabies) Subunit of microorganism: -inactivated toxin (tetanus and diphtheria toxoid) -recombinant proteins (hepatitis B, HPV) -polysaccharide (pneumococcus, meningococcus) -conjugate vaccines polysaccharide combined with more immunogenic conjugate to elicit T cell help -viral vector -mRNA

Answer 13

The pathogenic virus is isolated and grown in non-permissive cells to encourage mutations that attenuate growth in the original host You can also use different temperatures too In reality this process is very long More modern techniques would involve genetically altering your pathogens to remove virulence Eg: BCG (for TB) Oral polio vaccine Measles

Answer 14

Virus is inactivated with UV, chemicals or heat and then injected Eg inactivated polio vaccine (IPV), influenza, pertussis (whopping cough) Eg virus inactivated with formalin,virus cannot infect/replicate in cells UV and chemicals (eg formalin, phenol, B-propiolactone) are more commonly used that heat because heat often destroys surface exposed antigens, reducing immunogenicity Sinopharm and sinovac both created inactivated SARS-COV-2 vaccines

Answer 15

Recombinant DNA technology has resulted in the development of new vaccine technologies Benefits: -eliminate risk of infection -can be mass produced -easily and quickly attenuated -can be quickly engineered to account for evolution of viruses -some are cheap and more stable Recombinant protein production- Hepatitis B vaccine first licensed in 1986

Answer 16

Outer capsule is made of polysaccharide (sugar). Immune system doesn’t recognise it so hard to phagocytose Hides surface molecules from immune system Poorly immunogenic T-independent antigen responses are important

Answer 17

Encapsulated bacteria: -pneumococcus (streptococcus pneumoniae) -meningococcus (neisseria meningitidis) -haemophilus influenzae b Important cause of infections at the extremes of life: -pneumonia -bacteraemia -meningitis -otitis media Poor response in children under 2 years: -main burden of disease in this age group

Answer 18

B cells like to respond to this capsule Which means a lack T cell help: -lack of affinity maturation in germinal centres -poor memory induction

Answer 19

conjugate vaccines: T cell perspective: -conjugate polysaccharide to protein antigen -vaccine (containing polysaccharide and protein) internalised by antigen presenting cell -APC presents peptides to CD4+ T helper cell -T cell will have a normal T cell response B cells may respond to both antigens But they will all get help from the T cells responding to the protein which means GCs can form

Answer 20

Hib vaccine virtually eliminates risk of Hib meningitis in children Men ACWY conjugate vaccine against meningococcus serotype Cresponsible for cluster outbreaks of meningitis (uni students0 Preventative 13-valent conjugate vaccine against pneumococcus

Answer 21

Genes encoding surface proteins of pathogens can be inserted in safe viruses (eg vaccinia, adenovirus, canary pox) “Safe”= mild disease, normally some replication Immune response against virus and the inserted antigens “Oxford” develops vaccines using adenovirus viral vectors (most famously at start SARS-Cov 2 pandemic)

Answer 22

Adenovirus enters the body. Virus produces spike protein this is designed to be a single cycle so no risk of adenovirus infection MRNA material enters host cell. Cell uses mRNA to make spike (no DNA integration) Harmless spike protein released and presented to the immune system Spike specific T cells and antibodies produced So no risk of vaccine associated infection in immunodeficiency Block subsequent infection by blocking viral entry to cell

Answer 23

Problem: some proteins can also be poorly immunogenic Solutions: adjuvants -a substance that enhances the immunogenicity of substances mixed with it

Answer 24

1. Convert soluble antigens to particulate material -enhances uptake by APCs -provides a depot of slow release of antigen -example: —alum (aluminium hydroxide)- used in vaccines for man (not without controversy) 2. Create an inflammatory environment: -enhanced immunogenicity -leads to up-regulation of co-receptors and production of inflammatory cytokines- increases danger signals

Answer 25

How good is a vaccine at preventing infection Some are better than others: eg tetanus and diphtheria Length of response varies- pertussis catch up in pregnancy Vaccination programmes most effective when majority of susceptible population vaccinated herd immunity

Answer 26

Not all vaccines induce long lasting immunity- how long do you need it for Which vaccine, if any, best in at risk groups: -extreme old age -immunosuppression -immunodeficient (primary or secondary) Are boosters required If someone gets reinfected post vaccination is it a milder disease course On going safety data needed: eg VIIT (vaccine induced immune thrombocytopenia and thrombosis)

Answer 27

Situation in which enough of a population is vaccinated against an infectious organism Factors affecting herd protection: -coverage rates -susceptibility of hosts -vaccine effectiveness -force of transmission -crowding -nasopharyngeal carriage Individual protection versus community protection: -who are the groups you cant reach -or who cant reach you

Answer 28

Vaccines are not effective in all people Often those in greatest need receive the least benefit (the young, the elderly and those with co-morbidities) Dealing with social concerns is an on going issue Some disease are difficult to vaccinate against, either because of constant mutation (eg flu) or because of difficulties in identifying protective epitopes (HIV) As Ebola/SARS-CoV-2/monkey pox demonstrates new threats can appear rapidly

Answer 29

Flu vaccine developed in eggs Small ovalbumin content in flu vaccine Risk of anaphylaxis in a egg allergic patient

Answer 30

In the UK routine immunisation programme there are 3 vaccines that contain porcine gelatine: -Fluenz, Tetra, the nasal spray vaccine that protects children against flu. No alternative childhood spray MMR VaxPro, a vaccine that protects against measles, mumps and rubella. Priorix does not contain gelatine and is as safe and effective Zostavax the vaccine that protects older adults against shingles no alternative in the UK In the clinic order in Priorix and listen to patients concerns can’t assume anything as things are complicated

Answer 31

Patients on immunosuppression or who are immunosuppressed are at risk of developing the disease contained within the live vaccine Yellow fever in travel clinics Also MMR given at 1 year (BCG now given selectively) VZV for shingles and chicken pox

Answer 32

The group of experts that devise UK vaccination programmes: -consider the pros and cons of particular vaccinations -public health needs -cost effectiveness E.g how much disease do you have to prevent to allow a certain cost or risk of side effect Green book has the latest information on vaccines and vaccination procedures for vaccine preventable infectious diseases in the UK

Answer 33

Viruses are pathogenic in a number of cancers Human papilloma viruses - cervical, genital and oesophageal cancer Epstein Barr virus- B cell lymphoma, nasopharyngeal cancer HBV and HCV- hepatic cancer Human herpes virus 8- Kaposi’s sarcoma Human T lymphotropic virus 1 (HTLV1)- adult T cell lymphoma/leukaemia

Answer 34

Prevention: HPV and cervical cancer Research aims to provide remission/cure: -either alerts or enhances the immune response against cancer cells -introduce viral vectors that can manipulate DNA in cancer cells

Answer 35

Disproportionate fear of side effects Vaccine side effects do occur and there is a vaccine fund set up by the government to acknowledge this Individual vs the general population Misinformation feeding these fears -MMR and Andrew Wakefield -SARS-CoV-2 and various themes

Answer 36

By birth: developed enough to fight infection In utero: suppressed enough to prevent rejection

Answer 37

70% of conceptions do not survive Immunological causes: -autoantibodies —SLE —thyroid disease -NK cell abnormalities -anticardiolipin antibodies -mostly we don’t know

Answer 38

The mother and the placentas responsiveness to threat is diminished Maternal immunity down regulated -increase in regulatory T cells -reduced CD8 and NK cell cytotoxic responses Repressed paternal HLA class II in trophoblasts Placental tolerance: -synthesis of immunosuppressive molecules by the placenta —progesterone, PGE2, anti-inflammatory cytokines IL-10 and IL-4, complement regulatory proteins -down regulated expression of HLA class I in placenta -T cell costimulation down regulated -enhanced killing of immune activated cells

Answer 39

Associated with increased risk of infection Balance between tolerance and protection

Answer 40

IgG antibodies cross the placenta in the last trimester of pregnancy Protects the baby in the first 6 months of life whilst adaptive response under-developed Assuming baby is born at term, if premature baby might not have had IgG transfer increasing risk of infection When mother has autoimmune antibody: -can transfer onto foetus. Transient autoimmunity whilst maternal IgG wanes. Neonatal lupus etc

Answer 41

Antibodies can cause short term problems: -hepatitis -thrombocytopenia Antibodies can cause long term problems: -Eg RO antibodies attack myocardial conducting system causing congenital heart block so can’t get conduction of electrical waves. Permanent cardiac problems

Answer 42

Rh +ve father with Rh-ve mother when baby is Rh+ve 1st pregnancy- mum produces antibodies against babies Rh +ve antigens (inherited from dad) in 3rd trimester when get transplacental maternal foetal mixing. So mother starts producing immune response but isn’t much of a problem in first pregancy 2nd pregnancy when baby Rh+ve mother has preformed antibodies against baby red cells which attack baby red cells. Baby severely anaemic, splenomegaly, hepatomegaly, fatal If mum is Rh+ve not a problem

Answer 43

Anaemia commonly occurs in the baby because baby’s red cells are being destroyed by mums antibodies (type II hypersensitivity reaction) Mum is fine About 50% babies have mild disease Rare severe manifestation of this is hydrops Fetalis where fluid builds up in baby’s tissues and organs

Answer 44

Passively acquired maternal antibodies: -these antibodies are protective -trans placental in last trimester -protect for approximately 6 months Breast feeding: -anti microbial, anti inflammatory, immune modulators -most effective preventative measure for reducing the death rate for children under 5: —breast feeding > 6months may prevent 13% of early life deaths -reduced RSV infection, pneumonia, otitis media and GI infections Neonatal immune system: -vaccination

Answer 45

Preterm birth complications Pneumonia Intrapartum events Diarrhoea Neonatal sepsis Malaria Significant number of deaths to infection

Answer 46

Immune factors: -cells missing?(not really lymphocytes and neutrophil counts very high at birth) -immune functions are immature- suppressed in utero not yet developed Structural: -small airways Environmental factors: -clean water for bottle milk -lack of social distancing

Answer 47

Both innate and adaptive immune systems developed at birth but not as functionally efficient Newborns at higher risk of bacterial infections -often low virulence organisms: staphylococcus, pseudomonas These deficits are more striking in preterm infants

Answer 48

Small airways Sterile flora at birth- develops early in life Opsonic activity and complement reduced (C3 65% of adult levels) Phagocyte function reduced: opsonisation, reduced integrin and selectin Reduced monocyte motility Reduced antigen presenting cell function Adaptive immune response to protein antigens near normal -less to glycoproteins (improved by 6-9 months) -polysaccharides (improved by 1 year) B cells poorly active Higher numbers but poor function of lymphocyte and NK cells -lower levels of cytokines (IL-2, IL-4, IL-5, IL-12 and IFN-g)

Answer 49

Essential to immune and metabolic health Gut bacteria stimulate gut lymphoid tissue -protect against pathogens -influence oral tolerance and immune memory Precise implications on foetal and/or neonatal health still unclear -initial microbial exposure defines early life gut microbiome Can we manipulate developing gut microbiome and predisposition to disease

Answer 50

Increased infections with age -more opportunistic infections -reactivation of latent infections Increased autoimmunity Increased cancer

Answer 51

Impact on acute care Impact on social care Impact on economics and tax returns By 2034: 23% pop >65. 5% pop>85 years

Answer 52

“Remodelling and decline of the immune system” Higher risk of acute viral and bacterial infections Mortality rates from infection are 3x higher in elderly compared with younger adult patients Infectious diseases are still the 4th most common cause of death among the elderly in the developed world During a regular influenza season about 90% of the excess deaths occur in people aged over 65 Poor immune responses account for diminished efficacy of vaccines

Answer 53

Detect and kill pathogens -reduced - more severe infection Immune memory -reduced- recurrent infection Kill or remove damaged or transformed cells -reduced- more cancer and autoimmunity Differentiate between self and not self -reduced - collateral damage Thymus atrophies with age and mainly not functioning tissue 35 decline in thymic output per year in humans

Answer 54

T cell production and education reduced T cell function altered More T cells focused on controlling latent infections like CMV Reappearance of latent viral infections. Existing immunity is waning Incidence of shingles increases with age Reduced vaccination efficacy and longevity: -decline in tetanus antibody levels over time accelerates with age

Answer 55

Protect coding DNA from degradation and confer stability to the chromosome Telomere (DNA and protein) Loss of telomeres beyond a critical point leads to growth arrest

Answer 56

Reduction in tolerance mechanisms Rheumatoid factor and rheumatoid arthritis increases with age

Answer 57

Reduced peripheral tolerance capability This and other multiple reasons why

Answer 58

Aberrant immune responses can exacerbate inflammation -cardiovascular disease, stroke, Alzheimer’s disease Increased TFNa, IL-6, CRP, decreased IL-10 —> asymptomatic infections, macrophages, increased adiposity, senescent cells, reduced sex hormones Immune dysregulation rather than immunodeficiency

Answer 59

Tissue specific vs systemic ~3% population affected up to 10% lifetime risk General features: -B cell and T cell reactivity to self antigens -frequently autoantibodies produced Partial heredity Genetic predisposition Environmental triggers. ———— multi step model pathogenesis

Answer 60

Vast repertoire of antigen specific receptors carried by effector (T &B) cells, formed in an unbiased way

Answer 61

T cell tolerance; Central: -thymic positive selection -thymic negative selection Peripheral: -ignorance (privilege) -anergy -cell death ———— (no costimulation) -suppression (T reg cells ) B cell tolerance: Central: -early antigen encounter -pre lymphoid tissue -deletion or anergy Peripheral: -lack of T cell help

Answer 62

Sympathetic ophthalmia is a condition where you have a penetrating injury to eye and an immune response occurs The penetrating injury results in elements of infra-orbital structures eg retina (privileged areas of eye) being released and becoming known to immune system Then on contralateral side (no injury) you get a similar immune response in that eye Results in destruction of retina

Answer 63

Presentation of a self antigen and no other costimualtory signals between T cell and APC then T cell undergoes apoptosis or anergy Presentation of self antigen with danger signal providing co-stimulation eg infection. Bystander activation

Answer 64

Loss of Treg function in RA transcription factor associated with Treg is Foxp3 Lots of Tregs in healthy people and individuals with RA Healthy Tregs express lots CTLA-4 however in RA Tregs don’t produced CTLA-4 which results in them losing their function

Answer 65

Most peripheral immune tolerance occurs at the level of the T helper cell and so does some cancer immune evasion Diseases may occur when there’s a breakdown in the mechanisms which prevent the activation of Thelper cells Loss of T cell tolerance has consequences: production of autoantibodies

Answer 66

Complement dependent lysis- paroxysmal cold haematuria Opsonisation- most haemolytic anaemias Immune complexes- serum sickness, SLE Receptor blockade- myasthenia, pernicious anaemia Receptor stimulation- Graves’ disease

Answer 67

Antibodies to erythrocytes- cause haemolytic anaemia Antibodies to acetyl choline receptor cause myasthenia gravis Antibodies to heart muscle are secondary to myocardial infarction and do nothing Antibodies to everything are secondary to the core pathology in SLE but highly pathogenic

Answer 68

Thyroid: graves, hashimotos Kidney/lung: goodpastures syndrome Pancreas: diabetes mellitus Parietal cells/intrinsic factor: pernicious anaemia Adrenal: Addison’s disease Acetylcholine receptor: myasthenia gravis

Answer 69

Weight gain, constipation, fatigue, hair thinning, vague joint pains, neck swelling, hoarse voice Hashimotos: hypothyroidism, autoantibodies and cells destroy thyroid Antibodies against: TSH receptor, thyroid peroxidase, thyroglobulin Blocks TSH binding and function, induces tissue destruction

Answer 70

Weight loss, irregular heart beat, change in bowel habit (diarrhoea), hand tremor, anxiety, 2 months eye prominence, sore,dry eyes Hyperthyroidism Antibodies stimulate thyroid Cell division and thyroxine release Antibodies against thyroid antigens also stimulate; -orbital fat cells -muscle cells -fibroblasts

Answer 71

4 weeks: fatigue, nausea, increasing pallor 2 weeks: cough, SOB, haemoptysis, bloody urine, peripheral oedema, oliguria Admitted to ITU: ventilation and dialysis Specific antibodies to the capillary basement membrane of glomerulus and lung alveoli Bleeding into lungs

Answer 72

Rheumatoid arthritis affects: joints, nerve, skin, eye , lung, vasculature Systemic lupus erythematosus: affects potentially everything, most frequently: joints, skin, CNS, kidney, vasculature Scleroderma: affects: skin, lung, vasculature,kidney, joint, GIT

Answer 73

Sudden onset in hands, very stiff (2 hours), swollen,warm, tender joints Joints in hands, wrists, shoulders, feet and knees symmetrically A common chronic inflammatory joint condition 1% UK 600000 people Direct NHS costs £560m indirect £1.8bn Multifactorial aetiology Associated in some patients with autoantibodies Variable course with exacerbations and remissions Inflammation leads to joint damage (erosions) Can result in severe disability

Answer 74

Nodules Eye inflammation Lung fibrosis Vasculitis= blood vessel inflammation

Answer 75

In some but not all patients Rheumatoid factor: antibodies to Fc of IgG -Present in 60% RA -associated with severe, erosive disease in RA -prevalence increases with age 20% of >60s -non specific -not a diagnosis test for RA Anti-CCP (cyclic citrullinated peptide): -antibodies to modified proteins found in the joint and elsewhere -strongly associated with smoking in RA -present in 60% RA -associated with severe erosive disease -more specific than RhF-less false positives

Answer 76

HLA associations are interesting because HLA genes code for MHC proteins which presents antigen HLA genes also happen to be some of the most studied genes Non-biased methods of gene discovery have found strong associations in other genes Gene-environment interaction: Smoking causes high levels of citrullination in the lung

Week 10 Flashcards

(100 cards)