Week 10 Flashcards
how does the immune system achieve this
Danger signals (PAMPS,DAMPS)—> antigen presenting cells
—> instructions (pMHC, co-stimulatory mol, cytokines)
—> CD8 T cells (cytotoxic T lymphocytes), CD4 T cells (coordinate produce cytokines)
B cells <—>instructions (germinal centre reaction, CD40:CD40L, cytokines, co-stimulation)—> CD4 T cells
B cells produce antibodies
—> instructions (complement fixation, ADCC cytokines)
-complement C4 C3, neutrophils
Cells and molecules in the immune system
B cells: differentiates into plasma cells producing antibodies, opsonisation, complement activation, toxin neutralisation
T cells: CD4 helper T cells provide B cells with signals necessary for antibody production. CD8 cytotoxic T cells destroy virally infected cells. T regulatory cells suppress auto-reactive T cells
phagocytes: engulf and destroy extracellular pathogens, clears cellular debris, antigen presentation
Complement: opsonisation C3b, immune complex clearance C1q, terminal components create the membrane attack complex
NK cells: destroys virally infected cells and tumour cells
Immune deficiency
Exposure to pathogen
Virulence of pathogen
Immune competence
Immune deficiency timeline
Neonates (0-4wk) and infant (4-52wk): SCID,CID,severe neutropenia
Young children (1-4yrs): antibody deficiency XLA, complement deficiency, innate defects
Older children (4-16yrs): CVID, complement defects
Adults (16 years): CVID, secondary immunodeficiency
When to think about immunodeficiency
Several recurrent or invasive infections
Unusual organisms or site of infection
Severe recurrent or disproportionate inflammation
Unexplained lymphoproliferation
Primary and secondary immunodeficiency
Primary: genetic (FMHx!!), rare (450 different PIDs), often early in life but CVID in adulthood
Secondary: acquired, common (30x more common than PID), increasing likelihood with age, treatment and comorbidities.
The four Rs of immune responses
Recognition
Response Infections dominate
Regulation
Resolution and memory. Immune dysregulation
Where could the defect be
Innate defects (neutrophils, complement)
Global defect (signalling, cytokines)
T cell (cellular) defect + combined defect+ B cell (humoral) defect
Non immune defects: eg anatomical/structural problems, neurological problems, biochemical problems
The age, anatomical site, infectious and immune dysregulatory features of the presentation provide clues on where the defect is
What happens when they go wrong
B cells: can’t make antibodies. Recurrent bacterial sinopulmonary infections (encapsulated organisms). Chronic or recurrent gastroenteritis (enterovirus, giardia). Chronic enteroviral meningoencephalitis. Septic arthritis (strep, staph, mycoplasma, ureasplasma). Bronchiectasis
T cells: fungal infections (pneumocystis Jiroveci pneumonia). Several or unusual viral infections (EBV, CMV, adenovirus). Mycobacterial infection, failure to thrive, chronic diarrhoea, GVHD-like phenomenon (rash, abnormal LFTs), auto-immune disease
Phagocytes: skin abscesses or lymphadenitis, bacterial pneumonia, poor wound healing, delayed separation of the umbilical cord (LAD), chronic gingivitis, periodontal disease, mucosal ulcerations, disseminated NTM
Complement: recurrent neisserial infections, pyogenic bacterial infections, autoimmune disease (lupus), angioedema of face, hands, feet, GIT
NK cells: severe or recurrent herpes virus infections, HLH
Barrier problems (non-immune defect)
Kartagener’s syndrome: cilia defect leading to bronchiectasis
Cystic fibrosis: salt transfer defect results in sticky secretions
Ureteric reflux: inefficient flow
Eczema: filagrin defect
Neutrophils immunodeficiency
Primary immunodeficiency:
-congenital neutropenia
- leukocyte adhesion deficiency
-chronic granulomatous disease
Secondary immunodeficiency:
-cytotoxic chemotherapy
-BMT
-steroids
Neutrophils:
-immune first responders
-migrate to site of infection
-phagocytose and destroy pathogens
-form NETs to contain pathogens
-Make pus
Skin infections, abscesses, septicaemia, invasive fungal, infections
Leukocyte adhesion deficiency
Beta-2 integrins - if not genetically deficient unable to tightly bind and enter tissue, presents early in childhood
Binds ICAM1 on cell surface so tight binding does not occur
No pus
Chronic granulomatous disease
Staphylococcus
Aspergillus
Nocardia
Serratia
Klebsiella
BCGosis
Neutropenia (congenital/acquired)
Neutropenic sepsis
Acquired more common, when given cytotoxic chemotherapy
Complement immunodeficiency
Classical pathway: C1q, C2, C4– lupus like disease. Can’t clear apoptotic cells or activate Ab-C immunity
MBL deficiency (usually asymptomatic, may be a risk factor for recurrent infn)
Alternative pathway (factor B&D- Neiserria meningitis, factor I and H- aHUS)
-C3
—C5
TCC-(C5b-C9) Neiserria meningitis. Can’t punch holes in membranes of pathogens
Signalling problems
Immune cell signalling is very complex
It’s is relevant to disease and therapeutics
Monogenic defects in signalling pathways give characteristic disease
Mendellian susceptibility to mycobacterial infection (MSMD-IFNg receptor defect most common cause)
Naive T cell:
-Th1 T cell -> IFNg (acts on mono/mac). Th1:fights intracellular pathogens (eg MTB, NTM, salmonella)
-Th2 T cell-> IL-4. Th2: fights extracellular pathogens (eg worms, parasites)
-TH17 T cell-> IL-17. Th17: fights fungi (recruits neutrophils to mucosal surfaces)
Most commonly presents in children after BCG vaccination
Defect in interferon-gamma receptor. Prone to TB, salmonella
BCGosis lymph node spread of bacteria from vaccine strain
B cell problems
Primary immunodeficiency:
-X-linked agammglobulinaemia
-autosomal recessive agammaglobulinaemia
-hyper IgM syndrome
-common variable immunodeficiency
Secondary immunodeficiency:
-B cell depletion
-BMT
-lymphoma/leukaemia treatment
B cells:
-produce antibody
-professional APC
-CSR and AFM
-produce memory B cells
-produce plasma cells
X-linked agammaglobulinaemia (BTK deficiency)
Mainly boys. 1st child diagnosed slower
BTK allows B cells to move in
Pro B—> pre B dependent on BTK. BTK allows the B cell receptor to signal to keep the developing B cell alive
If deficiency in BTK
No antibodies: babies born without ability to produce antibody. Protected first months-maternal antibodies. After they’re very prone to: pneumococcus, haemophilus, moraxella, enterovirus
Present with recurrent pneumonias
Hyper IgM syndrome (CD40L deficiency)
Defect in interaction between T and B cells to produce class switching
IgM can be produced (naive B cells) but high affinity IgG (memory B cells) not produced
Also a wider defect with myeloid lineages
Common variable immunodeficiency
Incidence 1/10000, highly variable age of onset + symptoms
Hypogammaglobulinaemia: low IgG and low IgA/IgM
-100% of patients.—> recurrent infections (sinopulmonary) Bronchiectasis
Polyclonal lymphoproliferation—> enlarged LN, spleen lymphoma risk
Autoimmunity—> ITP, AIHA, hypothyroid, alopecia, vitiligo
Granulomatous disease—> GL-ILD, GI granulomata
Enteropathies —> chronic norovirus, IBD, (NRH)
The genetics underlying CVID are being unraveled by genomic medicine techniques
IgA deficiency
1:400 prevalence
IgA is so important for mucosal immunity but the fact individuals usually entirely well suggests there is compensation/redundancy
Usually an incidental finding
Sometimes associated with IgG2 subclass deficiency and infections and autoimmunity
Management of antibody deficiency
Antibody replacement (IVIG/SCIG)
Vaccines
Prophylactic antibiotics
Respiratory precautions
Early treatment of infection
T cell problems
Primary immunodeficiency:
-severe combined immunodeficiencies
-combined immunodeficiencies
-congenital athymia (eg 22q11 microdel)
Secondary immunodeficiency:
-T cell depleting therapy
-BMT
-immune suppression
-Acquired athymia
-HIV
T cells:
CD4+ coordinate immune responses
CD8+ destroy virally infected cells
Severe combined immunodeficiency (X-linked SCID most common; Yc deficiency)
T cell precursor——> naive T cell
Thymic T cell development
T cell receptor produced
Positive selection
Negative selection
22q11 microdeletion syndrome Di George syndrome
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
Consequence of improved treatments
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
What are vaccines
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
Mechanism of action
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
Producing that high affinity antibody
IgG antibody: as germinal centres develop
Less IgM antibody
Vaccination also leaves us with more antigen specific cells (memory cells)
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
Vaccine efficacy
Vaccination is the single most cost effective health care intervention
Huge impact on childhood morbidity and mortality
The ideal vaccine
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
Passive V active immunity
Passive: donating immunity
Active: activating the host to develop immunity
Passive immunoprophylaxis
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
Active vaccination
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
Live-attenuated
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
Inactivated
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
“Modern” vaccines
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
Bacterial capsules
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
Protecting against encapsulated bacteria
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
problem with immune responses to T independent antigens
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
How to get a T cell response to sugar
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
Success of conjugate vaccines
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
Viral vector vaccines
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)
How adenovirus and mRNA vaccines work
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
Adjuvants
Problem: some proteins can also be poorly immunogenic
Solutions: adjuvants
-a substance that enhances the immunogenicity of substances mixed with it
Adjuvants mechanisms of action
- 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) - Create an inflammatory environment:
-enhanced immunogenicity
-leads to up-regulation of co-receptors and production of inflammatory cytokines- increases danger signals
Vaccine effectiveness
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
Monitoring the response to vaccination (using them in clinic)
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)
Herd immunity
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
Many challenges remain
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
Egg allergy and flu vaccine
Flu vaccine developed in eggs
Small ovalbumin content in flu vaccine
Risk of anaphylaxis in a egg allergic patient
Porcine products in some vaccines
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
Live vaccines
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
Joint committee of vaccination and immunisation (JCVI)
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
Viruses and cancer
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
Successful cancer vaccines
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
Controversy in vaccination
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
The precarious balance of the early immune system
By birth: developed enough to fight infection
In utero: suppressed enough to prevent rejection
Pregnancy loss
70% of conceptions do not survive
Immunological causes:
-autoantibodies
—SLE
—thyroid disease
-NK cell abnormalities
-anticardiolipin antibodies
-mostly we don’t know
How does the foetus escape the maternal immune system
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
Maternal tolerance and immune suppression
Associated with increased risk of infection
Balance between tolerance and protection
Maternal antibody transfer
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
Neonatal lupus
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
rhesus incompatibility- blood group antigens
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
Haemolytic disease of the foetus and newborn
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
Immune protection in the newborn
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
Leading causes of death in children under 5
Preterm birth complications
Pneumonia
Intrapartum events
Diarrhoea
Neonatal sepsis
Malaria
Significant number of deaths to infection
Why is the infant susceptible to infection
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
The neonatal immune system
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
Low functional immune system
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)
The developing microbiome
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
The ageing immune system
Increased infections with age
-more opportunistic infections
-reactivation of latent infections
Increased autoimmunity
Increased cancer
The ageing population
Impact on acute care
Impact on social care
Impact on economics and tax returns
By 2034: 23% pop >65. 5% pop>85 years
Immunosenescence
“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
Ageing and the immune system
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
T cell ageing
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
Lymphocytes cannot proliferate forever
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
Autoantibodies and autoimmune disease increase with age
Reduction in tolerance mechanisms
Rheumatoid factor and rheumatoid arthritis increases with age
T regulatory function declines with age
Reduced peripheral tolerance capability
This and other multiple reasons why
Inflammageing
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
Autoimmunity= failure of self tolerance
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
Why do we need to maintain tolerance
Vast repertoire of antigen specific receptors carried by effector (T &B) cells, formed in an unbiased way
How do we maintain tolerance
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
Loss of ignorance (mechanism of loss of tolerance)
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
Mechanism of loss of tolerance cell death and anergy
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
Mechanisms of loss of tolerance suppression.
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
Summary of loss of tolerance
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
Autoimmunity
Complement dependent lysis- paroxysmal cold haematuria
Opsonisation- most haemolytic anaemias
Immune complexes- serum sickness, SLE
Receptor blockade- myasthenia, pernicious anaemia
Receptor stimulation- Graves’ disease
Autoantibodies cause and/or effect
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
Tissue specific autoimmunity
Thyroid: graves, hashimotos
Kidney/lung: goodpastures syndrome
Pancreas: diabetes mellitus
Parietal cells/intrinsic factor: pernicious anaemia
Adrenal: Addison’s disease
Acetylcholine receptor: myasthenia gravis
Tissue specific hashimotos
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
tissue specific Graves
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
Tissue specific Goodpasture’s syndrome
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
Systemic autoimmunity
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
Rheumatoid arthritis
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
RA is a systemic disease
Nodules
Eye inflammation
Lung fibrosis
Vasculitis= blood vessel inflammation
RA is associated with autoantibody production
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
Autoimmune disease is often associated with genetic predisposition
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
