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
