Theme 2- week 2 Flashcards
What are the main physiological functions of the immune system?
Recognise pathogens
Mount an immune response which requires- cell- cell communication
Clear the pathogen
Self-regulation
What is the innate immunity? Is it general or antigen specific? How fast is it? Does it remember antigens?
Innate immunity
General, not antigen specific but can recognise broad classes e.g. bacteria
Rapid speed of onset
Does not alter on repeated exposure
No memory
What is the adaptive immunity? Is it general or antigen specific? How fast is it? Does it remember antigens?
Adaptive immunity
antigen specific
Slower response, but more potent
Subsequent exposure- more effective response
memory
What are the responses of the immune system?
- nnate
- Barrier and chemical mechanisms
- Pathogen recognition
- Cellular
- Phagocytes Natural killer cells
- complement
- Adaptive
- Humoral (antibodies and B cells)
- Cellular
- B and T cells
Definiton of immunodeficency?
Clinical situations where the immune system is not effective enough to protect the body against infection
What is primary immunodeficency?
Primary- Inherent defect within the immune system- usually genetic
What is secondary immunodeficency?
Secondary- Immune system affected due to external causes
What are secondary causes of immunodeficency?
Breakdown in physical barriers: Cystic Fibrosis- compromised mucosal barrier which leads to recurrent infection
Protein loss
Burns, protein loosing enteropathy, malnutrition
Malignancy
Especially lymphoproliferative disease (disorder of lymph glands, spleen or bone marrow), myeloma (blood cancer from plasma cells in bone marrow)
Drugs
Steroids, DMARDS (disease modified antirheumatic drugs), Rituximab, anti-convultants (stops rapid firing of neurons during seizures), myelosuppressive (drug used before a bone marrow transplant to get rid of any cancer immune cells within the marrow)
Infection
HIV, TB
What do phagocytes do?
Neutrophils (short lived, migrate into tissues when needed, found in blood), macrophages (found in tissue and longer lived)
Eat bacteria, fungi à and then destroy them
Once bacterium ingested by phagocyte, endocytosed, phagosome binds with lysosome to form a phagolysosome, bacteria then destroyed and debris is exocytosed.
What are pathogen recognition receptors?
Pathogen recognition receptors (PRRs)- recognise conserved pathogen associated molecular patterns (PAMPs)- various types like TLRs, NLRs
What is in example of a PAMP?
Lipopolysaccharide is an example of a PAMP- present on bacteria
What do phagocytes use to detect pathogens?
Phagocytes use PRRs to detect pathogens
What are Toll like receptors?
Toll like receptors are a type of PRR
Examples of toll-like receptors and what they recognise?
Toll like receptors are a type of PRR
TLR4 – recognises lipopolysaccharide
TLR5- recognises Flagellin
What happens when TLR’s recognise?
Cascade of events involving various molecules intracellularly then production of inflammatory cytokines.
MyD88 and IRAK4 are involved in this cascade
Boy age 12 months :History of recurrent pneumococcal pneumonia
Investigations:
Normal levels of immunoglobulins, normal numbers of lymphocytes and neutrophils
CRP only marginally elevated during the infection- goes up in bacterial infection as stimulates liver to produce CRP
Clinical presentation:
- Recurrent bacterial infection, especially streptococcus and staphylococcus
- Pneumonia, meningitis, arthritis
- Poor inflammatory response
- Susceptibility to infection decreases with age
Treatment? What is the diagnosis?
- Rx: prophylactic antibiotics, iv immunoglobulin if severe
- MyD88 presents in a similar manner
Case 1 : IRAK4 deficiency
What can disorders of phagolysosomes lead to?
Phagolysosome- disorders of this can lead to a primary immunodeficiency
How do disorders of phagolysosomes lead to primary immunodeficency?
NADPH complex in phagolysosome- formed of several proteins including gp91phox (coded by the X chromosome)- releases an electron, binds to oxygens leading to a superoxide then produces hypochlorous acid (bleach that kills the bacteria/fungi)
6 years old boy
History of recurrent skin abscesses, 1 x previous pneumonia
Presented to hospital with a liver abscesses
Mothers brother-similar but milder symptoms
Investigations:
Normal immunoglobulins, lymphocytes and neutrophil count
Diagnosis?
Case 2: Chronic granulomatous disease
What causes chronic granulamatous disease?
Disease from an abnormality of gp91phox- encoded by the X chromosome- affects males and females carriers- collections of granulomas- collections of macrophages which go to the site of infection and can try engulf the bacteria but cannot destroy it
Symptoms of chronic granulamtous disease? What organisms cause it?
Recurrent abscesses: lung, liver, bone, skin, gut
Unusual organisms e.g. Staphylococcus, Klebsiella, Serretia, Aspergillus, Fungi
Rx: haemopoeitic stem cell transplant, antibiotics
What is the test for chronic granulamtous disease? What does it measure?
Tests rely on REDUCTION (gain of electron)
Neutrophil Function Test
Measure Dihydrorhodamine reduction using flow cytometry- molecule that you can measure if it released or not- can manipulate that- stimulate DHR- measure number of neutrophils reduced before and after stimulating the neutrophils
What colour should healthy neutrophils go after dye added in test?
Nitro blue tetrazolium dye reduction- healthy neutrophils should go purple
What are complements?
Non immunoglobulin proteins
What do complements do?
Cell lysis (kill invading bacterium)
Control of inflammation
Stimulate phagocytosis
What is the complement pathway?
Complement pathway- classical pathway, triggered by antigen antibody complexes. Alternative pathway- on polysaccharides on the surface of microbes, MBL pathway which is similar to the classical pathway.
All 3 culminate in the formation of the membrane attack complex which lyses bacterial cell surfaces.
What do membrane attack complexes do?
Membrane attack complex punches holes in the membrane and that causes cells to lyse. This leads to defects in complement that make you prone to infection.
What should complement do?
Complement should lyse foreign cells if the foreign cells are covered in antibody
Complement should lyse foreign cells if the foreign cells are covered in antibody. What will this do?
Will trigger the classical complement cascade
What does C2, C4 deficency cause?
C2,C4 deficiency
SLE- no clearing of cellular debris after an injury infection and leads autoimmunity, infections, myositis (inflammation and degeneration of muscle tissue)
What does C5-9 deficency cause?
C5-C9 (form membrane attack complex)Presents with repeated episodes of BACTERIAL meningitis
Particularly Neisseria meningitis
What does the antigen bind to in adaptive immunity? What does the thing it binds to present it to?
Antigen that binds to a B cell on the B cell receptor, present to MHC class 2 molecule which presents it to T helper cell.
What do T helper cells produce?
T helper cells (CD4): Produce cytokines that effect B cells and the recruitment of other immune cells. B cells differentiate to memory B cells and plasma cells which will produce antibodies
What are the types of T helper cells?
Various types T helper 1, T helper 2, T helper 9, T helper 17
What are the function of antibodies?
Abs- neutralises viruses or toxins, putting bacteria together, dissolving or precipitating antigen molecules. They activate complement and removing sinopulmonary bacterial infections
Male patient
Presented before the age of 5
3 hospital admissions from pneumonia
Recurrent chest infections in between
Sinusitis
Mothers brother passed away aged 35 from bronchiectasis- scarring of the lungs
Bloods:
No B cells, normal T cells – use flow cytometry to detect- measures individual cells
No IgG, IgA, IgM
CT: bronchial thickening, evidence of recent pneumonia
Diagnosis?
Primary Antibody deficiency
Types of primary antibodu deficency?
X linked agammaglobulinaemia (no Ab)- Suspicion confirmed with genetics
Defect in Bruton’s Tryrosine kinase (BTK):
- Needed for B cell signalling and B cell maturation
- B cell maturation not completed in the bone marrow
What is BTK deficency mechanism?
BTK is a downstream molecule of the B cell receptor which is an Ab stuck on the B cell, patient had no functioning BTK so has the disease- BTK encoded on the X chromosome- this leads to B cells in bone marrow where B cells are expressed, can’t mature passed this thus blockade at this stage. Females are carriers and males are affected.
What are other B cell defects?
CVID- common variable immune deficiency
IgA deficiency- most common antigen deficency
X linked hyper IgM syndrome
transient hypogammaglobulinaemia of infancy- when child born has IgG from mother not produced by themselves- can be a lag which leads to this disease
What do defects in B cells mean? What do you treat them with?
loss of antibody secretion
Usually leads to recurrent bacterial infection with pyogenic organisms
Treat with antibiotics then i.v IgG for life
Most are very serious
Some less serious e.g IgA deficiency
1 in 5-700
Some completely well
Higher risk of autoimmune diseases e.g. coeliac
50 year old female
History of rheumatoid arthritis- severe
No infections most of adult life, but two year history of recurrent bacterial chest infections- 5 courses of antibiotics over the winter period
PMH: asthma
Drug Hx: currently on methotrexate and infliximab, previously rounds on Rituximab. Has also had gold, sulfasalazine in the past
Ix: slightly low B and T cells, low IgG and IgA
Diagnosis?
Secondary antibody deficiency due to drugs
Comparatively common
What is the mechanism for rituximab on B cells?
Rituximab is on B cells- targets CD20 and eliminates them from the immune system, they will repopulate unlike in primary immunodeficiencies leads to a lower level of antibodies.
Rituximab, methotrexate, azathioprine, ciclosporin, prednisolone, cyclophosphamide affect the immune system.
HIV kills CD4 cells which causes secondary immunodeficency.
Antibody deficiency Treatment
Antibiotics
Immunoglobulin G replacement- given blood serum samples with IgG
What does chicken pox show as?
Mild disease
Typical vesicles
Severe herpes zoster infection
Fulminant disease
Haemorrhagic lesions
Child may have an immunodeficency
Female baby age 3months
Severe herpes zoster infection- what causes chicken pox
Hospitalised with extensive oro-pharyngeal candida
Parents first cousins- can be caused by consaguinity
Sibling died at age of 4 months with sepsis
What investigations? What diagnosis?
Investigations:
Normal levels of IgG, no IgA and reduced IgM
Lymphocyte markers show absent/reduced T and NK cells but present B cells
Severe Combined Immunodeficiency (SCID)
How to diagnose SCID?
Diagnosis
No T cells +
suggestive history
Treatment for SCID?
Paediatric emergency
Antibiotics, antivirals, antifungals
Asepsis
Haemopoietic stem cell transplant (only cure)
?screen
What are the causes of SCID?
Defect/absence of critical T cell molecule- TCR (T cell receptor), common gamma chain
Loss of communication- MHCII deficiency
Metabolic- Adenosine deaminase deficiency- leads to environment when B and C cells can’t survive in the blood
PRR (pathogen receptor recognition)- problem with IRAK4 what happens?
IRAK4à recurrent pneumonia, poor inflammatory response
Disorder of the function of phagocytes What happens?
Disorder of the function of phagocytes- digest bacteria but cannot destroy ità CGD (chronic granuloma disease)
Complement deficency probelm?
Complement- bacterial meningitis
What are primary antibody immunodeficencies caused by?
Antibodies- recurrent sinopulmonary infection- primary- innate inherited defect- X linked agammaglobulinaemia
What are secondary antibody immunodeficencies caused by?
secondary if we use more drugs
What is T cell deficency caused by?
T cells- SCID
Immunomodulation-definition
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response
A therapeutic effect of immunomodulation may lead to what?
A therapeutic effect of immunomodulation may lead to immunopotentiation, immunosuppression, or induction of immunological tolerance
Biologic- Immunomodulators Definition
Medicinal products produced using molecular biology techniques including recombinant DNA technology
Main classes of biologic immunomodulators?
Main classes
- Substances that are (nearly) identical to the body’s own key signaling proteins
- Monoclonal antibodies
- Fusion proteins
What are TNF molecules?
These all target TNF molecules which is an inflammatory cytokine which are used for various inflammatory conditions.
What does it mean fully humanised? Example of something that is?
Adalimumab which is monoclonal antibody which is fully humanised (from non-humans species to make more similar to humans).
What is chimeric? What is an example of chimeric?
Chimeric- problem with this is that it contains murine (relating to rodent) components which can be immunogenic and can cause an immune response against them.
Prior to having fully humanised monoclonal antibody which was targeting TNF was Infliximab- made of part human IgG molecule and part mouse which is attached for particular antibody.
What is etanercept?
Etanercept where can create a fusion protein where combine Fc portion of antibody with TNF receptor 2 which is found on surface cell which contain TNF with high affinity.
What is cerolizumab?
Certolizumab- uses a small proportion of antibody attached to a small arm of antibody attached to the regulated tail which allows it to become more stable in circulation- can target and neutralise TNF but this molecule unlike monoclonal antibodies doesn’t have potentially other side effects.
What is immunopotentiation
Enhancement of the immune response by increasing the speed and extent of its development and by prolonging its duration.
How can immunopotentation occur?
Immunisation:
- Active
- Passive
Replacement therapies
Immune stimulants
Definiton of immunisation passive?
Definition
transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection
Immunisation-passive problems?
Risk of transmission of viruses
Serum sickness- type 3 hypersensitive response
Immunisation-passive types?
- Convalescent plasma
- Pooled specific human immunoglobulin- form a pool from humans to give to patient
- Animal sera (antitoxins an antivenins)- inject into animals and they generate antibodies which can be used later on to neutralise- used in snake bites
Immunisation-passive uses?
COVID19, Hep B prophylaxis and treatment
Botulism, VZV (pregnancy), diphtheria, snake bites
Immunisation-active Definition
To stimulate the development of a protective immune response and immunological memory
Immunisation-active Immunogenic material?
- Weakened forms of pathogens
- Killed inactivated pathogens
- Purified materials (proteins, DNA, RNA)- recombinant vaccines
- Adjuvants- stimulates the immune response
Immunisation-active problems?
- Allergy to any vaccine component
- Limited usefulness in immunocompromised
- Delay in achieving protection
What are examples of replacement therapies and immune stimulation?
- Pooled human immunoglobulin (IV or SC)- Used in Rx of antibody deficiency states
- G-CSF/GM-CSF- small peptides to stimulate bone marrow- Act on bone marrow to increase production of mature neutrophils
- γ-interferon- Can be useful in treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 deficiency
Examples of immunosuppression?
- Corticosteroids
- Cytotoxic/ agents
- Anti-proliferative/activation agents
- DMARD’s- Disease-modifying antirheumatic drugs
- Biological-DMARD’s
What can corticosteroids do to the body?
- Decreased neutrophil margination
- Reduced production of inflammatory cytokines
- Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
- Lymphopenia- lower than normal lymphocytes
- Decreased T cells proliferation
- Reduced immunoglobulins production
What are the side effects of corticosteroids?
Carbohydrate and lipid metabolism
- Diabetes
- Hyperlipidaemia
Reduced protein synthesis
- Poor wound healing
Osteoporosis
Glaucoma and cataracts
Psychiatric complications
Corticosteroids-uses
- Autoimmune diseases -CTD (connective tissue diseases), vasculitis, RA
- Inflammatory diseases- Crohn’s, sarcoid, GCA (giant cell arteritis- swelling of BV)/polymyalgia rheumatica
- Malignancies- Lymphoma
- Allograft (organ from one person to another) rejection- transplantation
Drugs targetting lymphocytes- What do antimetabolites do? Examples?
Antimetabolites- prevent T cell proliferation
Azathioprine (AZA)
Mycophenolate mofetil (MMF)
Drugs targeting lymphocytes- what do calcineurin inhibitors do? Examples?
Calcineurin inhibitors – inhibit early stages of T cell activation
Ciclosporin A (CyA)
Tacrolimus (FK506)
Drugs targeting lymphocytes- MTOR inhibitors- what do they do? Examples?
M-TOR inhibitors- inhibit further stages of T cell activation
Sirolimus
Drugs targeting lymphocytes- IL-2 receptor mABs- what do they do?
IL-2 receptor mABs- block signalling of IL-2 receptor
Basiliximab
Daclizumab
What is CyA? What does it do?
Calcineurin inhibitors
Binds to intracellular protein cyclophilin
What is tacrolimus? What does it do?
Calcineurin inhibitors
Binds to intracellular protein FKBP-12
What is mode of action calcineurin inhibitors?
Mode of action
Prevents activation of NFAT (nuclear factor of activate T cells)
Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription
What are T cell effects of calcineurin inhibitors?
T cell effects
Reversible inhibition of T-cell activation, proliferation and clonal expansion- can control immunosuppression
What is sirolimus? What does it do?
Sirolimus (rapamycin)
Macrolide antibiotic
Also binds to FKBP12 but different effects
Inhibits mammalian target of rapamycin (mTOR)
What is the mode of action of sirolimus?
Mode of action
Inhibits response to IL-2
T cell effects of sirolimus?
T cell effects
Cell cycle arrest at G1-S phase
Calcineurin/mTOR-side-effects
- Hypertension
- Hirsutism- women grow facial hair and on chest and back
- Nephrotoxicity
- Hepatotoxicity
- Lymphomas
- Opportunistic infections
- Neurotoxicity
- Multiple drug interactions (induce P450)
Clinical use of drugs targetting lymphocytes?
Transplantation- Allograft rejection
Autoimmune diseases
What do antimetabolites do?
Inhibit nucleotide (purine) synthesis
What is azathioprine and what does it do?
Antimetabolites
Azathioprine
Guanine anti-metabolite
Rapidly converted into 6-mercaptopurine
What is mycophenolate? What does it do?
Antimetabolites
Mycophenolate mofetil (MMF)- Prevents production of guanosine triphosphate
What are the T and B cell effects of antimetabolites?
T and B cells effects
Impaired DNA production
Prevents early stages of activated cells proliferation
What doanti metabolites and cytotoxic drugs like methotrexate (MTX) and cyclophosphamide do?
Methotrexate (MTX)- Folate antagonists
Cyclophosphamide- Cross-link DNA
What are the advantages of antimetabolites?
Advantages of these are that the T cells that are activated are the ones that are rapidly dividing and in autoimmune conditions, the T cells that are rapidly dividing are against self-antigens of against transplant organs- when use the antimetabolite the cells that are potentially affected more are the cells that are rapidly dividing thus the autoreactive T cells are the ones being targeted preferentially by antimetabolite drugs
Cytotoxic drugs-side-effects
ALL
- Bone marrow suppression- as divides to form RBCs and neutrophils etc
- Gastric upset- as cells dividing rapidly to provide protection to acid environment
- Hepatitis
- Susceptibility to infections
Cytotoxic drugs-side-effects- Cylophosphamide
Cystitis
Cytotoxic drugs-side-effects- MTX
Pneumonitis- inflammation of lung tissue
Cytotoxic drugs-clinical uses
AZA/MMF
Autoimmune diseases (SLE, vasculitis, IBD)
Allograft rejection
Cytotoxic drugs-clinical uses- MTX
MTX
RA, PsA (psoriatic arthritis, Polymyositis, vasculitis
GvHD in BMT
Cytotoxic drugs-clinical uses- Cyclophosphamide
Cyclophosphamide
Vasculitis (Wagner’s, CSS)
SLE
Biologics-examples
- Anti-cytokines (TNF, IL-6 and IL-1)
- Anti-B cell therapies
- Anti-T cell activation
- Anti-adhesion molecules
- Complement inhibitors
- Check point inhibitors
Anti-cytokines mAB’s- Anti-TNF uses?
Anti-TNF
First biologics to be successfully used in therapy of RA (multiple different agents now licensed)
Used in a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis)
Caution: increase risk of TB
Anti-cytokines mAB’s (monoclonal antibodies)- Anti-IL-6 (Tocilizumab) use?
Blocks IL-6 receptor
Used in therapy of RA and AOSD (adult-onset Still’s disease- type of arthritis)
May cause problems with control of serum lipids
Anti-cytokines mAB’s (monoclonal antibodies)- Anti-IL-1 use?
Used in treatment of AOSD and autoinflammatory syndromes
Rituximab what is it?
Chimeric mAb (part mouse part human) against CD20- B cell surface
Rituximab uses?
- Many uses:
- Lymphomas, leukaemias
- Transplant rejection
- Autoimmune disorders- targets specific proportion of B cells- only binds to the population that is within the circulation- doesn’t affect the cells that are dividing within the bone marrow- advantages is if you are targeting the cells in circulation you are hoping to wipe out all of the auto-immune diseases and not destroying the early B cells in the bone marrow. Allowing long lived plasma cells to produce Ab to provide protection against various infections.
Example of adoptive immunotherapy?
Bone marrow transplant (BMT)
Stem cell transplant (SCT)
Adoptive immunotherapy uses?
- Immunodeficiencies (SCID)- replace immune system with donor one
- Lymphomas and leukaemias
- Inherited metabolic disorders (osteopetrosis)
- Autoimmune diseases
What are check point inhibitor uses?
These drugs used for treatment in malignancies
WHat happens in normal T cell activation?
In normal T cell activation there is APC which can stimulate the immune cells by interaction with T cell receptor and providing co-stimulatory signals but tumours have evolved ways to interfere with activation of T cells so they can block this important signal which is necessary for T cell activation.
How do tumours interfere with T cell activation?
- Tumour cells can express certain molecules such as PDL-1 which inhibits activation of T cells. There are monoclonal antibodies which interfere with these processes. CTLA-4 supress the molecule on T cells preventing T cell activation
- By providing anti-CTLA4 antibodies into the system you restart T cell activation and allow immune system to be rebooted
- Anti-PDL1 monoclonal antibody which blocks the molecule PDL1 which is produced by tumours which reduces T cell activation
What are examples of immunomodulators?
- Immune suppressants
- Allergen specific immunotherapy
- Anti-IgE monoclonal therapy
- Anti-IL-5 monoclonal treatment
When is allergen specific immunotherapy needed?
Indications:
- Allergic rhinoconjutivitis not controlled on maximum medical therapy
- Anaphylaxis to insect venoms
What is the mechanism for allergen specific immunotherapy?
Mechanisms:
Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T reg cells and tolerance
Routes for allergen specific immunotherapy?
Routes:
SC or sublingual for aero-allergens
Side effecrs of allergen specific immunotherapy?
Side-effects:
Localised and systemic allergic reactions
What is omalizumab used for?
Omalizumab
- mAb (monoclonal Ab) against IgE
- Used in Rx (to take) of asthma
- NICE approved for chronic urticaria and angioedema
- May cause severe systemic anaphylaxis
What does mepolizumab do? What does it prevent?
- mAb against IL-5- cytokine that activates eosinophils and causes recruitment and activation
- Prevents eosinophil recruitment and activation
- NICE approved for asthma
- No clinical efficacy in hypereosinophilic syndrome
