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Semester 4 Missed Lectures > Immunity > Flashcards

Immunity Flashcards

1
Q

What are the 4 types of blood groups and what are their associated antigens and antibodies?

A
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2
Q

What are the different rhesus antigens?

A

C, c, D, E, e.

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3
Q

What are the symptoms of haemolytic disease of the newborn?
State why they occur.

A

Enlarged liver or spleen due to extramedullary haematopoiesis.
Generalised oedema due to heart failure from severe anaemia.
Yellowing of the skin and sclera due to excess bilirubin accumulation.

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4
Q

What lab tests are performed during pregnancy to confirm destruction of red blood cells?

A

Testing the amniotic fluid or blood from the umbilical cord for bilirubin (unconjugated).

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5
Q

How can haemolytic disease of the newborn be predicted?

A

Testing the mother for her rhesus antigens - negative is more likely.
Testing the baby for their rhesus antigens - positive is more likely.
Testing the mother for autoantibodies against rhesus D antigens.
Testing for anaemia or bilirubin from the umbilical vein.

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6
Q

How does RhoGam work?

A

Binds to fetal blood rhesus D antigens, preventing the identification of the positive antigen, preventing production of anti-rhesus-D antibodies.

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7
Q

When should RhoGam be administered?

A

From week 8 if anti-rhesus D antibodies have been formed before.
From week 28 if the mother’s status wasn’t known prior to this pregnancy.

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8
Q

What is the direct and indirect Coombs test?

A

Direct - tests the baby’s blood for rhesus-D antibodies, bound to the RBCs after birth.

Indirect - tests the mother’s blood for rhesus-D antibodies.

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9
Q

What are some serological tests that can help confirm diagnosis of myasthenia gravis?

A

Anti-AChR antibodies.
Anti-striated muscle antibodies.
Anti-tyrosine antibodies.
Anti-thyroid antibodies.

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10
Q

Why can babies transiently present with myaesthenia gravis?

A

The anti-AChR antibodies are IgG and so can cross the placenta, but are eventually degraded within the body so no longer block the AChRs.

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11
Q

Other than myaesthenia gravis, what are some type V hypersensitivity reactions?
Also, state what subset of hypersensitivity type V is of.

A

Grave’s disease - stimulates TSH receptors.
Pernicious anaemia - protein blockade, against intrinsic factor in gastric parietal cells.

Type II hypersensitivity reactions.

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12
Q

What is an antigen?

A

Any substance that triggers an immune response as form of effector T/B cells and antibodies.

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13
Q

What are some cell bound antigens seen in type II hypersensitivity reactions?

A

Exogenous - blood group antigens, rhesus D antigens.

Endogenous - self-antigens (autoimmune).

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14
Q

What are the potential complications of haemolytic disease of the newborn?

A

Hydrops fetalis.
Hepatomegaly/ splenomegaly.
Severe hyperbilirubinaemia.
Kernicterus - brain damage due to unconjugated bilirubin crossing the BBB.

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15
Q

What is the Fc receptor, and how can we target this?

A

A receptor on immune cells and components that can be blocked by immunoglobulins to prevent activation.

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16
Q

What is the pathogenesis of type IV hypersensitivity reactions?

A

Sensitisation - antigen presenting cells present the antigen to t-helper1 cells, activating them.

Effector - TH1 then produces cytokines such as IFN-gamma, TNF-beta, interleukin-1 and -2.
The cytokines then activate the macrophages, causing superoxide radicals and nitric oxide to be produced, destroying tissues.

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17
Q

What are some steroid sparing agents used in treatment of type III and type IV hypersensitivity reactions?

A

Anti-proliferative - azathioprine, mycophenolate meofetil.
Cytotoxic - cyclophosphamide.
Anti-metabolite - methotrexate.
Anti-T-cell - cyclosporin.

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18
Q

What are the functions of TH2 cells, and what are they activated by?

A

B-cells - IgE and IgG production.
Eosinophils - killing pathogens.
Mast cells - allergies.

IL-4.

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19
Q

What are the different types of allergens?
State some examples.

A

Seasonal exposures - tree/ grass pollens.

Perennial exposure (all the time) - house mite dust, animal dander and fungal spores.

Accidental exposure - insect venom, medicines such as penicillin, latex, foods (milk, nuts and shellfish).

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20
Q

What is the hygiene hypothesis?

A

Children exposed animals, pets and microbes in the early postnatal period have greater protection against certain allergic diseases.

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21
Q

What is the biodiversity hypothesis?

A

Western lifestyle induces alteration of the symbiotic relationships with parasites and bacteria, leading to dysbiosis (compositional and functional alterations of the microbiome).

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22
Q

What can the impact of dysbiosis be?

A

Increased auto-immune diseases - crohns, UC, allergies, etc.
Obesity.
Type II diabetes.
Colorectal cancer.
Autism.

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23
Q

What is the sensitisation of allergies?

A
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24
Q

What is the effector phase of allergens?

A
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25
Q

What are the red and white patches of urticaria due to?

A

Red - vasodilation.
White - increased vascular permeability.

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26
Q

What are some signs and symptoms of anaphylaxis?

A
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27
Q

What are some treatments for abnormal adaptive immune responses against the allergens?

A

TH2 response - allergen desensitisation.
Omalizumab - anti-IgE monoclonal antibody.
Mepolizumab - anti-IL5 monoclonal antibody.

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28
Q

What are the two classifications of auto-immune diseases?
State some examples of each.

A

Organ specific - Goodpasture’s syndrome, haemolytic anaemia, myaesthenia gravis, grave’s disease.

Non-organ specific - rheumatoid arthritis, SLE.

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29
Q

What is allergic asthma?

A

The symptomatic presentation of asthma of wheeze, cough, shortness of breath and tight chest, secondary to an allergy.

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30
Q

What is urticaria?
State the two types.

A

Maculopapular pruritic or itchy rash, which can be chronic or acute.
Acute is less than 6 weeks.
Chronic is greater than 6 weeks - chronic spontaneous urticaria.

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31
Q

State some differences between IgE and non-IgE mediated food allergies - symptoms onset, common foods and presenting age.

A
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32
Q

What is pollen food syndrome?

A

The most common food allergy in adults, where a cross-reactivity between the pollens of fruit, vegetables, nuts and pollens cause hay fever, due to having a similar structure as birch pollen.

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33
Q

Why do patients not get systemic symptoms with pollen food syndrome?

A

The stomach acids and heat denature the allergens, preventing absorption.

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34
Q

What is the immune-dominant protein of eggs and why?

A

Ovomucoid - it is heat stable, not heat labile.

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35
Q

What factors influence the presentation of food allergy?

A

Age.
Natural history of the allergy.
Cross-reactivity amongst other foods.
Food processing.

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36
Q

What are often the first changes seen in deteriorating children?

A

Changes in respiratory rate - can increase or decrease.

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37
Q

What value determines whether a skin-prick test is positive, and what are the controls of this test?

A

If the rash is 3mm or more, then it is positive.

Positive control - histamine, to check that the test works.
Negative control - saline.

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38
Q

What is the most common cause of an urticaric rash, and what are the associated symptoms?

A

Viral infections.

Headaches and fever, most commonly.

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39
Q

What is the dual allergen hypothesis?

A

Oral exposure to potential allergens can lead to the development of Th1 and Treg memory cells, which increases the likelihood of tolerance for that allergen.

Cutaneous exposure to allergens through the skin can lead to development of Th2 memory cells, which increases the likelihood of allergy.

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40
Q

What interleukins cause the class switching of B-cells?
Explain this.

A

IL-4 and IL-13.

B-cells begin to produce IgE instead of IgM, upon sensitisation of an allergen.

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41
Q

What are the 9 most common IgE food allergens?

A

Milk.
Eggs.
Fish.
Crustacean fish.
Tree nuts.
Peanuts.
Wheat.
Soya.
Seasame.

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42
Q

What are the 4 most common non-IgE food allergens?

A

Soya.
Wheat.
Egg.
Milk.

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43
Q

What are some non-allergen factors that can increase the risk of IgE-mediated allergies?

A

Alcohol consumption.
Exercise.
Menstrual period.

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44
Q

What are the exposure, most common allergens, timing, environment and reproducibility of an IgE mediated food allergy?

A

Exposure - eating, skin contact or inhaled by aerosol.

Allergens - milk, egg, peanut and tree nuts.

Timing - typically 5-30 minutes, always within 1-2 hours of ingestion, at first known exposure.

Environment - new part of the diet; during weaning or at restaurants.

Reproducibility - always has symptoms with exposure.

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45
Q

What are the exposure, most common allergens, timing, environment and reproducibility of an non-IgE mediated food allergy?

A

Exposure - eating or if breastfed, through the mother’s diet.

Allergen - soya or milk.

Timing - within 1-72 hours after ingestion, within the first year of life.

Environment - regular part of the diet, of the person or mother (breastfed).

Reproducibility - symptoms settle on dietary exclusion within 2-14 days.

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46
Q

How can we confirm a non-IgE mediated food allergy?

A

Remove the potential allergen for 4 weeks, where symptoms should improve.
Add the potential allergen back into the diet, and the symptoms should worsen again.

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47
Q

What are the common symptoms for non-IgE mediated food allergies?

A

Eczema.
Fore- and midgut - vomiting, reflux, colic, dysphagia, food bolus impaction.
Hindgut - diarrhoea/ constipation, mucous and/ or blood stools, erythema around the anus.

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48
Q

What are the red flags for IgE and non-IgE mediated food allergies?

A

IgE - anaphylaxis.
Non-IgE - vomiting and diarrhoea, leading to shock and collapse. Poor growth.

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49
Q

What are the different types of food challenges?

A

Open food challenge - the patient knowingly ingests the food.
Single blinded challenge - the food is ingested by the patient without their knowledge.
Double-blinded placebo controlled food challenge - within a research setting, where the investigator and patient doesn’t know when they are ingesting the food.

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50
Q

What does a positive SPT and sIgE show, physiologically?

A

IgE bound to cutaneous mast cells, leading to the release of histamine-containing granules.

Specific IgE - a specific IgE within the blood.

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51
Q

If a baby who is breastfeeding has an allergy to cows milk, what is the first line treatment?

A

Maternal exclusion of all milk products, to continue the baby breastfeeding.

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52
Q

What does the higher the specific IgE concentration show?

A

The increased likelihood that they have the allergy.

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53
Q

What are some differences between pollen food syndrome and a primary nut allergy?

A

PFS:
- Has a history of isolated symptoms in the oropharynx or throat.
- Has a reaction to raw but not cooked nuts.
- Has a reaction to raw fruits.
- Has previously tolerated nuts.

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54
Q

What are some nuts that frequently cause pollen food syndrome?

A

Hazelnuts.
Peanuts.
Almonds.
Walnuts.
Brazil nuts.

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55
Q

What is the interpretation of the following results?

1) History of acute reaction with identifiable trigger, with a positive test.

2) No history with a positive test.

3) Has no reaction to the food and has a positive test.

A

1) Allergy.
2) Sensitisation.
3) Sensitisation but tolerant.

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56
Q

What is FPIES?

A

Food protein-induced enterocolitis syndrome - a non-IgE mediated food allergy that typically presents in infancy with repetitive vomiting, around 1-4 hours after food ingestion.

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57
Q

What are some common symptoms and complications of FPIES?

A

Pale/ lethargy/ limpness/ floppy.
Diarrhoea.
Dehydration.

Hypotension.
Hypothermia.

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58
Q

What are the most common foods that cause FPIES?

A

Milk.
Soya.
Fish.
Egg.
Rice.

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59
Q

What is anaphylaxis?

A

A severe life threatening systemic hypersensitivity reaction that has a rapid onset with airway, breathing or circulation problems, which is usually associated with skin or mucosal changes.

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60
Q

What are the 3 pathogenesis’ of anaphylaxis?

A

IgE - food, drug, insect stings or other allergic reactions.

Immunological others - immune aggregates, complement system activation, coagulation system activation, autoimmune mechanisms.

Non-immunological - exercise, cold, alcohol, medicines.

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61
Q

What are some symptoms of anaphylaxis associated with the following systems, and state what mediators are associated here:
- Upper respiratory.
- Lower respiratory.
- Digestive.
- Cardiovascular.
- Skin.

A
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62
Q

What are the most common known allergens causing anaphylaxis in adults and children?

A

Adults - tree pollen and unidentified nuts.
Children - milk.

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63
Q

What are some factors that amplify the effects of anaphylaxis?

A

Age - very old or very young.
Asthma and other respiratory diseases.
CVD.
Exercise.
Infection and stress.

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64
Q

What are the 2 criteria of diagnosing anaphylaxis?

A

1:
- Acute onset illness, with involvement of the skin and/ or mucosal tissue with.
- Respiratory compromise, reduced BP or end-organ dysfunction, or severe gastrointestinal symptoms.

2:
- Acute onset hypotension or bronchospasm or laryngeal involvement, after exposure to a known or highly probable allergen.

65
Q

What is the acute management of anaphylaxis?

A

Remove the allergen.
Posture - laid down or sitting up.
IM adrenaline.
IV fluid bolus.

66
Q

What is the optimal method for further doses of adrenaline?

A

IV via needle or syringe as there is a more sustained optimal concentration.

67
Q

Why is IV fluid given in anaphylaxis?

A

Restores venous return.
Can help to distribute the adrenaline.

NOTE: crystalloids first and then Hartmann’s or plasma-Leyte.

68
Q

What is done for refractory anaphylaxis?

A

Expert help is sought.
An IV access is established.
Give rapid IV fluid bolus.
Start adrenaline infusion.
Non-sedating antihistamines after stabilisation.
Corticosteroids after initial resuscitation.

69
Q

Define:
- rhinitis.
- rhino-conjunctivitis.
- rhinosinusitis.

A

Rhinitis - inflammation of the nasal mucosa with rhinorrhoea, nasal blockage, itchiness and/ or sneezing.

Rhino-conjunctivitis - inflammation of the nasal mucosa with rhinorrhoea, nasal blockage, itchiness and/ or sneezing; involving the conjunctivae.

Rhinosinusitis - inflammation of the nasal mucosa with rhinorrhoea, nasal blockage, itchiness and/ or sneezing; involving the sinus linings.

70
Q

What are the 3 types of rhinitis?

A

Allergic.
Infective - most commonly viral.
Non-allergic - a risk factor for the development of asthma, which may be eosinophilic and steroid-responsive.

71
Q

What are the allergens of allergic rhinitis?

A

Hay.
Pollen.
Dust.
Animal hair.
Mould spores.

72
Q

What are the 4 classifications of allergic rhinitis?

A

Intermittent vs persistent - less/ more than 4 days a week, or less/ more than 4 consecutive weeks.

Mild vs moderate-severe - changes or not to:
- Sleep.
- Daily activities, sport and leisure.
- Work and school.
- Symptoms present and troublesome or not.

73
Q

What is the aetiology of allergic rhinitis?

A

Genetic predisposition.
Environmental factors.
Urban environments.
Epigenetic modifications.

74
Q

What are the early and late phase response in allergic rhinitis?

A

Acute - within minutes:
- Histamine, tryptase, prostaglandins and leukotrienes are released.
- Mucosal oedema, mucous hypersecretion and sensory nerve stimulation occurs.

Late - 4-6 hours:
- Chemokines and cytokines such as IL-4 and IL-5 are released.
- Infiltration of inflammatory cells; T-cells, eosinophils, basophils, neutrophils and monocytes occurs.

75
Q

What occurs in house-dust mite exposure?

A

Proteases from the HDMs disrupt the epithelial barrier, causing infiltration.
CD40 is cleaved from dendritic cells.
IgE overproduction from-cells occurs.
Th1 cell proliferation is decreased.
Increased IL-6 secretion, causing Th2 proliferation.
IL-4 and IL-13 are released from Th2.
HDM proteases cleve pulmonary surfactant, decreasing lung clearance of allergens.

76
Q

What are some common co-morbidities of allergic rhinitis?

A

Asthma.
Conjunctivitis.
Rhinosinusitis.
Otitis media with effusion.
Oral allergy syndrome - throat and laryngeal effects.
Sleep problems and secondary effects - concentration, mood, behaviour and work/ school performance.

77
Q

How is allergic rhinitis diagnosed?

A

For more than 1 hour a day, there must be 2 or more of the following:
- Sneezing, nasal itching, itching of the palate.
- Rhinorrhoea.
- Nasal obstruction.
- Snoring, sleep problems, repeated sniffing, nasal voice.
- With or without conjunctivitis.

78
Q

What can be seen on examination of a patient with allergic rhinitis?

A

Allergic salute/ horizontal nasal crease across the nasal dorsum.
Dennie-Morgan lines.
Hypertrophic, pale and boggy inferior turbinates.
Clear, coloured or purulent secretions.

79
Q

What are some differential diagnoses for children below and above the age of 2?

A

Below:
- Adenoidal hypertrophy.
- Acute or chronic sinusitis.
- Choanal atresia.
- Foreign bodies.

Above:
- Acute infectious rhinitis.
- Chronic non-allergic rhinitis.
- Atrophic rhinitis.
- Rhinitis medicamentosa.
- Nasal polyps.

80
Q

What is allergic rhinitis a risk factor for?

A

The development of asthma.

81
Q

What are some investigations for allergic rhinitis?
State when each of them are useful.

A

Skin prick test - first line.
Specific allergen IgE - extensive skin disease, unable to discontinue antihistamines, dermatographism.

82
Q

What are the treatments for allergic rhinitis?

A

Avoidance of allergens.

Saline rinses.
Antihistamines.
Intranasal steroids.
Combinations - antihistamines and Intranasal steroids.
Ipratropium bromide.
Immunotherapy.

83
Q

What are the surgical interventions for allergic rhinitis?

A

Septoplasty.
Turbinate reduction.

84
Q

What are some symptomatic therapies for allergic rhinitis?

A

New antihistamines - fexofenadine, cetirizine, loratadine.
Intranasal antihistamines - olopatadine.
Intranasal corticosteroids.
Leukotriene receptor antagonists - montelukast.
Nasal decongestants.
Nasal sprays - pseudophedrine (sudafed).

85
Q

What intranasal corticosteroids are given for those >3 and >4?

A

> 3 - mometasone furoate.
4 - fluticasone propionate.

86
Q

How do nasal decongestants work?

A

Agonistic actions at alpha-1 and alpha-2 adrenergic receptors on endothelial cells of nasal mucosa, reducing mucosal swelling.

87
Q

What can cause rhinitis medicamentosa and what is given to treat this?

A

Overuse of nasal decongestants.

Intranasal corticosteroids.

88
Q

What are some immunomodulating therapies for allergic rhinitis?

A

Subcutaneous immunotherapies.
Sublingual immunotherapies.

Given if SNOT-20 score is high.

89
Q

How do immunotherapies work in allergic rhinitis?

A

Regulatory cells - Treg, Breg, Tfr, DCreg, NKreg, IL-10+ILC cells - are induced to produce IL-10.
IL-10 suppressed Th2 cells.
Immunoglobulin class switch occurs, from IgE to IgA.

90
Q

Why does Grave’s disease cause exophthalmos?

A

Infiltration of T-cells behind the eyes, causing muscle inflammation.

91
Q

What are the genetic factors associated with Hashimoto’s disease?

A

HLA-DR3 and HLA-DR4 - HLA class II alleles.

92
Q

What is mimicry?

A

Where autoantibodies attack self-antigens due to the epitope of the tissue being similar to that of an infectious microbe.

93
Q

How long can transient auto-immune conditions affecting newborn babies last for?

A

6 months as IgE/ IgG crosses the placenta, but fades after this period of time.

94
Q

What are autoimmune rheumatic diseases?

A

A heterogenous group of diseases that affect multiple systems, that result from a break in immune tolerance by producing pathogenic antibodies.

95
Q

What life limiting condition is rheumatoid arthritis associated with?

A

Cardiovascular disease.

96
Q

What 3 auto-immune diseases more commonly manifest in childhood?

A

Type I diabetes mellitus.
Coeliac disease.
Auto-immune hepatitis.

97
Q

What is immunological tolerance?

A

A diverse range of host processes that prevent potentially harmful immune responses against host antigens.

98
Q

What organ of the body usually removes auto reactive T- or B-cells?

A

The thymus.

99
Q

What are some autoantibody-driven causes for tissue damage?
State which hypersensitivity reactions these are more commonly seen in.

A

Complement activation.
Antibody-mediated cell cytotoxicity.
Neutrophil activation.

Most commonly seen in type II and type III hypersensitivity reactions.

100
Q

What are some autoreactive T cell-driven causes for tissue damage?
State which hypersensitivity reaction these are more commonly seen in.

A

Cytotoxic T cells.
Macrophages.

Type IV hypersensitivity.

101
Q

How is indirect immunofluorescence performed?

A

A healthy tissue biopsy is taken, which acts as a template.
Serum is taken from the affected patient, and applied to the healthy tissue.
A fluorescent dye is then given which binds to the autoantibodies/ autoreactive T cells.

102
Q

What are the different tissues and techniques used for the following diseases?

A
103
Q

What are AIRE mutations and what syndrome can it cause?

A

Auto-immune regulatory genes, causing APECED syndrome - a group of diseases affecting more than 1 endocrine gland.

104
Q

What auto-immune disease can chlamydia trachomatis cause?

A

Haemolytic anaemia.

105
Q

Before diagnosing rheumatic diseases, what other conditions which can cause multi-system features need to be ruled out?

A

Infections, such as sepsis and HIV.
Cancer.

106
Q

What are the importance of autoantibodies to clinicians?

A

They aid diagnosis.
They are associated with specific clinical features.
They can help guide disease prognosis.
They can stratify therapy.

107
Q

What auto-antibodies are associated with lupus?

A
108
Q

What does A RASH POINTS MD mean?

A
109
Q

What is the classification criteria for rheumatoid arthritis based off of?

A

Joint distribution - 0-5.
Serology - 0-3.
Symptoms duration - 0-1.
Acute phase reactants - 0-1.

Definite rheumatoid arthritis is 6 or more.

110
Q

What are the routine tests and autoantibody tests performed for rheumatoid arthritis?

A
111
Q

How does synovitis occur in rheumatoid arthritis?

A

Interaction of macrophages and T- and B-lymphocytes cause an over-production of TNF-alpha.
TNF-alpha causes over-production of IL-6 and other cytokines.

112
Q

In rheumatoid arthritis, what do the self-proteins that the body has a loss of tolerance to contain?

A

Citrullinate residues.

113
Q

What does ACPA denote?

A

Anti-CCP (citrulinated protein) and anti-rheumatoid factor.

114
Q

What is the pathogenesis for SLE?

A

Cell death causes cellular blebs containing nuclear constituent antigens to form.
Phagocytes fail to remove these blebs, so they are transferred to lymphoid tissues to be taken up by APCs.
The antigens are presented to T-cells, which then cause B-cells to produce autoantibodies against the antigens.

115
Q

What are the immunological consequences for SLE?

A

Autoantibodies form circulating complexes or deposit by binding directly to tissues.

Activation of complement and influx of neutrophils, causing inflammation.

Abnormal cytokine production.

116
Q

Where do the immune complexes get deposited in, in SLE nephritis?

A

Glomeruli and mesangium.

117
Q

What are the immune deposits of SLE nephritis?

A

IgG, IgM and IgA.
Complement components - C3, C1q, C4.

118
Q

What are the two arms of an antibody and what are their functions?

A

FAB - contains the hypervaraibe region of light chains which can binds to antigens.

Fc - binds to receptors of other immune cells, eliciting an immune response.

119
Q

What are the functions of monoclonal antibodies?

A

Used for diagnosis of conditions, via immunohistochemistry - fluorescent tags or enzyme linked.

Therapeutics.

120
Q

What are monoclonal antibodies?

A

Monovalent antibodies which bind to the same epitope and are produced from a single B-lymphocyte.

121
Q

What is the hyrbidoma generation?

A

A specific epitope on an antigen is injected into a mouse.
The mouse then produces B-lymphocytes in response to the antigen and so the spleen is removed.
The B-lymphocytes are then harvested from the spleen.
The B-lymphocytes are then fused with immortal myeloma cells, forming a hybridoma cell.
These hybridoma cells are then cultured.
Selected hybridomas then have their specific desired monoclonal antibodies removed for use.

122
Q

What are the characteristics of monoclonal antibodies?

A

They are specific.
They can be targeted against almost any cell-surface receptor.

123
Q

What are the 4 types of ‘naked’ monoclonal antibodies?

A

Murine - 100% foreign. Has the suffix -omab.

Chimeric - 65% human, containing a human fc region. Has the suffix -ximab.

Humanised - over 90% human. Has the suffix -zumab.

Fully human - has the suffix -umab.

124
Q

What is the relevance of have a greater proportion of the monoclonal antibody as human?

A

They are recognised less as foreign and so are removed by the body less quickly - have a longer half life - they are less immunogenic.

125
Q

What are conjugated monoclonal antibodies and what characteristic must they have to be functional?

A

An antibody-drug compound, where the drug is a highly toxic compound.

The antibody must be internalised by the target cell, where the toxic compound can be cleaved from the antibody by lysozyme, allowing it to destroy the target cell.

126
Q

What are bispecific antibodies?

A

Antibodies that can bind to two or more different epitopes, used to target tumour antigens and engage T-cells by bringing them closer to the target cell (usually cancer).

127
Q

What are the different mechanisms of action of monoclonal antibodies?

A

Bind to cell surface receptors inducing cell death.

Binding to cell-surface receptors activating:
- Antibody-dependent cell-mediated cytotoxicity.
- Complement-dependent cytotoxicity.

Internalisation for antibodies delivering toxins into the cancer cell.

Cell checkpoint inhibitors of T-cells, allowing them to help kill cancer cells.

Binding with cell surface receptors activating or inhibiting signalling within the cell.

128
Q

What is cluster of differentiation classification?

A

The different types of cell surface receptors, which an be used to kill certain cancer cells.

129
Q

How does rituximab work?

A

Kills mature B-cells that all contain CD20, including the lymphomas, by activating other immune cells - ADCC pathway.

The maturing B-cells within the bone marrow do not express the CD20 so are not killed.

130
Q

What are the different types of lymphomas?

A

B-cell and T-cell neoplasms - clinal proliferations of lymphoid cells, causing enlargement of lymph nodes.

131
Q

What are some extra-nodal areas that are often involved in lymhpomas?

A

Spleen.
Bone marrow.
Liver.
Skin.
Testes.
Bowel.

132
Q

What are some B-symptoms for lymphoma?
State the relevance of this.

A

Drenching night sweats.
Fever over 38 degrees Celsius.
Weight loss of greater than 10% in 6 months.

Worse prognosis for people that present with these symptoms.

133
Q

What are some different high and low grade B-cell lymphomas and their presentation?

A

High grade - follicular lymphomas, where the B-cells retain their follicular pattern. These have a slower onset.

Low grade - diffuse large cell B-cell lymphoma, where the larger B-cell lymphocytes are found in a diffuse pattern all over the lymph node. These present with a faster onset.

134
Q

What are the different treatment strategies in lymphoma?

A

Chemotherapy.
Radiotherapy.
Monoclonal antibody therapy.
Emerging new targeted therapy.
Stem cell transplantation.
Steroids.

135
Q

What are autologous and allogeneic stem cell transplants?

A

Autologous - the removal of their own stem cells, administration of chemotherapy and then re-administration of their own stem cells.

Allogeneic - the administration of other peoples stem cells.

136
Q

What are the side effects of monoclonal antibodies?

A

To non-fully human monoclonal antibodies:
- Mild reactions at their first infusion is relatively common.
- Very uncommonly, there can be severe infusion reactions.

137
Q

What are the common experiences for infusion related reactions?

A

Facial flushing.
Nausea.
Vomiting.

138
Q

How are infusion related reactions prevented?

A

Start at a slow infusion rate and slowly increase if tolerated.
Steroids.
Anti-histamines.
Paracetamol.

Ensure the patient has stopped their anti-hypertension medications for at least 12 hours before their infusion.

139
Q

What are some monoclonal antibodies used to treat solid cancers, and what are their mechanism of action?

A

Trastuzumab - inhibits HER-2 signalling.
Ipilimumab - inhibits CTLA-4 signalling.
Nivolumab/ pembrolizumab - inhibits PD1 signalling.

140
Q

What are some monoclonal antibodies used to treat autoimmune conditions, and what are their mechanism of action?

A

Infliximab and adalimumab - TNF-alpha.

141
Q

What are some monoclonal antibodies used to treat cardiology, and what are their mechanism of action?

A

Abciximab - platelet glycoproteins IIb/IIIa inhibitor.

142
Q

What are some monoclonal antibodies used to treat respiratory, and what are their mechanism of action?

A

Mepolizumab - IL-5 inhibitor.

143
Q

What are some monoclonal antibodies used to treat dermatology, and what are their mechanism of action?

A

Ustekinumab - IL-12 and IL-23 inhibitor.

144
Q

What is given to prevent tumour lysis syndrome?

A

Allopurinol - decreases uric acid production.

Rasburicase - increases excretion of uric acid.

145
Q

How do CD8+ cells kill cancer cells?

A

They bind to cancer cells and release enzymes such as perforin and granzyme.

146
Q

How do tumours evade the immune system?

A

Down-regulation of MHC molecules, preventing recognition of the tumour cells, by the immune system.

Binding to T-cells by the cancer cells by certain ligands can cause T-cell inhibition, preventing their activation.

Immunosuppression - activation or differentiation of T-cells is inhibited.

147
Q

What are checkpoints inhibitors?

A

Checkpoint inhibitors are drugs that inhibit immune checkpoints - certain molecules that are over expressed on cancer cells - leading to T-cell activation.

148
Q

What are some immune checkpoints on T-cells that are over-expressed on cancer cells?

A

PD-1.
CTLA-4.
PD-L1.

149
Q

What are the drawbacks to checkpoint inhibitors?

A

They can stimulate auto-immune conditions.

150
Q

What are some targets for cancer vaccines?

A

Tumour-associated antigens - self-proteins that are over-expressed in cancers.
Cancer testis antigens - non-self antigens.
Oncoviral antigens.
Shared and private neoantigens - foreign to the body.

151
Q

How are cancer vaccines formed?

A

A cancer tissue is sampled.
The DNA is sequenced.
Neoantigens and HLA are found.
Vaccine development.
Administration.
Immune monitoring.

152
Q

How do chimaeric antigen receptors (CARs) work?

A

T-cells from patients are genetically engineered, by inserting DNA through lentiviruses forming CARs, allowing them to bind to the cancer.

153
Q

How are non-self T-cells modified for CAR therapy?

A

Removal of CD7 (present on most T-cells) - prevents the removal from T-cells.
Removal of CD52 to prevent rejection.
Removal of T-cell receptors to prevent the T-cell from attacking the body’s tissues.

154
Q

Describe how the bispecific antibody aduzumab works.

A

It has two arms:
- CD3 arm which binds to the T-cell.
- CD20 arm which binds to the neoplastic B-cell.

This brings the T-cell close to the B-cell, whilst activating it, allowing for perforin and granzymes to kill the cancer cell.

155
Q

What are the advantages and disadvantages of bispecific antibodies?

A

Advantages:
- Good access to them.
- Favourable toxicity.

Disadvantages:
- Dependent on the persons T-cell function.
- Durability less clear.
- Long term administration.

156
Q

What are some T-cell engaging toxicities?

A

Cytokines release syndrome.
Immune effector cell-associated neurotoxicity syndrome (ICANS).
Aplasia - B-cell absence.
Infection.
Mutations leading to antigen escape.

157
Q

What is cytokine release syndrome?
State how it is treated and some symptoms (haematological, constitutional, cardiovascular, renal, pulmonary, hepatic, gastrointestinal and MSK).

A

An early response to T-cell therapy, causing expansion and activation of T-cells.

It is treated with steroids and tociluzumab (IL-6 inhibitor).

158
Q

What is immune effector cell-associated neurotoxicity syndrome?
State how it is treated and some symptoms of it.

A

It is an antigen independent reaction, occurring 1-3 weeks after therapy starts, causing damage to the blood-brain barrier.

It is treated with steroids.

159
Q

Why do T-cells engaging therapies fail?
Describe them.

A

Tumour intrinsic factors - target antigen loss, switching of the lineage (phenotype), or loss of CD58 so does not interact with T-cells.

Tumour extrinsic factors - limited CAR T-cell expansion, T-cell exhaustion, reduced CAR T-cell persistence.

Immune biomarkers.

Semester 4 Missed Lectures (4 decks)

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