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MCD 2- Immunology > Immunology > Flashcards

Immunology Flashcards

1
Q

What does an appropriate immune response respond to?

A

Foreign harmful agents
E.g. viruses, bacteria, fungi, parasites

-> eliminate pathogens (if pathogen has already caused damage, repair quickly)

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2
Q

What is the role of antigens in appropriate immune reactions?

A

Involves antigen recognition by cells of immune system

Antibody production

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3
Q

What does an appropriate immune tolerance respond to?

A

Self and foreign harmless proteins

E.g. Food, pollens, other plant proteins, animal proteins, commensal bacteria

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4
Q

What is the role of antigens in appropriate immune tolerance?

A

Involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production

Ag recognition in absence of ‘danger’ signals-> tolerance

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5
Q

What results from antigen recognition in presence/absence of ‘danger’ signals?

A

Ag recognition in absence of ‘danger’ signals-> tolerance

Ag recognition in presence of ‘danger’ signals-> immune reactivity

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6
Q

What causes type I immediate hypersensitivity?

A

Anaphylaxis
Asthma
Rhinitis= seasonal/perennial
Food allergy

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7
Q

What happens in immediate hypersensitivity?

A

PRIMARY AG EXPOSURE
Sensitisation not tolerance
IgE antibody production
IgE binds to mast cells and basophils

SECONDARY AG EXPOSURE
More IgE Ab produced
Antigen cross-links IgE on mast cells/basophils
Degranulation

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8
Q

What are the clinical presentations of Type II antibody-dependent hypersensitivity?

A

Depends of target tissue

Organ-specific autoimmune diseases
Autoimmune cytopenias

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9
Q

What are the organ specific autoimmune diseases in Type II antibody-dependent hypersensitivity?

A

ORGAN SPECIFIC AUTOIMMUNE DISEASES
Organ-specific autoimmune diseases
Myasthenia gravis (Anti-acetylcholine R Ab)
Glomerulonephritis (Anti-glomerular basement membrane Ab)
Pemphigus vulgaris (Anti-epithelial cell cement protein Ab)
Pernicious anaemia (Intrinsic factor blocking Abs)

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10
Q

What are the autoimmune cytopenias in Type II antibody-dependent hypersensitivity?

A

AUTOIMMUNE CYTOPENIAS (Ab mediated blood cell destruction)
Haemolytic anaemia
Thrombocytopenia
Neutropenia

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11
Q

How do you test for specific autoantibodies in Type II antibody-dependent hypersensitivity?

A

Immuno fluorescence

ELISA e.g. anti-CCP (cyclic citrullinate peptide antibodies for rheumatoid arthritis)

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12
Q

What happens in Type III immune complex mediated hypersensitivity?

A

Formation of ag-ab complexes in blood

Deposition of these formations in a tissue

Complement and cell recruitment/activation

Activation of other cascades e.g. clotting

Tissue damage (vasculitis)

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13
Q

What tissue damage (vasculitis) results from Type III immune complex mediated hypsersensitivity?

A

Systemic lupus erythematosus

Vasculitides (poly artertisis nodosum, many different types)

Renal (glomerulonephritis)

Skin

Joints

Lung

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14
Q

What causes Type IV delayed hypersensitivity responses?

A

Chronic graft rejection
GVHD
Coeliac disease
Contact hypersensitivity

Many others:
Asthma
Rhinitis
Eczema

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15
Q

What are the three main varieties of Type IV delayed hypersensitivity responses?

A

Th1
Cytotoxic
(Th2)

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16
Q

What are the mechanisms of type IV delayed hypersensitivity responses?

A

Transient/persistent ag
T cell activation of macrophages, CTLs

Much of tissue damage dependent upon TNF

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17
Q

What does IL-2 act on in type IV delayed hypersensitivity responses?

A

Cytotoxic T lymphocyte (CTL)

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18
Q

What does FGF act on in type IV delayed hypersensitivity responses?

A

Fibroblasts-> angiogenesis and fibrosis

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19
Q

What often causes type IV delayed-type cell-mediated hypersensitivity?

A

Nickel

Contact hypersensitivity

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20
Q

What immune reactants are in Type I, II, III or IV?

A 
I= IgE
II= IgG
III= IgG
IV= Th1, Th2, CTL
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21
Q

What antigens are in Type I, II, III or IV?

A 
I= soluble antigen
II= cell-or matrix associated antigen OR cell-surface receptor 
III= soluble antigen
IV= soluble antigen (Th1), soluble antigen (Th2), cell-associated antigen (CTL)
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22
Q

What are the common features of type I-IV hypersensitivity?

A

Inflammation

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23
Q

What are the features and signs of inflammation in type I-IV hypersensitivity?

A

Vasodilatation, increased blood flow

Increased vascular permeability

Inflammatory mediators and cytokines

Inflammatory cells and tissue damage

Signs= redness, heat, swelling, pain

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24
Q

What causes increased vascular permeability (in inflammation due to hypersensitivity)?

A

C3a, C5A, histamine, leukotrienes

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25
Q

What cytokines are involved in inflammation due to hypersensitivity?

A 
IL-1
IL-6
IL-2
TNF
IFN-y
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26
Q

What chemokines are involved in inflammation due to hypersensitivity?

A

IL-8/CXCL8

IP-10/CXCL10

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27
Q

What is the inflammatory cell infilitrate in inflammation due to hypersensitivity?

A

Cell trafficking- chemotaxis

Neutrophils, macrophages, lymphocytes, mast cells

Cell activation

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28
Q

What is the prevalence of atopy in young adults in the UK?

A

50%

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29
Q

How can the severity of allergy vary?

A

From mild occasional to severe chronic or life threatening anaphylaxis

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30
Q

What are the genetic risk factors for atopics?

A

80% have family hx

Polygenic (50-100 genes)

Genes of IL-4 gene cluster (chr 5) linked to raised IgE, asthma, atopy

Genes of chr 11q (IgE R) linked to atopy and asthma

Genes linked to structural cells linked to eczema (filaggrin) and asthma (IL-33, ORMDL3)

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31
Q

What are the environmental risk factors for atopics?

A

Age (increases from infancy, peaks in teens, reduces in adulthood)

Gender (asthma more common in M children and F adults)

Family size (more common in small families)

Infections (early life infections protect)

Animals (early exposure protects)

Diet (breast feeding, anti-oxidants, fatty acids protect)

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32
Q

Which allergies are increasing in prevalence in the UK?

A

Asthma
Hay fever
Eczema

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33
Q

What type of inflammation is in anaphylaxis, urticaria and angioderma?

A

Type I hypersensitivity (IgE mediated)

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34
Q

What type of inflammation is in idiopathic/chronic urticaria?

A

Type II hypersensitivity (IgG mediated)

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35
Q

What type of inflammation is in asthma/rhinitis/eczema?

A

Mixed inflammation

Type I hypersensitivity (IgE mediated)

Type IV hypersensitivity (chronic inflammation)

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36
Q

What do you need to express allergy disease?

A

Development of sensitisation to allergens instead of tolerance

Exposure to produce disease (memory response= any time after sensitisation)

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37
Q

What happens in primary sensitisation to allergens in atopic airway disease?

A

E.g. in airway disease- antigen is inhaled

In airway lumen, allergen picked up, processed and presented to naive T cells (CD4+) by dendritic cells

Naive T cell then differentiated to form either Th1, Th2 or T-reg cell

(Decision between the 3 pathways of differentiation= not fully understand)

T-reg cells secrete IL-10
Th1 secretes IFN-y
-> both inhibit the differentiation of the naive t-cell into Th2 cells

Th2 cells secrete IL-4 and IL-13 which stimulate the proliferation and differentiation of B cells into plasma cells (which then synthesise and release IgE)

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38
Q

What happens on secondary exposure to an allergen in allergic disease?

A

Memory T cells rapidly differentiate to Th2 cells-> IgE secretion from plasma cells

IgE then binds to IgE Rs on mast cells, cross-linking the Rs, causing mast cell degranulation and release of inflammatory mediators

Th2 also release IL-5 which cause eosinophils to release inflammatory mediators

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39
Q

What are eosinophils? Where are they present/ recruited from/ generated? What do they look like?

A

2-5% of blood leukocytes

Present in blood, most reside reside in tissues

Recruited during allergic inflammation
Generated from bone marrow

Polymorphous nucleus- two lobes
Contain large granules- toxic proteins

Lead to tissue damage

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40
Q

What are mast cells?

A

Tissue resident cells

IgE Rs on cell surface

Cross-linking of IgEs leads to mediator release (preformed: histamine, cytokines, toxic proteins) and newly synthesised leukotrienes and prostaglandins

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41
Q

What are neutrophils important in (allergy/atopy)?

A

Virus induced asthma
Severe asthma
Atopic eczema

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42
Q

What are neutrophils?

A

55-70% of blood leukocytes

Contain several lobes

Granules contain digestive enzymes

Also synthesize:
Oxidant radicals
Cytokines
Leukotrienes

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43
Q

What is the immunopathogenesis of asthma?

A

ACUTE INFLAM OF AIRWAYS
Mast cell activation and degranulation
- Pre stored mediators= histamine
- Newly synthesised mediators= prostaglandins, leukotrienes

Acute airway narrowing

CHRONIC INFLAM OF AIRWAYS
Cellular infiltrate (Th2 lymphocytes, eosinophils)
Smooth muscle hypertrophy
Mucus plugging
Epithelial shedding
Sub-epithelial fibrosis
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44
Q

What happens to the airways in asthma?

A

Acute airway narrowing

Airway wall edema

Mucus secretion

Vascular leakage

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45
Q

What is the two-phase response to single allergen?

A

Inhaled allergy (0h)

Early response (within 1h)= big reduction in PEF %

Late response (between 4-6h)= reduction in PEF%

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46
Q

What are the clinical features of asthma?

A

Reversible generalised airway obstruction (chronic episodic wheeze)
Bronchial hyper-responsiveness (bronchial irritability)
Cough
Mucus production
Breathlessness
Chest tightness

Response to treatment
Spontaneous variation
Reduced and variable peak flow (PEF)

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47
Q

When is wheezing worst in an asthmatic person?

A

On walking

When waking up

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48
Q

What are the types of allergic rhinitis?

A

Seasonal- hay fever, tree pollens, grass

Perennial- HDM, animals

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49
Q

What are the symptoms of allergic rhinitis?

A

Sneezing
Rhinorrhoea
Itchy nose, eyes
Nasal blockage, sinusitis, loss of smell / taste

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50
Q

What is allergic eczema?

A

Chronic itchy skin rash

Flexures of arms and legs

HDM sensitisation and dry cracked skin

Complicated by bacterial and (rarely) viral infections (herpes simplex)

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51
Q

What happens to eczema in adulthood?

A

50% clears up by 7y

90% clears up by adulthood

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52
Q

What are the common food allergies in infancy-3 years?

A

Eggs

Cows milk

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53
Q

What are the common food allergies in children/adults?

A 
Peanut
Shellfish
Nuts 
Fruits 
Cereals 
Soya
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54
Q

What are mild food allergy symptoms?

A

Itchy lips, mouth, angioedema, urticaria

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55
Q

What are severe food allergy symptoms?

A

Nausea, abdo pain, diarrhoea

Anaphylaxis

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56
Q

What is anaphylaxis?

A

Anaphylaxis: severe generalised allergic reaction

Uncommon, potentially fatal

Generalised degranulation of IgE sensitised mast cells

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57
Q

What are the symptoms of anaphylaxis?

A

Itchiness around mouth, pharynx, lips

Swelling of the lips, throat and other parts of the body

Wheeze, chest tightness, dyspnoea

Faintness, collapse

Diarrhoea and vomiting

Death if severe and untreated

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58
Q

What are the systems involved in anaphylaxis?

A

Cardiovascular- vasodilatation, cardiovascular collapse

Respiratory- bronchospasm, laryngeal oedema

Skin- vasodilatation, erythema, urticaria, angioedema

GI- vomiting, diarrhoea

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59
Q

How do you investigate and diagnose allergy?

A

Careful history essential

Skin prick testing

RAST (blood specific IgE):
- Total IgE

Lung function (asthma)

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60
Q

What is the emergency treatment for anaphylaxis?

A

EpiPen and anaphylaxis kit
antihistamine, steroid, adrenaline

Seek immediate medical aid

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61
Q

How is anaphylaxis prevented?

A

Avoidance of the known allergy
Always carry a kit and EpiPen
Inform immediate family & caregivers
Wear a MedicAlert® bracelet

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62
Q

How is allergic rhinitis treated?

A

Anti-histamines (sneezing, itching, rhinorrhoea)
Nasal steroid spray (nasal blockage)
Cromoglycate (children, eyes)

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63
Q

How is ezcema treated?

A

Emollients

Topical steroid cream

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64
Q

How do you treat very severe allergic rhinitis and eczema?

A

Anti-IgE
Anti-IL4/13
Anti-IL5 mAb

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65
Q

How do you treat asthma?

A
  1. Use short acting β2 agonist drugs as required by inhalation e.g. Salbutamol
  2. Inhaled steroid low-moderate dose
    - E.g. Beclomethasone/ Budesonide (50-800μg per day)
    - Fluticasone (50-400μg per day)
  3. Add further therapy
    - Add Long acting β2 agonist, leukotriene antagonist
    - High dose inhaled steroids - up to 2mg per day via a spacer
  4. Add courses of Oral Steroids
    - Prednisolone 30mg daily for 7-14 days
    - Anti-IgE, anti-IL4/13, anti-IL-5 mAbs
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66
Q

How can immunotherapy be used in allergy?

A

Effective for single antigen hypersensitivities

  • Venom allergy - bee or wasp stings
  • Pollens
  • HDM
  • Antigen used is purified

Subcutaneous immunotherapy (SCIT)

  • 3 years needed
  • Weekly/monthly 2hr clinic visits

Sublingual immunotherapy (SLIT)

  • Can be taken at home
  • 2-3yrs enough
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67
Q

Why do corneas fail?

A

Degenerative disease, infections, trauma

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68
Q

Why do skin/composite organs fail?

A

Burns, trauma, infections, tumours

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69
Q

Why does bone marrow fail?

A

Tumours, hereditary diseases

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70
Q

Why do kidneys fail?

A

Hypertension, diabetes, glomerulonephritis, hereditary conditions

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71
Q

Why do livers fail?

A

Cirrhosis (viral hepatitis, alcohol, auto-immune, hereditary conditions), acute liver failure (paracetamol)

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72
Q

Why do hearts fail?

A

Coronary artery or valve disease, cardiomyopathy (viral, alcohol), congenital defects

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73
Q

Why do lungs fail?

A

COPD)/emphysema (smoking, environmental), interstitial fibrosis/interstitial lung disease (idiopathic, autoimmune, environmental), cystic fibrosis (hereditary), pulmonary hypertension

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74
Q

Why do pancreases fail?

A

Type I diabetes

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75
Q

Why does the small bowel fail?

A

Mainly children (short gut), hereditary conditions or related to prematurity (in adults- Crohn’s, vascular disease)

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76
Q

What are the types of transplantation?

A 
Autografts
Isografts
Allografts
Xenografts
Prosthetic graft
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77
Q

What is an autograft?

A

Transplant within the same individual

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78
Q

What is an isograft?

A

Transplant between genetically identical individuals of the same species

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79
Q

What is an allograft?

A

Transplant between individuals of the same species (can be deceased and living donor)

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80
Q

What is a xenograft?

A

Transplant between individuals of different species

E.g. heart valves (pig/cow), skin

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81
Q

What is a prosthetic graft?

A

Transplant with plastic and metal

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82
Q

Where is a transplanted kidney placed?

A

Normally right ileac fossa

Below diseased kidneys (normally left in)

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83
Q

What are the common transplants by the NHS?

A 
Kidney
Pancrease
Cardiothoracic
Liver
Intestinal
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84
Q

What kinds of organs/cells can be transplanted?

A

Solid organs (kidney, liver, heart, lung, pancreas)

Small bowel

Free cells (bone marrow, pancreas islets)

Temporary: blood, skin (burns)

Privileged sites: cornea

Framework: bone, cartilage, tendons, nerves

Composite: hands, face, larynx

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85
Q

Who are the donors for allografts?

A

Deceased

  • DBD
  • DCD

Living

  • BM, kidney, liver
  • Genetically related or unrelated
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86
Q

What kinds of deceased donors are there?

A

BDB= donor after breath death (heart-beating, brain dead)

  • RTA, massive cerebral haemorrhage
  • Confirm brain death (can’t be reversible)
  • Harvest organs and cool to minimise ischaemic damage

DCD= donor after cardiac death (non-heart beating donors)

  • Heart stopped before organ harvest
  • Longer period of warm ischaemia time
  • Suitable for kidney
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87
Q

What are the criteria for DBD (heart-beating) deceased donors?

A

Irremediable structural brain damage of KNOWN cause

Apnoeic coma (not due to
depressant drugs, metabolic or endocrine disturbance, hypothermia and neuromuscular blockers)

Demonstrate lack of brain stem function (check pupils, cornea, eye movements, CNs, gag reflex, respiratory movements)

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88
Q

Which deceased donors are excluded from giving organs?

A

Viral infection (HIV, HBV, HCV)
Malignancy
Drug abuse, overdose or poison
Disease of the transplanted organ

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89
Q

What happens to removed organs to be transplanted?

A

Removed organs are rapidly cooled and perfused

Absolute maximum cold ischaemia time for kidney 60h (ideally <24h)

Much shorter for other organs (except
cornea 96h, longer with cryopreservation)

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90
Q

What is the process of transplant selection (listing)?

A

Referral of patients to transplantation centres for assessment

MDTs assess suitability for transplantation- eligibility criteria

Patient is placed on the NHS Transplant List

Contraindications

  • Too early to be placed on waiting list
  • Co-morbidity- medical, psychiatric, surgical (e.g. CV disease, malignancy, compliance)
  • Patient does not want a transplant
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91
Q

How are transplants allocated?

A

National guidelines
Evidence based compute algorithm

Time on waiting list (super-urgent transplants supersede)

What is the best use for organ in terms of patients survival and graft survival?

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92
Q

What is NHSBT?

A

NHS blood and transplant

NHSBT monitors allocation

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93
Q

After time on waiting list, which factor is most important in choosing who gets an available kidney allograft from a (DBD)?

  1. Distance between retrieval centre and transplantation centre
  2. Size matching between donor and recipient
  3. Sex matching between donor and recipient
  4. Tissue matching between donor and recipient (histocompatibility)
  5. Age of recipient
  6. Good age match between recipient and donor
A
  1. Tissue matching between donor and recipient (histocompatibility)
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94
Q

What are the 5 tiers of patients in kidney donation?

A

Paediatric or adult

Highly sensitised or not

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95
Q

What are the 7 elements in kidney allocation?

A 
Waiting time
HLA match and age combined
Donor-recipient age difference
Location of patient relative to donor
HLA-DR homozygosity
HLA-B homozygosity
Blood group match
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96
Q

How does allocation of donor organs vary nationally and locally?

A 
NATIONAL- to individual, ranked patients
Kidneys= DBD donors
Livers= super urgent patients only
Pancreas
Bowel
Heart= urgent patients only
LOCAL/REGIONAL
Kidneys= DCD donors
Livers= elective patients (+DCD)
Hearts= elective patients
Lungs= all patients
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97
Q

In England, what proportion of potential donors after brain death without any medical contraindication to donation go on to donate organs?

  1. 100%
  2. 75%
  3. 50%
  4. 25%
A
  1. 50%
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98
Q

What was the main obstacle to donation (of DBD patients)?

  1. Patient not tested for brain death on ICU (organisational failure)
  2. Patient confirmed brain-dead; contraindications to use of organ found
  3. Family not approached for consent (organisational failure)
  4. Family approached but declined consent to donation
A
  1. Family approached but declined consent to donation
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99
Q

What are the strategies to increase transplantation activity?

A

COORDINATION
Bereavement service and family interviews
A&E/ICU involvement for potential donors

DECEASED DONATION
Marginal donors e.g. DCD, elderly, sick

LIVING DONATION (increasing, also increased elderly)
Transplantation across tissue compatibility barriers
Exchange programmes: organ swaps for better tissue matching

FUTURE
Xenotransplantation
Stem cell research

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100
Q

What is the average half-life of a kidney transplant?

  1. 2.5 years
  2. 5 years
  3. 10 years
  4. 20 years
A
  1. 10 years
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101
Q

What are the most relevant protein variations in clinical transplantation?

A

ABO blood group

HLA coded on Chr6 by MHC

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102
Q

What does HLA stand for?

A

Human leukocyte antigens

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103
Q

What does MHC stand for?

A

Major histocompatibility complex

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104
Q

What is the ABO blood group?

A

Way of grouping blood

A and B proteins on RBCs (and endothelial lining of blood vessels in transplanted organ)

Naturally occurring anti-AB antibodies

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105
Q

What RBC type, antibodies in plasma and antigens in RBC are present in someone with A blood?

A

RBC type= A
Antibodies in plasma= Anti-B
Antigens in RBC= A antigen

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106
Q

What RBC type, antibodies in plasma and antigens in RBC are present in someone with B blood?

A

RBC type= B
Antibodies in plasma= Anti-A
Antigens in RBC= B antigen

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107
Q

What RBC type, antibodies in plasma and antigens in RBC are present in someone with AB blood?

A

RBC type= AB
Antibodies in plasma= None
Antigens in RBC= A and B antigens

108
Q

What RBC type, antibodies in plasma and antigens in RBC are present in someone with O blood?

A

RBC type= O
Antibodies in plasma= Anti-A and Anti-B
Antigens in RBC= None

109
Q

What would happen if a heart from a B donor was given to a patient with blood group A?

A

Patient serum contains naturally occurring anti-B antibodies (circulate, pre-formed)

Bind to B blood group antigens on donor epithelium

-> Antibody-mediated rejection

110
Q

What does the antibody activate to lead to an immune response in transplants?

A

Antibody activates complement pathway and macrophages

111
Q

What does ABO-incompatible transplantation involve?

A 
Remove the antibodies in the recipient (plasma exchange)
Good outcomes (even if the antibody comes back)

Can be done for kidney, heart, liver

112
Q

What is HLA?

A

Human leukocyte antigens

Cell surface proteins on highly variable portion

Variability= important in defence (against neoplasia and infections)

113
Q

How are foreign antigens recognised?

A

Foreign protein binds to antigen presenting cell (which has HLA)

T cells see peptides exhibited on a defined framework

If HLA isn’t match-> recognised as foreign

114
Q

What are the classes of HLA and where are they expressed?

A

Class I (A,B,C)= expressed on all cells

Class II (DR, DQ, DP, DM, DO)= expressed antigen-presenting cells but also can be up-regulated on other cells

115
Q

Why is HLA (ABC) described as highly polymorphic?

A

Lots of alleles for each locus

Each individual has most often 2 types for each HLA molecule

116
Q

How many mismatches can there be in HLA matching?

117
Q

What effect does minimising HLA differences between donor and recipient on transplant outcome?

A

Minimising difference-> improved transplant outcome

118
Q

Why is exposure to foreign HLA molecules dangerous?

A

Exposure to foreign HLA molecules -> immune reaction to the foreign epitopes

The immune reaction can cause immune graft damage and failure -> rejection of organ

119
Q

How can organ rejection be confirmed?

A

Most common cause of graft failure (why we use immunosuppressive drugs)

Diagnosis= histological exam of graft biopsy

120
Q

What kinds of organ rejection are there?

A 
Hyperacute
Acute
Chronic
T-cell mediated
Antibody-mediated
121
Q

What happens in T-cell mediated organ rejection?

A

Graft infiltration by alloreactive CD4+ cells

Cytotoxic T cells

  • > Release of toxins to kill target (Granzyme B)
  • > Punch holes in target cells (Perforin)
  • > Apoptotic cell death (Fas -Ligand)

Macrophages

  • > Phagocytosis
  • > Release of proteolytic enzymes
  • > Production of cytokines
  • > Production of oxygen radicals and nitrogen radicals
122
Q

What happens in antibody-mediated organ rejection?

A

Antibody against graft HLA and AB antigen (anti-HLA antibodies bind to donor HLA antigens)

Antibodies arise

  • Pre-transplantation (“sensitised”)
  • Post-transplantation (“de novo”)

Involved C4d

123
Q

When does antibody-mediated organ rejection often happen?

A

After a lot of transfusions, pregnancy or if already had a graft

124
Q

Why is post transplant monitoring for rejection important?

A

To look for deteriorating graft function

Subclinical

125
Q

What can be used to monitor for deteriorating graft function in organ transplantation (kidney, liver and lung)?

A

Kidney transplant= rise in creatinine, fluid retention, hypertension

Liver transplant= rise in LFTs, coagulopathy

Lung transplant= breathlessness, pulmonary infiltrate

126
Q

How can organ rejection be prevented?

A

Maximise HLA compatibility

Life-long immunosuppressive drugs

127
Q

What do immunosuppressive drugs target?

A

T cell activation and proliferation

B cell activation and proliferation

Antibody production

128
Q

What does Bortezomib do?

A

Proteosome inhibitor

Has anti T cell actions but causes plasma cell apoptosis

129
Q

What is the standard immunosuppressive regime?

A

PRE-TRANSPLANTATION
Induction agent= T cell depletion or cytokine blockade

FROM TIME OF IMPLANTATION
Base line immunosuppression
Signal transduction blockade, usually a CNI inhibitor Tacrolimus or Cyclosporin, sometimes mTOR inhibitor (Rapamycin)
Antiproliferative agent: MMF or Azathioprine
Corticosteroids

IF NEEDED (ACUTE REJECTION)
T cell mediated= steroids, anti-T cell agents
Antibody-mediated= IVIG, plasma exchange, anti-CD20, anti-complement
130
Q

What are the risks of immunosuppression?

A

Infection
Tumours
Drug toxicity

131
Q

What are common types of post transplantation infection?

A

CONVENTIONAL
Increased risk= bacterial, viral, fungal

OPPORTUNISTIC
Cytomegalovirus
BK virus
Pneumocytis
Carinii
132
Q

Give examples of post transplantation malignancy

A

Skin cancer (e.g. squamous cell carcinomas)
Post transplant lymphoproliferative disorder (driven by Epstein Barr)
Others

133
Q

What is autoimmunity?

A

Adaptive immune responses against self (particularly lymphocytes- by autoantigens)

134
Q

How does normal autoimmunity become autoimmune disease?

A

Genetic and environmental factors

Breakdown of self tolerance

135
Q

What factors cause autoimmune disease?

A

Genes= twin studies, GWAS (e.g. 40 key loci in SLE)

Sex= women more susceptible

Infections (inflammatory environment)

Diet (obesity, high fat, effects on gut microbiome)

Stress

Microbiome (perturbation may help trigger autoimmune disease)

136
Q

What are the mechanisms of autoimmunity?

A

Adaptive immune response against self (same as immune against pathogens)

T cell tolerance broken in autoimmune disease

Chronic because always have self tissue

Effector mechanisms (e.g. those of hypersensitivity reactions- type II, III and IV)

137
Q

How many chronic autoimmune disorders have been identified?

138
Q

What percentage of people have autoimmune disease?

139
Q

What percentage of people with autoimmune diseases are women?

A

80%

NB. not the case in UC or T2DM

140
Q

What is the hygiene hypothesis?

A

Study that states a lack of early childhood exposure to infectious agents, symbiotic microorganisms (such as the gut flora or probiotics) and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system

141
Q

What are the most important autoimmune diseases?

A 
Rheumatoid arthritis
T2DM 
MS
SLE
ATD (autoimmune thyroid disease) e.g. Hashimoto's and Grave's
142
Q

What is the target of Graves’ disease?

143
Q

What is the target of Hashimoto’s thyroiditis?

144
Q

What is the target of T2DM?

145
Q

What is the target of Goodpasture’s syndrome?

146
Q

What is the target of pernicious anaemia?

147
Q

What is the target of primary biliary cirrhosis?

A

Liver, bile

148
Q

What is the target of Myasthenia gravis?

149
Q

What is the target of dermatomyositis and polymyositis?

A

Skin and muscles

150
Q

What is the target of vasculitis?

A

Blood vessels

151
Q

What is the target of Rheumatoid arthritis?

152
Q

What is the target of SLE?

A

Multiple targets

153
Q

How can you describe autoimmune reactions in humans?

A

Organs affected
Involvement of specific autoantigens
Types of immune response

154
Q

What causes autoimmune haemolytic anaemia?

A

TYPE II= antibody to insoluble antigen

Autoantibodies against red blood cells

Result in clearance or complement-mediated lysis of autologous erythrocytes

Direct link between autoantibodies and disease

155
Q

What are the 3 main immune reactions known to play a direct role in the pathology of human autoimmune disease?

A

Antibody response to cellular or extracellular matrix antigen (Type II)

Immune complex formed by antibody against soluble antigen (Type III)

T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV)

156
Q

What happens in autoimmune thrombocytopenia purpura?

A

TYPE II= antibody to insoluble antigen

Autoantigen= platelet integrin gpIIb:IIa

Leads to abnormal bleeding

157
Q

What happens in Goodpasture’s syndrome?

A

TYPE II= antibody to insoluble antigen

Autoantigen= non-collagenous domain of basement membrane collagen type IV

Leads to glomerulonephritis, pulmonary haemorrhage

Can detect with fluorescent anti-IgG stain

158
Q

What happens in Pemphigus vulgaris?

A

TYPE II= antibody to insoluble antigen

Autoantigen= epidermal cadherin

Leads to blistering of skin

159
Q

What happens in acute rheumatic fever?

A

TYPE II= antibody to insoluble antigen

Autoantigen= steptococcal call wall antigens, antibodies cross react with cardiac muscle

Leads to arthritis, myocarditis, late scarring of heart valves

160
Q

What happens in Graves’ disease?

A

TYPE II= antibody to insoluble antigen

Autoantigen= thyroid-stimulating hormone receptor

Leads to hyperthyroidism

161
Q

What happens in Myasthenia gravis?

A

TYPE II= antibody to insoluble antigen

Autoantigen= ACh R

Leads to progressive weakness

162
Q

What happens to the immune complex in SLE?

A

SLE

Immune complex deposition in glomerulus

163
Q

What is the main difference between type II and type III immune response?

A

II= injury caused by anti-tissue antibody e.g. tissue injury (involves neutrophils and macrophages)

III= immune complex-mediated tissue injury e.g. vasculitis (involves neutrophils)

164
Q

What happens in SLE?

A

Type II= immune complex disease deposited in glomerulus

Autoantigen= DNA, histones, ribosomes, snRNP, scRNP

Leads to glomerulonephritis, vasculitis, arthritis

165
Q

What causes insulin-dependent diabetes mellitis?

A

Type IV= T-cell mediated

Autoantigen= pancreatic beta cell

Leads to B cell destruction

166
Q

What causes insulin-dependent rheumatoid arthritis?

A

Type IV= T-cell mediated

Autoantigen= unknown synovial joint antigen

Leads to joint inflammation and destruction

167
Q

What causes MS?

A

Type IV= T-cell mediated

Autoantigen= myelin basic protein, proteolipid protein

Leads to brain degeneration (demyelination), weakness and paralysis

168
Q

What is the normal T-cell response to antigens?

A

Antigen presented to T cells by MHC expressed on surface of antigen presenting cells

Leads to proliferation and function

169
Q

How do we know T cells are involved in autoimmune disease initiation?

A

HLA associations strongly imply a role for T cells in initiating autoimmune disease

170
Q

How can the study of cows provide evidence for the concept of tolerance against self?

A

Non-identical cow twins have different blood group antigens and so would be expected to react to each others cells and tissues

Adult cattle tolerate blood transfusions from a non-identical twin

They also accept skin grafts from each other

Show tolerance against self

171
Q

Why is timing important in mice studies to show the concept of tolerance against self?

A

Spleen and marrow cells need to be given from donor to neonate (not adult) to prevent rejection of skin graft

Medawar et al, 1953

172
Q

How can mouse studies show that tolerance has specificity?

A

Spleen and bone marrow cells given to neonate from mouse 1 as neonate (mouse 2)

Skin graft from mouse 1 rejected when mouse 2 is adult

173
Q

What is immunological tolerance?

A

Acquired inability to respond to an antigenic stimulus

3 As= acquired, antigen specific and active process in neonates

174
Q

How does self tolerance work?

A

Central tolerance

Peripheral tolerance

  • Anergy
  • Active suppression (regulatory T cells)
  • Immune privilege, ignorance of antigen
175
Q

What happens if self tolerance fails?

A

Central or peripheral tolerance mechanism fails

Leads to autoimmune disease

176
Q

What is central tolerance? What cells are involved?

A

Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self

Lymphoid progenitors make immature B cells and pre T-cells

Pre T-cells to thymus then exported to periphery

B cells- immunoglobulin secreting plasma cells

177
Q

What do T cells recognise?

A

Peptides presented on MHC in the thymus

T cell can bind strongly to MHC I or II and then destroy it (even if it’s self)

178
Q

Does central tolerance fail in autoimmune disease?

A

Yes in APECED

Autoimmune
PolyEndocrinopathy-
Candidiasis-
Ectodermal 
Dystrophy
179
Q

What is APECED?

A

Rare autoimmune disease which affects the endocrine glands

Thyroid

Kidneys

Chronic mucocutaneous candidiasis

Gonadal failure

Diabetes mellitus

Pernicious anaemia

180
Q

What causes APECED?

A

Failure to delete T cells in thymus (so persistence of autoreactive cells)

Due to mutations in TF AIRE (autoimmune regulator) gene

AIRE is important for expression of ‘tissue-specific’ genes in the thymus

Involved in negative selection of self reactive T cells in thymus

181
Q

What are most autoimmune diseases associated with?

A

Multiple defects and genetic traits

E.g.
Genes affecting induction of tolerance (B lymphocyte activation: CD22, SHP-1) autoantibody production

Apoptosis (Fas, Fas-ligand): failure in cell death

Clearance of antigen (Complement proteins C1q, C1r and C1s): abundance/persistence of autoantigen

182
Q

Outline T cell selection in the thymus

A

Dependent on MHC: peptide: T-cell receptor (TCR) interaction

Most cells die by neglect: no or very weak recognition

Negative selection occurs for cells with high affinity TCRs, which die by apoptosis

Surviving cells are MHC-restricted, with low/intermediate affinity for self-peptide

Only 5% survive selection

183
Q

Outline B cell selection in the bone marrow

A

Crosslinking of surface immunoglobulin by polyvalent antigens expressed on bone marrow stromal cells facilitates deletion

184
Q

When are antigens expressed if not the thymus or bone marrow?

A

Some may be expressed after immune system has matured

185
Q

What is anergy?

A

Absence of costimulation

T cells need costimulation for full activation (e.g. by CD80, CD86 and CD40)

Absent on most cells of the body

Without costimulation then cell proliferation and/or factor production does not proceed

Subsequent stimulation leads to a refractory state termed ‘ANERGY’

186
Q

What is immunological ignorance?

A

Occurs when:

Antigen concentration is too low in the periphery

Relevant antigen presenting molecule is absent (most periph cells are MHC class II negative)

At immunologically privileged sites where immune cells can’t normally penetrate (e.g. eye, CNS, PNS and testes)

187
Q

Give an example of failure of immunological ignorance?

A

Sympathetic opthalmia

Trauma to one eye-> release of sequestered intraocular protein antigens

Released intraocular antigens are carried to lymph nodes and activate T cells

Effector T cells return via bloodstream and attack antigen in both eyes

188
Q

What do autoreactive T cells that don’t respond to the autoantigen respond to? Examples

A

Controlled by other cell types

Regulatory T cells:
CD4
CD25
CTLA4
FOXP3
189
Q

What is IPEX?

A

Failure in regulation of peripheral tolerance (accumulation of autoreactive T cells)

Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome

Fatal recessive disorder presenting early in childhood

Mutation in the FOXP3 gene which encodes a transcription factor critical for the development of regulatory T-cells

190
Q

What are the symptoms of IPEX?

A 
Early onset insulin Dependent diabetes mellitus
Severe enteropathy
Eczema
Variable autoimmune phenomena
Severe infections
191
Q

How can infections affect the tolerant state?

A

Molecular mimicry of self molecules (activation of T cells)

Activation of APCs

Induce changes in the expression and recognition of self proteins

Induction of co-stimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment

Failure in regulation : effects on regulatory T-cells

Immune deviation: shift in type of immune response e.g. Th1-Th2

Tissue damage at immunologically privileged sites

192
Q

What does the induction and maintenance of peripheral tolerance depend on?

A 
Site of antigen expression (MHC expression, immune privilege)
Timing of antigen expression
Amount of antigen expression
Costimulation
T cell help for B cell responses 
Regulation

Infections may help break tolerance by a variety of mechanisms

193
Q

What is paraneoplastic cerebellar degeneration (PCD)?

A

Autoimmune reaction targeted against components of the CNS mostly to Purkinje cells (motor neuron type in cerebellum)

Leads to neurological symptoms e.g. severe vertigo, unintelligible speech, truncal and appendicular ataxia

194
Q

How do cancer and immunology relate?

A

Certain tumours can express antigens that are absent from (or not detectable in) corresponding normal tissues

The immune system can, in principle, detect these antigens and launch an attack against the tumour

This may result in auto-immune destruction of normal somatic tissues

Also, some people have very small cancers or microscopic colonies of cancer cells (has immune control stopped it?)

Transplantation has lead to melanomas (donors were controlling tumours, recipient can’t)

Men have more risk of malignant cancers, women have stronger immune response

Immunosuppression leads to increased malignancy risk

195
Q

What is the main aim of immunotherapy?

A

Tries to enhance immune responses to existing cancer

196
Q

What is the cancer immunity cycle? What cells are involved?

A
  1. Release of cancer cell antigens (cancer cell death)
  2. Cancer antigen presentation (dendritic cells/APCs)
  3. Priming and activation (APCs and T cells)
  4. Trafficking of T cells to tumours (CTLs)
  5. Infiltration of T cells into tumours (CTLs, endothelial cells) (TIL)
  6. Recognition of cancer cells by T cells (CTLs, cancer cells)
  7. Killing of cancer cells (immune and cancer cells)= IMMUNE SELECTION PRESSURE
197
Q

What usually initiates cancer?

A

Multiple sporadic events over time

E.g. irradiation, chemical mutagens, spontaneous DNA replication errors, tumour virus-induced changes in genome

198
Q

What happens in cancer?

A

Cancer initiated

Aberrant regulation of apoptosis and cell cycle results in tumour growth

Tumour growth EVENTUALLY results in inflammatory signals

Innate immunity recruited (dendritic cells, macrophages and NK cells)

Then draining lymphnode

Subsequent recruitment of adaptive, antigen-specific immunity (B and T cells)

199
Q

What are the requirements for activation of an adaptive

anti-tumour immune response?

A

Local inflammation in the tumour

Expression and recognition of tumour antigens

200
Q

What are the problems with immune surveillance of cancer?

A

Takes the tumour a while to cause local inflammation

Antigenic differences between normal and tumour cells can be very subtle

201
Q

What could cancer immunotherapy do?

A

Can we ‘teach’ the adaptive immune system to selectively detect and destroy tumour cells?

I.e. if spontaneous activation needs not met

202
Q

How do immune responses to tumours have similarities with those infected with viruses?

A

T cells can ‘see’ inside cells, and can

recognise tumour-specific antigens

203
Q

What is the function of MHC class I/II molecules?

A

‘Display’ contents of cell for surveillance

by T cells e.g. infection, carcinogenesis

204
Q

Give examples of proteins that can cause cancer?

A

VIRAL
Epstein Barr virus
Human papillomavirus

MUTATED CELL PROTEINS
TGF-B receptor II

205
Q

What viruses can cause cancer opportunistically?

A

Opportunistic malignancies in immunosuppression

EBV-positive lymphoma: Post-transplant immunosuppression

HHV8-positive Kaposi sarcoma: HIV

206
Q

What viruses can cause cancer in immunocompetent individuals?

A

HTLV1-associated leukaemia/lymphoma

HepB virus- and HepC virus-associated hepatocellular carcinoma

Human papilloma virus-positive genital tumours (tumour cells express viral antigens)

207
Q

How is cervical cancer induced and maintained?

A

By E6 and E7 (intracellular antigens) oncoproteins of HPV

Tumour cells express viral antigens

208
Q

What is the drug for HPV vaccination?

A

Gardasil 9

Surface proteins, incorporated into VLPs

209
Q

What is the relationship between consequences of cervical HPV infection and HPV-specific T cell immunity?

A

HPV16

  • Strong immunity-> clearance HPV-infection, immunological memory
  • (MINORITY) Immune failure-> cervical neoplasia (no or non-functional immunity)
  • Preventative vaccination
210
Q

Explain the concept of tumour-associated antigens giving named examples, and explain how they differ from tumour-specific antigens

A

Tumour-associated antigens (TAA) derive from normal cellular proteins which are aberrantly expressed (timing, location or quantity)

Because they are normal self proteins, for an immune response to occur tolerance may need to be overcome

211
Q

What are ectopically expressed autoantigens? Example

A

Expressed where they shouldn’t be

Cancer-testes antigens (developmental antigens)= silent in normal adult tissues except male germ cells

MAGE family (associated with melanoma)

212
Q

What is HER2 associated with?

A

Human epidermal growth factor receptor 2 (HER2): overexpressed in some breast carcinomas

213
Q

What is Mucin 1 (MUC-1) associated with?

A

Membrane-associated glycoprotein, overexpressed in very many cancers

214
Q

What is carcinoembryonic antigen associated with?

A

Normally only expressed in foetus/embryo, but overexpressed in a wide range of carcinomas

215
Q

What tumour-associated antigens are associated with prostate cancer?

A

Prostate-specific antigen (PSA)
Prostate-specific membrane antigen (PSMA)
Prostatic acid phosphatase (PAP)

216
Q

What is tyrosinase?

A

Differentiation type antigen

Many people have poor self tolerance (not expressed sufficiently in thymus)

Could be useful in immunotherapy (studies carried out for melanoma, accompanied by auto-immune skin depigmentation vitiligo)

217
Q

What are the two major problems of targeting tumour-associated auto-antigens for T cell-mediated immunotherapy of cancer?

A

Auto-immune responses against normal tissues

Immunological tolerance

  • Normal tolerance to auto-antigens
  • Tumour-induced tolerance
218
Q

Summarise approaches being used and developed for tumour immunotherapy, including antibody-based therapy, tumour vaccination and immune checkpoint blockade

A

Antibody-based therapy

Therapeutic vaccination

Immune checkpoint blockade

Adoptive transfer of immune cells

Combinations of above

219
Q

What are the types of monoclonal antibody-based therapy?

A

Naked e.g. Herceptin (anti-HER2)

Conjugated e.g. to a radioactive particle (zevalin, anti-CD20 linked to yttrium-90) or toxic drug (kadcyla, anti HER2 linked to cytotoxic drug)

Bi-specific antibodies e.g. genetically engineered to combine 2 specificities

220
Q

What is the FDA-approved vaccine to treat cancer?

A

(Not by NICE, but for sale in UK)

Provenge for advanced prostate cancer

Cytokine that stimulates patients WBCs leading to DC maturation and enhanced PAP-specific T cell responses

221
Q

What is the aim of the immune checkpoint blockade?

A

Reduce or remove negative regulatory controls of existing T cell responses (rather than directly stimulating new responses)

Targets CTLA-4 and PD-1 pathways

E.g. Ipilimumab (anti CLTA4), Nivolumab (anti PD1)

222
Q

What is adoptive transfer of cells (ACT)?

A

T cell source (patient)

Non-specific TIL expansion, antigen-specific expansion and genetic engineering

Culture

Expansion

Re-infusion (into patient)

223
Q

What are CARs?

A

Chimeric antigen receptors are engineered receptors

Graft an arbitrary specificity onto an immune effector cell (T cell)

224
Q

Outline the basic microanatomy of the skin

A

Stratum cornea
Epidermis
Dermis (papillary, reticular, hypodermis)
Subcutaneous tissue

With sweat glands, sebaceous gland, hair follicle and blood vessels

225
Q

What are the layers of the epidermis?

A

From superficial to deep

Stratum corneum= dead keratinocytes, at surface these flake off
Stratum lucidum
Stratum granulosum= living keratinocytes
Stratum spinosum= living keratinocytes with dendritic cells
Stratum basale= dividing keratinocyte (stem cell), tactile cell, melanocyte
Dermis= sensory nerve ending

226
Q

Outline the proliferation of keratinocytes

A

Basal cell
Prickle cell
Granular cell
Keratin

227
Q

Describe the structure of the stratum corneum. What is the function?

A

Corneocytes and lipids

Important for barrier function of skin

228
Q

What layer of the skin is defective in eczema?

A

Stratum corneum

229
Q

What gene is commonly mutated in eczema?

A

Filagrin gene

230
Q

What are the types of eczema?

A

Atopic
Seborrhoeic
discoid
Allergic contact

231
Q

What is atopic eczema? (Biology and types)

A

Defective barrier function of the skin-> dry skin
Defective barrier allows penetration of irritants, allergens (dust) and pathogens (s. aureus)-> inflammation of skin

Filagrin gene mutations 10% cases

Common, relapsing and remitting
Very common itchy skin condition (dermatitis)
Onset often within first 6 months of life
Many children will grow out of it

232
Q

What is atopy? Give examples of atopic diseases

A

Atopy= tendency to develop hypersensitivity

Atopic diseases= eczema, asthma, hayfever

233
Q

What is the atopic march?

A

The incidence of atopic diseases by age
Eczema and food allergy peak very early (before 5y) and then decline
Asthma peaks later (approx 5y) then slower decline
Rhinitis increases from 5y-10y and slightly declines

234
Q

What factors affect atopic eczema?

A

INTRINSIC
Defects in epidermal skin barrier e.g. filaggrin gene mutations

EXTRINSIC= penetration of exogenous agents
Allergens, irritant and pathogens

Mast cell degranulation-> releases histamine

235
Q

What immunological components are involved in atopic eczema?

A

ACUTE
Activation of CD4+ lymphocytes and the TH2 immune response

CHRONIC
Activation of CD4+ and CD8+ lymphocytes and the Th1 immune response

Mast cell degranulation-> releases histamine

236
Q

What is palmar hyperlinearity a sign of?

A

Filagrin gene mutation

Eczema (and dry skin)

237
Q

Where does infantile atopic eczema occur?

A

Often on face and areas where baby can rub

Face also has problem of food spillage

238
Q

Where are the common sites of eczema outbreaks?

A 
CHILDREN
Hands, wrists, elbows, forearms
Feet, back of calves and knees
Neck and chest
Cheeks
Scalp

ADULTS
Hands, wrists, elbows, upper arm shoulder area
Back of knees
Neck
Face
Also minor on trunk and front of legs (excluding knee)

239
Q

What is lichenification in eczema?

A

Chronic stratching-> thicken skin (lichenified)

Skin markings easily seen

240
Q

What is eczema herpeticum?

A

Virus easily proliferates onto skin in patient with eczema

241
Q

What often colonises severe eczema?

A

S. aureus colonises eczema everywhere and makes it worse

242
Q

What is seborrhoeic eczema? Where does it occur?

A

Very common type of eczema affecting babies and adults
Often not itchy
Overgrowth of malassezia species of yeast on the skin with associated skin inflammation
(Commensal so naturally occur but overproliferation leads to reaction between yeast and skin)

Rash has a distinctive distribution including nasolabial folds, eyebrows, scalp, central chest and sometimes axillae and groins

243
Q

What is allergic contact dermatitis?

A

e.g. Nickel allergy or cosmetics can induce eczema where it is in contact with skin

People with atopic eczema are more likely to develop this

Also commonly to henna or hair dye with black dye (PPD)
Can lead to sensitization which would cause severe local allergic reaction and be permanently sensitized to hair dye

244
Q

What is discoid eczema?

A

Pattern of eczema in patients with dry skin who have overwashed or been in dry climate -> (dry it out)-> eczema patches look like discs

245
Q

What is psoriasis?

A

Inflammatory dermatosis

Starts in teens or 40s/50s

Appears as salmon pink plaques

246
Q

What are the types of psoriasis?

A

Chronic plaque
Guttate
Palmoplantar pustulosis
Generalised pustular psoriasis

30% have psoriatic arthritis too

247
Q

What causes psoriasis?

A

Genetic susceptibility and environmental triggers

Many genes are implicated including PSOR1

T lymphocytes move out of blood vessels into the dermis and initiate the release of cytokines, e.g. TNFa

Epidermis becomes thickened and produces more keratinocytes than normal, neutrophils infiltrate the epidermis and lymphocytes infiltrate the dermis

Triggers include infections, drugs and stress

248
Q

Outline the histology of psoriasis

A 
Hyperkeratosis
Parakeratosis
Acanthosis
Inflammation
Dilated blood vessels
Scales and plaques
249
Q

Where do psoriasis lesions usually appear?

A 
Scalp
Face
Armpit
Elbows
Trunk
Groin and genitals
Buttocks
Knees
250
Q

What are psoriasis vulgaris soles?

A

Well-demarcated, erythematous plaques with thick, yellowish scale and desquamation

Occur on sites of pressure e.g. plantar feet (similar lesions were present on the palms)

Symmetrical because inflammatory process

251
Q

What can happen to the nail in psoriasis?

A

Subungual hyperkeratosis (keratinisation under nail)
Dystophic nail
Loss of cuticle
Oncholysis (nail split away from nail bed)
Pitting (holes in nails)

252
Q

What is guttate psoriasis?

A

Starts with strep sore throat
Genetic susceptibility
Leads to outbreak of psoriasis

253
Q

What is palmoplantar pustolosis?

A

Neutrophils congrWegate and form pustules

On hand

254
Q

What is generalised pustular psoriasis?

A

Widespread involvement of skin
Superficial pustules
Each of these are pustules filled with lots of neutrophils
Fever and malaise, high heart rate
Life threatening (need immunosuppressant)

255
Q

What is acne?

A

Very common condition which mainly affects teenagers and young adults

Disease of the pilosebaceous unit of the skin

256
Q

What causes acne?

A

Multifactorial pathogenesis

Hyperkeratinisation of the epidermis in the infundibulum of the hair follicles
Accumulation of dead keratinocytes in the lumen of the hair follicle
Increase sebum production stimulated by androgens
Proliferation of propionibacterium acnes within the pilosebaceous unit
Rupture of the inflamed pilosebaceous unit, with further inflammation of the surrounding skin

OTHER
Comedone formation
Genetic predisposition
Propionibacteria acnes
Androgenic stimulation (increased sebum production by sebaceous gland)
257
Q

What are the key clinical features of acne?

A

Open and closed comedones
Papules
Pustules
Nodules and scars on the face, chest and back

258
Q

What is the difference between whiteheads and blackheads?

A

Whiteheads= closed comedones

Blackheads= open comedones

259
Q

Where is the basement membrane?

A 
Between epidermis and dermis
Attaches them (involves anchoring fibrils)

NB. Ectoderm-> epidermis and mesoderm-> dermis)

260
Q

What is bullous pemphigoid?

A

Autoimmune bullous inflammatory condition (causes tense blisters= bullae)

Due to splitting away of epidermis from dermis

Most common in elderly

261
Q

What are the clinical features of bullous pemphigoid?

A

Intense pruritus
Followed by the development of tense blisters (bullae) on an erythematous background of skin or mucous membranes

Itchhy and distressing

Risk of infections and sepsis without treatment

(Treat with oral and topical steroids)

262
Q

What is the immunological basis of bullous pemphigoid?

A

IgG autoantibodies to basement membrane antigens BP180 (type XVII collagen) or BP230 result in cleavage of the skin at the dermo epidermal junction leading to sub epidermal blisters

Epidermis splits away from dermis

263
Q

What is epidermolysis bullosa?

A

Defective proteins attaching dermis and epidermis

Genetic blistering skin disease

Can be mild excess blistering or severe (in babies- held and touched-> shin shearing-> blistering and scarring)

264
Q

What is pempigus vulgaris?

A

Uncommon autoimmune bullous inflammatory disease

Usually affects middle aged individuals (especially Middle Eastern or Asian)

265
Q

What are the clinical features of pempigus vulgaris?

A

Flaccid blisters which easily break

Leave erosions and crusted lesions

266
Q

What is the immunological basis of pempigus vulgaris?

A

IgG autoantibodies bind to epidermal cell surface proteins desmogleins 1 and 3
Leads to loss of cell-cell adhesion (acantholysis) within the epidermis
Causes flaccid blisters in the skin or mucous membranes

267
Q

What forms the connections between keratinocytes?

A

Between keratinocyte plasma membranes= desmogleins and desmocollins

Attach in attachment plaque of keratinocyte to plasophilin, plakoglobin and desmoplakin

Also Keratin intermediate filaments within keratinocyte

MCD 2- Immunology (1 decks)

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