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Year 5 Pathology > Immunology 2 > Flashcards

Immunology 2 Flashcards

1
Q

What populations are affected by familial Mediterranean fever

A

Sephardic>Ashkenazy Jews

Armenian, Turkish and Arabic people

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2
Q

Briefly describe the pathogenesis of familial Mediterranean fever

A

It is an autosomal recessive condition
The affected gene is the MEFV gene which codes pyrin-marenostrin.
Pyrin marenostrin is mainly expressed in neutrophils and is important in the regulation of cryopyrin driven activation of neutrophils.
The failure leads to acute episodes of unregulated neutrophil activation.
This causes the fevers and inflammation (e.g. pericarditis, arthritis etc)

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3
Q

MEFV gene codes for…

A

Pyrin marenostrin

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4
Q

Clinical features of familial Mediterranean fever

A

Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis

Long term risk of amyloidosis (due to high inflammation) causing:
Nephrotic syndrome
Renal failure

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5
Q

Treatment of familial mediterranean fever

A

Colchicine 500ug bd
Anakinra (Interleukin 1 receptor antagonist)
Etanercept (TNF alpha inhibitor)
Type 1 interferon

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6
Q

List 3 monogenic auto-immune diseases

A

APS-1/APECED
ALPS
IPEX

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7
Q

Briefly describe the pathogenesis of auto-immune polyendocrine syndrome type 1

A

Also known as Auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome / APECED

It is an autosomal recessive disorder. The gene affected codes for the auto-immune regulator (AIRE).
This is a transcription factor important in development of T cell tolerance in the thymus as it upregulates expression of self antigens by thymic cells which ultimately increases T cell apoptosis.

The autoreactive T cells that are released promote maturation of B cells against the the parathyroid and adrenal glands. This leads to antibody production.

It also causes mild immune deficiency causing Candida infections

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8
Q

Clinical features of autoimmune polyendocrine syndrome

A

Hypoparathyroidism
Addison’s
(autoimmune)

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9
Q

Briefly describe pathogenesis of Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome (IPEX)

A

Monogenic

Mutations in Foxp3 (Forkhead box p3) which is required for development of Treg cells

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10
Q

Clinical features of Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome (IPEX)

A

Overwhelming disease leads to early death without treatment

Endocrinopathy
usually Insulin dependent diabetes mellitus, Thyroid disease

Diarrhoea

Eczematous dermatitis

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11
Q

Briefly describe the pathogenesis of Auto-immune lymphoproliferative syndrome

A

Monogenic
Mutations within the Fas pathway. This leads to a variety of phenotypes depending on the mutations. The main effect is failure of lymphocyte apoptosis, this leads to failure of lymphocyte homeostasis and failure of tolerance.

This commonly leads to auto immune cytopenias and high lymphocyte numbers with large spleen and lymph nodes.

May be associated with lymphoma

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12
Q

Clinical features of autoimmune lymphoproliferative syndrome

A

High lymphocyte levels with large spleen and lymph nodes
Autoimmune cytopenias

May be associated with lymphoma

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13
Q

Gene affected in IPEX

A

foxp3

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14
Q

List 5 polygenic auto-inflammatory diseases

A 
Crohns disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis
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15
Q

Mutations found in Crohn’s disease also found in…

A

Severe psoriasis and psoriatic arthritis

Gene is NOD2/CARD15

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16
Q

Crohn’s disease involves dysfunction of which immune system?

A

Innate

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17
Q

The temporal artery arises from which artery

A

External carotid

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18
Q

The opthalmic artery arises from which artery

A

Internal carotid

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19
Q

The most common systemic vasculitis in elderly is…

A

Giant cell arteritis

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20
Q

ICAM 1 polymorphism affects

A

Cell migration

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21
Q

IL6, IL8 and IL 10 gene promoter polymorphism affects

A

Cytokine expression

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22
Q

Toll like receptor 4 polymorphisms affect

A

Dendritic cell activation

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23
Q

Nitric oxide synthase polymorphisms can cause…

A

Tissue destruction

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24
Q

Clinical features of giant cell arteritis

A

Temporal headache
Claudication pain on chewing
Visual loss reflecting involvement of ophthalmic artery
Scalp tenderness

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25
Q

List 3 mixed pattern (immunological diseases involving both innate and adaptive immune system)

A

Ankylosing spondylitis
Psoriatic arthritis
Behcet’s syndrome

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26
Q

Role of Human leukocyte antigen B27

A

Presents antigen to CD8 T cells.

Ligand for killer immunoglobulin receptor

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27
Q

Role of interleukin receptor type II

A

Decoy receptor that inhibits activity of IL1

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28
Q

List genetic polymorphisms implicated in ankylosing spondylitis

A 
HLAB27 
ILR2
IL23R
ERAP1 (ARTS1)
ANTXR2
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29
Q

Clinical features of ankylosing spondylitis

A 
Low back pain and stiffness 
Symptoms worse after periods of rest
Pain and swelling usually affecting hips and knees
Enthesitis
Uveitis
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30
Q

Treatment of ankylosing spondylitis

A

Non-steroidal anti-inflammatory drugs

Immunosuppression – TNF alpha antagonists

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31
Q

Ankylosing spondylitis typically involves which joints?

A

Sacroiliac

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32
Q

Ankylosing spondylitis has …% heritability

A

90%

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33
Q

Treatment of giant cell arteritis

A

Immunosuppression with corticosteroids

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34
Q

Investigations (and results) used to diagnose giant cell ateritis

A

High CRP and ESR

Abnormal temporal artery biopsy with intimal proliferation, disrupted internal elastic lamina, mononuclear cells throughout the vessel wall

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35
Q

List 6 polygenic auto-immune diseases

A 
Rheumatoid arthritis	
Systemic lupus erythematosus (SLE)
Myaesthenia Gravis	
Primary biliary cirrhosis 
Pernicious anaemia	
Addison disease
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36
Q 
Genetic polymorphisms involved in 
Goodpastures 
Graves disease
SLE
Type 1 diabetes
A

Goodpastures: HLA-DR15

Graves disease: HLA-DR3

SLE: HLA-DR3

Type 1 diabetes: HLA -DR3/DR4

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37
Q

Protein tyrosine phosphatase non-receptor 22 is… there is an allele that increases susceptibility to…

A

Lymphocyte specific tyrosine phosphatase which
suppresses T cell activation

Rheumatoid arthritis
Systemic lupus erythematosus
Type 1 diabetes

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38
Q

CTLA4 is…

There is an allele that increases susceptibility to…

A

Receptor for CD80/CD86, expressed on T cells, that influences T cell activation

Systemic lupus erythematosus,
Type 1 diabetes
Auto-immune thyroid disease

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39
Q

3 mechanisms of peripheral tolerance (brief)

A

anergy – by cells lacking co-stimulatory molecules
regulation - by regulatory cell populations
immune privilege – lymphocytes denied entry

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40
Q

Central tolerance of B cells develops in….

A

Bone marrow

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41
Q

Central tolerance:

Immature B cells undergo apoptosis if…

A

They bind to polyvalent antigens (leads to crosslinking)

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42
Q

For full activation T cells require co-stimulation with…

A

CD28 on the T cell binds to CD80/86 on the APC

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43
Q

Regulatory T cells secrete

A

TGF beta, IL10

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44
Q

Sites in the body not normally exposed to the immune system

A

The eye
The testes
The central nervous system

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45
Q

What is a type 1 hypersensitivity reaction

Brief pathogenesis

A

Rapid IgE mediated allergic reaction.
IgE on mast cells crosslink causing degranulation
Inflammatory mediators released

Increased vascular permeability
Leukocyte chemotaxis
Smooth muscle contraction

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46
Q

What is a type 2 hypersensitivity reaction

Brief pathogenesis

A

Antibodies react to cellular antigen
This leads to antibody dependent destruction via phagocytes, NK cells and complement.

Phagocytes attracted via Fc recepors
NK cells released cytolytic granules when Fc binds to Fc receptors on the NK cell
Complement (classical) pathway activation leading to cell lysis

The antibodies can also bind to receptors on cells causign blockade (sometimes called type 5 reaction)

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47
Q

Name 5 syndromes caused by type 2 hypersensitivity reactions

A 
Myaesthenia gravis 
Graves disease 
Autoimmune haemolytic anaemia 
Goodpasture disease 
Pemphigus vulgaris
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48
Q

Autoantigen involved in Goodpasture disease

A

Noncollagenous domain of basement membrane collagen type IV

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49
Q

Clinical features of goodpasture disease

A

Glomerulonephritis, pulmonary hemorrhage

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50
Q

Autoantigen involved in pemphigus vulgaris

A

Epidermal cadherin

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51
Q

What is a type 3 hypersensitivity reaction

Brief pathogenesis

A

Antibodies form an immune complex with a soluble antigen. This leads to activation of complement and infiltration (into tissues) of macrophages and neutrophils.

Cytokine and chemokine expression
Granule release from neutrophils
Increased vascular permeability

This leads to inflammation and vascular damage. It causes: Cutaneous vasculitis
Glomerulonephritis
Arthritis

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52
Q

List 3 conditions caused by type 3 hypersensitivity reactions

A

SLE
Cryoglobulinaemia
Rheumatoid arthritis

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53
Q

Clinical features of cryoglobulinaemia

A

Rash, glomerulonephritis, arthritis

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54
Q

Autoantigen(s) in cryoglobulinaemia

A

Fc region of IgG

Hepatitis C antigens

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55
Q

Autoantigen in rheumatoid arthritis (type 3 hypersensitivity)

A

Fc region of IgG

Cyclic citrullinated peptide

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56
Q

Autoantigens in SLE

A

DNA, Histones, RNP

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57
Q

What is a type 4 hypersensitivity reaction

brief pathogenesis

A

Delayed type hypersensitivity…T-cell mediated response
T cell primed against a self-peptide.
TNF induction
Macrophage recruitment

Causes inflammation and tissue damage

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58
Q

List 3 conditions mediated by type 4 hypersensitivity reactions

A

T1DM
Rheumatoid arthritis
MS

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59
Q

Autoantigen in MS

A

Myelin Basic Protein

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60
Q

Autoantigen in rheumatoid arthritis (type 4 hypersensitivity)

A

Unknown synovial joint antigen

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61
Q

Autoantigens in T1DM

A 
Pancreatic b-cell antigen, specifically: 
Glutamic acid dehydrogenase (GAD 65)
Islet antigen 2 (IA2)
Islet cell
Insulin
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62
Q

T cell type involved in T1DM

A

CD8

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63
Q

T cell type involved in MS

A

CD4

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64
Q

Antiobody type in Graves disease

A

IgG stimulating the TSH receptor

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65
Q

Which type of hypersensitivity applies to Hashimoto’s thyroiditis

A

Type II and type IV hypersensitivity

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66
Q

Antibody type in Hashimoto’s thyroiditis

A

Anti-thyroid peroxidase antibodies
Anti-thyroglobulin antibodies

However: Few indications for testing thyroid antibodies because high prevalence in normal individuals. Just do thyroid biochemistry

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67
Q

Clinical features of pernicious anaemia

A

Vitamin B12 deficiency
Macrocytic anaemia
Neurological features with subacute combined degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy

Antibodies to gastric parietal cells or intrinsic factor - are useful in diagnosis

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68
Q

Antibodies involved in pernicious anaemia

A

Antibodies against gastric parietal cells and intrinsic factor

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69
Q

Clinical features of myasthaenia gravis

A

Fluctuating weakness
Extra-ocular weakness or ptosis is very common
EMG studies abnormal

Tensilon test positive:  
Inject edrophonium (an anti-cholinesterase brand name tensilon) to prolong life of acetylcholine and allow it to act on residual receptors)
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70
Q

Anti-acetylcholine receptor antibodies present in

~….% patients and are useful in diagnosis of myasthaenia gravis

A

75%

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71
Q

List polymorphisms involved in rheumatoid arthritis

A

HLA DR4 and DR1
IL-1, TNF, IL6 and IL10
PAD2 and PAD4
PTPN22

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72
Q

What are PAD2 and PAD4 and why are they important in immunology?

A

Peptidylarginine deiminases
They convert the amino acid arginine into citrulline. This controls the expression of genes in the developing embryo.

Also the immune system often attacks citrullinated proteins causing autoimmune diseases such as RA and MS.

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73
Q

Environmental factors that increase activity of PAD enzymes

A 
Smoking 
Porphyromonas gingivalis (causes gum infection)

The effect is increased citrullination which can lead to RA.

(Smoking is associated with erosive RA)

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74
Q

Role of PAD in rheumatoid arthritis

A

They convert the amino acid arginine into citrulline.
The immune system often attacks citrullinated proteins causing autoimmune diseases such as RA.

Antibodies to cyclic citrullinated peptide are commonly found in RA:
Around 95% specificity for diagnosis of rheumatoid arthritis
Around 60-70% sensitivity for diagnosis of rheumatoid arthritis (similar sensitivity to rheumatoid factor)

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75
Q

Antibodies in rheumatoid arthritis

A

IgM against Fc region of IgG (can also be IgG and IgA subtype). This is rheumatoid factor
Antibodies against cyclic citrullinated peptide

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76
Q

Autoantigen in rheumatoid arthritis (type 2 hypersensitivity)

A

Citrullinated proteins

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77
Q

Clinical features of SLE

A

CNS: seizures
Skin: Butterfly rash, discoid lupus
Heart and lungs: serositis, endocarditis, myocarditis, pericarditis, pleuritis
Kidney: Glomerulonephritis
Blood: Heamolytic anaemia, leucopenia, thrombocytopenia
Joints: Arthritis
Other: lymphadenopathy

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78
Q

Epidemiology of SLE

A

Frequency 1:2000
Female preponderance
Incidence highest in 2nd and 3rd decades

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79
Q

Immune abnormalities involved in lupus pathogenesis

A

Abnormalities in clearance of apoptotic cells
Polymyorphisms in genes encoding complement, MBL, CRP

Abnormalities in cellular activation
Polymorphisms in genes encoding/controlling expression of cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules

B cell hyperactivity and loss of tolerance

Antibodies directed particularly at intracellular proteins
? Debris from apoptotic cells that have not been cleared
Nuclear antigens - DNA, histones, snRNP
Cytoplasmic antigens - Ribosome, scRNP

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80
Q

Cause of high ESR in SLE

A

High total Ig leads to clumping of red cells (rouleaux) which fall more quickly.

Patients will have normal CRP

Characteristic also seen in Sjogrens and myeloma

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81
Q

SLE investigations (and results)

A

Inflammatory markers:
Raised ESR normal CRP

ANA positive:
anti dsDNA

Complement:
C3 and C4 low in severe active disease
C3 normal and C4 low in active disease
Both normal in inactive disease

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82
Q

Anti-Ro and La are also characteristically found in…

A

Sjogren’s syndrome

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83
Q

Clinical features of antiphospholipid syndrome

A

Antiphospholipid syndrome

Recurrent venous or arterial thrombosis

Recurrent miscarriage

May occur alone (primary) or in conjunction with autoimmune disease (secondary

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84
Q

2 antibodies involved in antiphospholipid syndrome

A

Anti-cardiolipin antibody

Lupus anti-coagulant (Prolongation of phospholipid-dependent coagulation tests cannot be assessed if the patient is on anticoagulant therapy

Note: 40% of patients have discordant antibodies
If there is a clinical suspicion of the antiphospholipid syndrome, both tests should be performed.

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85
Q

Features of systemic sclerosis pathogenesis

A

Inflammation with Th17 and Th2 cells dominating

Cytokines lead to activation of fibroblasts and development of fibrosis

Polymorphisms in TGF-b have also been described

Cytokines lead to activation of endothelial cells and contribute to microvascular disease

Loss of B cell tolerance to nuclear antigens

Polymorphisms within type I collagen alpha 2 chains and fibrillin 1 may be important

86
Q

Dominant T cell subtype in systemic sclerosis

A

Th17 and Th2

87
Q

Limited Cutaneous Systemic Sclerosis

A 
Calcinosis
Raynauds
Oesophageal dysmotility
Sclerodactyly 
Telangectasia

Primary pulmonary hypertension

Skin involvement does not progress beyond forearms (although it may involve peri-oral skin)

88
Q

Clinical features of diffuse cutaneous systemic sclerosis

A

Skin involvement does progress beyond forearms

- CREST features
- More extensive gastrointestinal disease
- Interstitial pulmonary disease
- Scleroderma kidney / renal crisis
89
Q

Antibodies involved in limited cutaneous systemic sclerosis

A

Anti-centromere antibodies

90
Q

Antibodies involved in diffuse cutaneous systemic sclerosis

A

Anti-topoisomerase antibodies (scl70)
Anti-RNA polymerase antibody
Anti-fibrillarin (anti-U3RNP) antibody

Anti-PM-Scl antibody
Anti-U1RNP (anti-nRNP) antibody

91
Q

Antibodies involved in Churg-Strauss

A

pANCA

92
Q

Antibody involved in autoimmune haemolytic anaemia

A

Anti-Rh blood group antigen

93
Q

Antibody involved in mixed connective tissue disease

A

Anti-U1RNP antibody (speckled pattern)

94
Q

Antibody involved in dermatomyositis

A

Anti-Jo-1 (histidyl-tRNA synthetase)

95
Q

Dermatomyositis is caused by a type… immune response

A

3

96
Q

Main inflammatory cells involved in dermatomyositis

A

CD4 T cells and B cells

97
Q

Antibody involved in polymyositis

A

Anti-Jo-1 (histidyl-tRNA synthetase)

98
Q

Pathogenesis of polymyositis

A

Within muscle – CD8 T cells surround HLA Class I expressing myofibres
CD8 T cells kill myofibres via perforin / granzymes – Type IV response

99
Q

Clinical features of dermatomyositis and polymyositis

A

Muscle
Progressive and symmetrical weakness predominantly affecting the proximal muscle groups.
May involve pharyngeal or respiratory muscles

Skin
Periorbital oedema with heliotrope discoloration of eye lids
Scaley red rash on extensor surface of fingers, elbows, knees
Gottron’s papules

Lungs
Some types may be associated with interstitial lung disease

Fevers/arthritis/raynauds may also be present

Strong association with presence of underlying malignancy

100
Q

Antibodies involved in SLE

A 
Antibodies against:
dsDNA
Histones 
Ro
La
Sm
U1RNP (speckled)
101
Q

Investigations and results in dermatomyositis

A

Investigations:
Elevated creatinine kinase

Abnormal EMGs

Abnormal MRI of involved muscle

Abnormal biopsy of involved muscle

Positive ANA:
Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic) (DM)
Anti-signal recognition peptide antibody (nuclear and cytoplasmic) (PM)
Anti-Mi2 (nuclear) (DM>PM)

102
Q

Antibodies involved in Wegener’s/GPA

A

c-ANCA

103
Q

Antibodies involved in microscopic polyangitis (MPA)

A

pANCA

104
Q

Antibody that can cause congenital heart block in infants of mothers with SLE

A

Anti-Ro antibody

105
Q

ANCA antibodies target…

A

Neutrophils

106
Q

Small vessel vasculitis e.g. GPA is caused by type…hypersensitivity

A

2

107
Q

cANCA is associated with antbodies to…

A

Associated with antibodies to enzyme proteinase 3

108
Q

pANCA is associated with antbodies to

A

Myeloperoxidase

109
Q

pANCA is positive in…

A

eGPA (Churg-Strauss)

Microscopic polyangitis

110
Q

cANCA is positive in…

A

GPA (Wegener’s)

111
Q

Half life of IVIG

A

18 days

112
Q

Examples of specific immunoglobulins used

A

Hepatitis B immunoglobulin
Tetanus immunoglobulin
Rabies immunoglobulin
Varicella Zoster immunoglobulin

113
Q

Uses of IFN-alpha

A

Hepatitis C, Hepatitis B, Kaposi’s sarcoma

Hairy cell leukaemia, chronic myeloid leukaemia, multiple myeloma

114
Q

Uses of IFN-Beta

A

Relapsing MS in past

115
Q

Uses of IFN gamma

A

Chronic granulomatous disease

116
Q

Mechanism of action of Ipilimumab

A

Antibody that blocks CTLA4.
CTLA4 acts as an off switch when T cells bind to CD80/CD86.
Blocking it allows T cell activation.
Cytotoxic T cells recognise and destroy cancer cells.

117
Q

Ipilimumab is used for…

A

Advanced melanoma

118
Q

Mechanism of action of Pembrolizumab

A

The antibody blocks the PD1 (programmed cell death 1) receptor.
PD1 is a downregulator of the immune system. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells).

When the receptor is blocked T cells are able to become activated and recognise and destroy cancer cells.

119
Q

Mechanism of action of Nivolumab

A

The antibody blocks the PD1 (programmed cell death 1) receptor.
PD1 is a downregulator of the immune system. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells).

When the receptor is blocked T cells are able to become activated and recognise and destroy cancer cells.

120
Q

Uses of Nivolumumab

A

Advanced melanoma

121
Q

Uses of pembolizumab

A

Advanced melanoma

122
Q

Mechanism of action of corticosteroids

A

Inhibit phospholipase A2.
PLA2 breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (eg prostaglandin)s, leukotrienes) by cyclo-oxygenases.

Blocking it prevents arachidonic acid and prostaglandin formation and therefore reduces inflammation.

123
Q

Effects of corticosteroids on phagocyte function

A

Decreased traffic of phagocytes to inflamed tissue
Decreased expression of adhesion molecules on endothelium

Blocks the signals that tell immune cells to move from bloodstream and into tissues

Results in transient increase in neutrophil counts

Decreased phagocytosis

Decreased release of proteolytic enzymes

124
Q

Effects of corticosteroids on lymphocyte function

A

Lymphopenia
Sequestration of lymphocytes in lymphoid tissue
Affects CD4+ T cells > CD8+ T cells > B cells

Blocks cytokine gene expression

Decreased antibody production

Promotes apoptosis

125
Q

Mechanism of action of cyclophosphamide

A

Alkylates guanine base of DNA
Damages DNA and prevents cell replication
Affects B cells > T cells, but at high doses affects all cells with high turnover

126
Q

Uses of cyclophosphamide

A

Multisystem connective tissue disease or vasculitis with severe end-organ involvement
eg GPA (Wegener’s granulomatosis), SLE
Anti-cancer agent

127
Q

Cells affected by cylcophosphamide

A

Affects B cells > T cells, but at high doses affects all cells with high turnover

128
Q

Key side effects of cyclophosphamide

A

Toxic to proliferating cells:
Bone marrow depression
Hair loss
Sterility (male»female)

Haemorrhagic cystitis:
Toxic metabolite acrolein excreted via urine

Malignancy:
Bladder cancer
Haematological malignancies
Non-melanoma skin cancer

Infection: 
Pneumocystis Jiroveci (propylactic septrin)
129
Q

Toxic metabolite of cyclophasphamide

A

acrolein

130
Q

Mechanism of action of azathioprine

A

Metabolised by liver to 6 mercaptopurine
Blocks de novo purine (eg adenine, guanine) synthesis – prevents replication of DNA
Preferentially inhibits T cell activation & proliferation

131
Q

Cells affected by azathioprine

A

Preferentially inhibits T cell activation and proliferation.

132
Q

Uses of azathioprine

A

Transplantation
Auto-immune disease
Auto-inflammatory diseases, eg Crohn’s, ulcerative colitis

133
Q

Key side effects of azathioprine

A

Bone marrow suppression:
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
1:300 individuals are extremely susceptible to bone marrow suppression s
Thiopurine methyltransferase (TPMT) polymorphisms
Unable to metabolise azathioprine
Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy

Hepatotoxicity:
Idiosyncratic and uncommon

Infection:
Serious infection less common than with cyclophosphamide

134
Q

Mechanism of action of MMF

A

Blocks de novo nucleotide synthesis
– prevents replication of DNA
Prevents T>B cell proliferation

135
Q

Uses of MMF

A

Widely used in transplantation as alternative to azathioprine
Also used in auto-immune diseases and vasculitis as alternative to cyclophosphamide

136
Q

Cells affected by MMF

A

Prevents T>B cell proliferation

137
Q

Key side effects of MMF

A

Bone marrow suppression Infection
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive

Infection
Particular risk of herpes virus reactivation
Progressive multifocal leukoencephalopathy (JC virus)

138
Q

Pathogenesis of PML

A

PML is a demyelinating disease, in which the myelin sheath covering the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the subcortical white matter, particularly that of the parietal and occipital lobes. PML destroys oligodendrocytes and produces intranuclear inclusions. PML is similar to another demyelinating disease, multiple sclerosis, but progresses much more quickly. The breakdown of myelin is commensurate with the degree of immunocompromise.

The cause of demyelination is the JC virus. Usually reactivated and most deadly in immunodeficient or immunocompromised patients.

139
Q

Problems with plasmaphoresis (for autoimmune disease/organ rejection)

A

Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent

140
Q

Indications for plasmaphoresis

A

Severe antibody-mediated disease: e.g Goodpastures syndrome
Severe acute myasthenia gravis:
Severe vascular rejection:

141
Q

Mechanism of action of ciclosporin

A

Calcineurin inhibitor
Calcineurin is important in the T cell signal pathway leading to increased IL2 production. Inhibiting calcnineurin decreases IL2 production and therefore also decreases.

142
Q

Mechanism of action of tacrolimus

A

Calcineurin inhibitor
Calcineurin is important in the T cell signal pathway leading to increased IL2 production. Inhibiting calcnineurin decreases IL2 production and therefore also decreases.

143
Q

Mechanism of action of sirolimus

A

inhibits mTOR to inhibit activation and proliferation of t cells and B cells.

144
Q

Indications for tacrolimus

A

Rejection prophylaxis in transplantation

145
Q

Indications for sirolimus

A

Rejection prophylaxis in transplantation

146
Q

Indications for ciclospirin

A

Rejection prophylaxis in transplantation

147
Q

Key side effects of tacrolimus

A 
Hypertension 
Nephrotoxicity 
Neurotoxic 
Diabetogenic
gingival hypertrophy
148
Q

Key side effects of ciclosporin

A 
Hypertension 
Nephrotoxicity 
Neurotoxicity 
Diabetogenic 
Dysmporphism
Gingival hypertrophy
149
Q

Mechanism of action of Tofacitinib

A 
JAK inhibitor (JAK1 and JAK3) 
JAK is important in cell signalling. It is part of the JAK STAT signalling pathway that increases DNA transcription.
150
Q

Mechanism of action of Apremilast

A

PDE4 inhibitor.
PDE4 breaks down cAMP. cAMP downregulates expression of a number of pro-inflammatory cytokines such as TNF-alpha. Therefore the apremilast causes downregulation of pro-inflammatory cytokines.

151
Q

Key side effects of apremilast

A

Headache, back pain, nausea, diarrhea, fatigue, nasopharyngitis and upper respiratory tract infections.

Depression
Weight loss

152
Q

Key side effects of Tofacitinib

A

Carcinogenesis, mutagenesis, and impairment of fertility

153
Q

Uses of apremilast

A

Plaque psoriasis and psoriatic arthritis

154
Q

Before starting azathioprine you must test for polymorphisms of

A

TPMT

155
Q

Mechanism of action of antithymocyte globulin

A

Rabbit or horse derived antibodies against human T cells. Leads to:
Lymphocyte depletion
Modulation of T cell activation
Modulation of T cell migration

156
Q

Uses of antithymocyte globulin

A

Allograft rejection: renal, heart

Daily intravenous infusion

157
Q

Key adverse effects of antithymocyte globulin

A

Infusion reactions
Leukopenia
Infection
Malignancy

158
Q

Mechanism of action of basiliximab

A

Blocks CD25 (alpha chain of IL-2 receptor). It therefore inhbits T cell proliferation.

159
Q

Indications for basiliximab

A

Prophylaxis of rejection in transplantation. IV given before and after surgery

160
Q

Key adverse effects of basiliximab

A

Infusion reactions
Infection
Concern re long term risk malignancy
GI disturbance

161
Q

Mechanism of action of abatacept

A

Anti-CTLA4 antibody.
Abatacept consists of a fusion protein of the extracellular domain of CTLA-4 and human IgG.
It binds to the CD80/86 protein on the APC and prevents it from delivering the co-stimulatory (CD28 binding to CD80/86) signal to the T cell.

The T cell is not activated.

162
Q

Clinical features of a cytokine storm

A

fevers, myalgias

increased vascular permeability:
pulmonary oedema
cerebral oedema
cardiovascular collapse
poor peripheral perfusion
shock
163
Q

Mechanism of action of rituximab

A

Anti-CD20.

Binds to B cells expressing this (so not mature plasma cells) and causes them to be destroyed (by NK cells).

164
Q

Key adverse effects of abatacept

A

Infusion reactions
Infection (TB, HBV, HCV)
Caution wrt malignancy

165
Q

Indications for abatacept

A

Rheumatoid arthritis

Intravenous 4 weekly
Subcutaneous weekly

166
Q

Indications for rituximab

A

Lymphoma
Rheumatoid arthritis
SLE

2 doses intravenous every 6-12 months (RA)

167
Q

Key adverse effects of rituximab

A

Infusion reactions
Infection (PML)
Exacerbation CV disease

168
Q

Mechanism of action of Natalizumab

A

Anti-alpha4 integrin antibody.

α4-integrin is required for white blood cells to move into organs, and natalizumab’s mechanism of action is believed to be the prevention of immune cells from crossing blood vessel walls to reach affected organs

Overall effect is inhibition of T cell migration.

169
Q

Indications for natilizumab

A

Highly active relapsing-remitting multiple sclerosis
Crohn’s disease

Intravenous every 4 weeks

170
Q

Key adverse effects of natilizumab

A

Infusion reactions
Infection (PML)
Hepatotoxic
Concern re malignancy

171
Q

Mechanism of action of efalizumab

A

Antibody specific for CD11a

Lymphocyte function-associated antigen 1, also known as LFA-1 is found on all T-cells and also on B-cells, macrophages and neutrophils and is involved in recruitment to the site of infection. It binds to ICAM-1 on antigen-presenting cells and functions as an adhesion molecule.

Overall effect: Inhibits T cell migration

172
Q

Indications for efalizumab

A

Psoriasis

Withdrawn following fatal cases of PML!!!

173
Q

Key adverse effects of efalizumab

A

Infusion reactions
Infection (PML)
Concern re malignancy

Withdrawn following fatal cases of PML!!!

174
Q

Mechanism of action of tocilizumab

A

Anti-IL6 antibody

IL6 produced by macrophages and T cells
Receptors on monocytes, neutrophils, B cells and T cells.
Tocilizumab binds to both soluble and membrane bound IL6 receptors.

Overall effect:
Reduces macrophage, T cell, B cell, and neutrophil activation

175
Q

Indications for toxilizumab

A

Castleman’s disease
Rheumatoid arthritis

IV every 4 weeks

176
Q

Monoclonal antibodies against TNFa

A

Infliximab – anti-TNFa
Adalimumab – anti-TNFa
Certolizumab – anti-TNFa
Golimumab – anti-TNFa

177
Q

Target of etancercept

A

TNF receptor.

Therefore inhibits TNFa and TNFb

178
Q

Allergen desensitization. Maintenance dose frequency and duration of maintenance treatment

A

Maintenance dose administered monthly for 3-5 years

179
Q

Indications for anti-TNFa monoclonal antibodies

A

Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis and psoriatic arthritis
Inflammatory bowel disease

Subcutaneous or intravenous

180
Q

Key adverse effects of anti-TNFa monoclonal antibodies

A 
Infusion or injection site reactions
Infection (TB, HBV, HCV)
Lupus-like conditions
Demyelination
Malignancy
181
Q

Indications for etanercept

A

Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis and psoriatic arthritis

Subcutaneous weekly

182
Q

Key adverse effects of etanercept

A 
Injection site reactions
Infection (TB, HBV, HCV)
Lupus-like conditions
Demyelination
Malignancy
183
Q

Mechanism of action of ustekinumab

A

Antibody to p40 subunit of IL-12 and IL-23

Receptors for IL12 and IL23 found on NK cells and T cells

184
Q

Receptors for IL12 and IL23 found on which cells?

A

T cells

NK cells

185
Q

Key adverse effects of ustekinumab

A

Injection site reactions
Infection (TB)
Concern re malignancy

186
Q

Indications for ustekinumab

A

Psoriasis, psoriatic arthritis

Subcutaneous every 12 weeks

187
Q

Subunits that form IL12 and IL23

A

IL-12 comprises p40+p35

IL-23 comprises p40+p19

188
Q

Mechanism of action of denosumab

A

Antibody directed at RANK ligand

RANK is on osteoclasts.

Denosumab binds to the ligand and prevents binding with the receptor leading to inhibition of RANK mediated osteoclast differentiation and function.

189
Q

Indications for denosumab

A

Osteoporosis

Subcutaneous every 6 months

190
Q

Key adverse effects of denosumab

A

Injection site reactions
Infection
Avascular necrosis of jaw

191
Q

Immunosuppression side-effects:

Features of injection site reactions

A

Peak reaction at ~48 hours
May also occur at previous injection sites (recall reactions)
Mixed cellular infiltrates, often with CD8 T cells
Not generally IgE or immune complexes

192
Q

Immunosuppression side-effects:

A

Urticaria, hypotension, tachycardia, wheeze – IgE mediated
Headaches, fevers, myalgias – not classical type I hypersensitivity
Cytokine storm

193
Q

Vaccines that cannot be given to immunocompromised patients.

A

BCG
Measles
Polio
Yellow fever

194
Q

Malignancies linked with immunosupression

A

Lymphoma (EBV)
Non melanoma skin cancers (Human papilloma virus)
Melanoma (increased in cohort treated with anti-TNF alpha)

Note: Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation

195
Q

Most common allergic disorder in adults

A

Allergic rhinitis

196
Q

Typical symptoms of IgE allergic response

A

angioedema, urticaria, pruritus, rhinitis conjunctivitis, wheeze, diarrhoea vomiting and anaphylaxis.

197
Q

IgE allergic response occurs within what timeframe

A

within minutes upto 2 hours

198
Q

During acute allergic episode we can test for mast cell degranulation. What is measured?

A

Serum mast cell tryptase levels

Peak concentration at 1-2 hours; returns to baseline by 6-12 hours

199
Q

Antihistamines should be discontinued for at least…. before a skin test

A

Antihistamines should be discontinued for at least 48 hours beforehand.

200
Q

Indications for specific IgE testing (in allergy)

A

Patients who can’t stop anti-histamines

Patients with dermatographism

Patients with extensive eczema

History of anaphylaxis

Borderline/equivocal skin prick test results

201
Q

What is component resolved diagnostics?

A

Test measured iGE response to a specific allergen protein (conventional tests measure response to a range of allergen proteins, e.g. peanuts contain at least 5 major allergen proteins).

Can allow clinician to predict whether a patient will experience no or minor symptoms or major symptoms/anaphylaxis: may reduce the needs for food challenges

202
Q

Gold standard for food allergy diagnosis is

A

Food challenge test

203
Q

Causes of non-IgE mediated mast cell degranulation

A

Aspirin and NSAID
Intravenous contrast media
Opioid analgesics
Exercise

204
Q

Dose of IM adrenaline anaphylaxis (adults)

A

IM adrenaline 500ug

205
Q

Emergency management of anaphylaxis

A 
IM adrenaline 500ug
Oxygen 100%
Fluid replacement
Inhaled Bronchodilators
Hydrocortisone 100mg IV
Chlorpheniramine 10mg IV ( skin rash)
206
Q

Dose of adrenaline in an adult epipen

A

300ug adrenaline

207
Q

Dose of adrenaline in a paediatric epipen

A

150ug adrenaline

208
Q

Example of food hypersensitivity that is IgE and cell mediated

A

Atopic dermatitis

209
Q

Best single agent for mild/moderate allergic rhinitis

A

Steroid nasal spray

210
Q

You should start treatment for seasonal allergic rhinitis… before onset of pollen season

A

2-4 weeks

211
Q

Viral replication is detected by…

A

Pattern recognition receptors including TLRs and Rig Like receptors (RLRs)

Year 5 Pathology (7 decks)

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