Immunology 2 Flashcards Preview

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Flashcards in Immunology 2 Deck (211):
1

What populations are affected by familial Mediterranean fever

Sephardic>Ashkenazy Jews
Armenian, Turkish and Arabic people

2

Briefly describe the pathogenesis of familial Mediterranean fever

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)

3

MEFV gene codes for...

Pyrin marenostrin

4

Clinical features of familial Mediterranean fever

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

5

Treatment of familial mediterranean fever

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

6

List 3 monogenic auto-immune diseases

APS-1/APECED
ALPS
IPEX

7

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

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

8

Clinical features of autoimmune polyendocrine syndrome

Hypoparathyroidism
Addison's
(autoimmune)

9

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

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

10

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

Overwhelming disease leads to early death without treatment

Endocrinopathy
usually Insulin dependent diabetes mellitus, Thyroid disease

Diarrhoea

Eczematous dermatitis

11

Briefly describe the pathogenesis of Auto-immune lymphoproliferative syndrome

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

12

Clinical features of autoimmune lymphoproliferative syndrome

High lymphocyte levels with large spleen and lymph nodes
Autoimmune cytopenias

May be associated with lymphoma

13

Gene affected in IPEX

foxp3

14

List 5 polygenic auto-inflammatory diseases

Crohns disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis

15

Mutations found in Crohn's disease also found in...

Severe psoriasis and psoriatic arthritis

Gene is NOD2/CARD15

16

Crohn's disease involves dysfunction of which immune system?

Innate

17

The temporal artery arises from which artery

External carotid

18

The opthalmic artery arises from which artery

Internal carotid

19

The most common systemic vasculitis in elderly is...

Giant cell arteritis

20

ICAM 1 polymorphism affects

Cell migration

21

IL6, IL8 and IL 10 gene promoter polymorphism affects

Cytokine expression

22

Toll like receptor 4 polymorphisms affect

Dendritic cell activation

23

Nitric oxide synthase polymorphisms can cause...

Tissue destruction

24

Clinical features of giant cell arteritis

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

25

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

Ankylosing spondylitis
Psoriatic arthritis
Behcet’s syndrome

26

Role of Human leukocyte antigen B27

Presents antigen to CD8 T cells.
Ligand for killer immunoglobulin receptor

27

Role of interleukin receptor type II

Decoy receptor that inhibits activity of IL1

28

List genetic polymorphisms implicated in ankylosing spondylitis

HLAB27
ILR2
IL23R
ERAP1 (ARTS1)
ANTXR2

29

Clinical features of ankylosing spondylitis

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

30

Treatment of ankylosing spondylitis

Non-steroidal anti-inflammatory drugs
Immunosuppression – TNF alpha antagonists

31

Ankylosing spondylitis typically involves which joints?

Sacroiliac

32

Ankylosing spondylitis has ...% heritability

90%

33

Treatment of giant cell arteritis

Immunosuppression with corticosteroids

34

Investigations (and results) used to diagnose giant cell ateritis

High CRP and ESR

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

35

List 6 polygenic auto-immune diseases

Rheumatoid arthritis
Systemic lupus erythematosus (SLE)
Myaesthenia Gravis
Primary biliary cirrhosis
Pernicious anaemia
Addison disease

36

Genetic polymorphisms involved in
Goodpastures
Graves disease
SLE
Type 1 diabetes

Goodpastures: HLA-DR15

Graves disease: HLA-DR3

SLE: HLA-DR3

Type 1 diabetes: HLA -DR3/DR4

37

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

Lymphocyte specific tyrosine phosphatase which
suppresses T cell activation

Rheumatoid arthritis
Systemic lupus erythematosus
Type 1 diabetes

38

CTLA4 is...
There is an allele that increases susceptibility to...

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

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

39

3 mechanisms of peripheral tolerance (brief)

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

40

Central tolerance of B cells develops in....

Bone marrow

41

Central tolerance:
Immature B cells undergo apoptosis if...

They bind to polyvalent antigens (leads to crosslinking)

42

For full activation T cells require co-stimulation with...

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

43

Regulatory T cells secrete

TGF beta, IL10

44

Sites in the body not normally exposed to the immune system

The eye
The testes
The central nervous system

45

What is a type 1 hypersensitivity reaction
(Brief pathogenesis)

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

Increased vascular permeability
Leukocyte chemotaxis
Smooth muscle contraction

46

What is a type 2 hypersensitivity reaction
(Brief pathogenesis)

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)

47

Name 5 syndromes caused by type 2 hypersensitivity reactions

Myaesthenia gravis
Graves disease
Autoimmune haemolytic anaemia
Goodpasture disease
Pemphigus vulgaris

48

Autoantigen involved in Goodpasture disease

Noncollagenous domain of basement membrane collagen type IV

49

Clinical features of goodpasture disease

Glomerulonephritis, pulmonary hemorrhage

50

Autoantigen involved in pemphigus vulgaris

Epidermal cadherin

51

What is a type 3 hypersensitivity reaction
(Brief pathogenesis)

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

52

List 3 conditions caused by type 3 hypersensitivity reactions

SLE
Cryoglobulinaemia
Rheumatoid arthritis

53

Clinical features of cryoglobulinaemia

Rash, glomerulonephritis, arthritis

54

Autoantigen(s) in cryoglobulinaemia

Fc region of IgG
Hepatitis C antigens

55

Autoantigen in rheumatoid arthritis (type 3 hypersensitivity)

Fc region of IgG
Cyclic citrullinated peptide

56

Autoantigens in SLE

DNA, Histones, RNP

57

What is a type 4 hypersensitivity reaction
(brief pathogenesis)

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

Causes inflammation and tissue damage

58

List 3 conditions mediated by type 4 hypersensitivity reactions

T1DM
Rheumatoid arthritis
MS

59

Autoantigen in MS

Myelin Basic Protein

60

Autoantigen in rheumatoid arthritis (type 4 hypersensitivity)

Unknown synovial joint antigen

61

Autoantigens in T1DM

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

62

T cell type involved in T1DM

CD8

63

T cell type involved in MS

CD4

64

Antiobody type in Graves disease

IgG stimulating the TSH receptor

65

Which type of hypersensitivity applies to Hashimoto's thyroiditis

Type II and type IV hypersensitivity

66

Antibody type in Hashimoto's thyroiditis

Anti-thyroid peroxidase antibodies
Anti-thyroglobulin antibodies

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

67

Clinical features of pernicious anaemia

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

68

Antibodies involved in pernicious anaemia

Antibodies against gastric parietal cells and intrinsic factor

69

Clinical features of myasthaenia gravis

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)

70

Anti-acetylcholine receptor antibodies present in
~....% patients and are useful in diagnosis of myasthaenia gravis

75%

71

List polymorphisms involved in rheumatoid arthritis

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

72

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

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.

73

Environmental factors that increase activity of PAD enzymes

Smoking
Porphyromonas gingivalis (causes gum infection)

The effect is increased citrullination which can lead to RA.

(Smoking is associated with erosive RA)

74

Role of PAD in rheumatoid arthritis

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)

75

Antibodies in rheumatoid arthritis

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

76

Autoantigen in rheumatoid arthritis (type 2 hypersensitivity)

Citrullinated proteins

77

Clinical features of SLE

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

78

Epidemiology of SLE

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

79

Immune abnormalities involved in lupus pathogenesis

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

80

Cause of high ESR in SLE

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

81

SLE investigations (and results)

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

82

Anti-Ro and La are also characteristically found in...

Sjogren’s syndrome

83

Clinical features of antiphospholipid syndrome

Antiphospholipid syndrome

Recurrent venous or arterial thrombosis

Recurrent miscarriage

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

84

2 antibodies involved in antiphospholipid syndrome

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.

85

Features of systemic sclerosis pathogenesis

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

Dominant T cell subtype in systemic sclerosis

Th17 and Th2

87

Limited Cutaneous Systemic Sclerosis

Calcinosis
Raynauds
Oesophageal dysmotility
Sclerodactyly
Telangectasia

Primary pulmonary hypertension

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

88

Clinical features of diffuse cutaneous systemic sclerosis

Skin involvement does progress beyond forearms

- CREST features

- More extensive gastrointestinal disease

- Interstitial pulmonary disease

- Scleroderma kidney / renal crisis

89

Antibodies involved in limited cutaneous systemic sclerosis

Anti-centromere antibodies

90

Antibodies involved in diffuse cutaneous systemic sclerosis

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

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

91

Antibodies involved in Churg-Strauss

pANCA

92

Antibody involved in autoimmune haemolytic anaemia

Anti-Rh blood group antigen

93

Antibody involved in mixed connective tissue disease

Anti-U1RNP antibody (speckled pattern)

94

Antibody involved in dermatomyositis

Anti-Jo-1 (histidyl-tRNA synthetase)

95

Dermatomyositis is caused by a type... immune response

3

96

Main inflammatory cells involved in dermatomyositis

CD4 T cells and B cells

97

Antibody involved in polymyositis

Anti-Jo-1 (histidyl-tRNA synthetase)

98

Pathogenesis of polymyositis

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

99

Clinical features of dermatomyositis and polymyositis

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

Antibodies involved in SLE

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

101

Investigations and results in dermatomyositis

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

Antibodies involved in Wegener's/GPA

c-ANCA

103

Antibodies involved in microscopic polyangitis (MPA)

pANCA

104

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

Anti-Ro antibody

105

ANCA antibodies target...

Neutrophils

106

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

2

107

cANCA is associated with antbodies to...

Associated with antibodies to enzyme proteinase 3

108

pANCA is associated with antbodies to

Myeloperoxidase

109

pANCA is positive in...

eGPA (Churg-Strauss)
Microscopic polyangitis

110

cANCA is positive in...

GPA (Wegener's)

111

Half life of IVIG

18 days

112

Examples of specific immunoglobulins used

Hepatitis B immunoglobulin
Tetanus immunoglobulin
Rabies immunoglobulin
Varicella Zoster immunoglobulin

113

Uses of IFN-alpha

Hepatitis C, Hepatitis B, Kaposi’s sarcoma
Hairy cell leukaemia, chronic myeloid leukaemia, multiple myeloma

114

Uses of IFN-Beta

Relapsing MS in past

115

Uses of IFN gamma

Chronic granulomatous disease

116

Mechanism of action of Ipilimumab

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

Ipilimumab is used for...

Advanced melanoma

118

Mechanism of action of Pembrolizumab

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

Mechanism of action of Nivolumab

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

Uses of Nivolumumab

Advanced melanoma

121

Uses of pembolizumab

Advanced melanoma

122

Mechanism of action of corticosteroids

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

Effects of corticosteroids on phagocyte function

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

Effects of corticosteroids on lymphocyte function

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

Mechanism of action of cyclophosphamide

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

Uses of cyclophosphamide

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

127

Cells affected by cylcophosphamide

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

128

Key side effects of cyclophosphamide

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

Toxic metabolite of cyclophasphamide

acrolein

130

Mechanism of action of azathioprine

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

Cells affected by azathioprine

Preferentially inhibits T cell activation and proliferation.

132

Uses of azathioprine

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

133

Key side effects of azathioprine

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

Mechanism of action of MMF

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

135

Uses of MMF

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

136

Cells affected by MMF

Prevents T>B cell proliferation

137

Key side effects of MMF

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

Pathogenesis of PML

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

Problems with plasmaphoresis (for autoimmune disease/organ rejection)

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

140

Indications for plasmaphoresis

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

141

Mechanism of action of ciclosporin

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

Mechanism of action of tacrolimus

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

Mechanism of action of sirolimus

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

144

Indications for tacrolimus

Rejection prophylaxis in transplantation

145

Indications for sirolimus

Rejection prophylaxis in transplantation

146

Indications for ciclospirin

Rejection prophylaxis in transplantation

147

Key side effects of tacrolimus

Hypertension
Nephrotoxicity
Neurotoxic
Diabetogenic
gingival hypertrophy

148

Key side effects of ciclosporin

Hypertension
Nephrotoxicity
Neurotoxicity
Diabetogenic
Dysmporphism
Gingival hypertrophy

149

Mechanism of action of Tofacitinib

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

Mechanism of action of Apremilast

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

Key side effects of apremilast

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

Depression
Weight loss

152

Key side effects of Tofacitinib

Carcinogenesis, mutagenesis, and impairment of fertility

153

Uses of apremilast

Plaque psoriasis and psoriatic arthritis

154

Before starting azathioprine you must test for polymorphisms of

TPMT

155

Mechanism of action of antithymocyte globulin

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

156

Uses of antithymocyte globulin

Allograft rejection: renal, heart
(Daily intravenous infusion)

157

Key adverse effects of antithymocyte globulin

Infusion reactions
Leukopenia
Infection
Malignancy

158

Mechanism of action of basiliximab

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

159

Indications for basiliximab

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

160

Key adverse effects of basiliximab

Infusion reactions
Infection
Concern re long term risk malignancy
GI disturbance

161

Mechanism of action of abatacept

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

Clinical features of a cytokine storm

fevers, myalgias

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

163

Mechanism of action of rituximab

Anti-CD20.
Binds to B cells expressing this (so not mature plasma cells) and causes them to be destroyed (by NK cells).

164

Key adverse effects of abatacept

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

165

Indications for abatacept

Rheumatoid arthritis

Intravenous 4 weekly
Subcutaneous weekly

166

Indications for rituximab

Lymphoma
Rheumatoid arthritis
SLE

2 doses intravenous every 6-12 months (RA)

167

Key adverse effects of rituximab

Infusion reactions
Infection (PML)
Exacerbation CV disease

168

Mechanism of action of Natalizumab

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

Indications for natilizumab

Highly active relapsing-remitting multiple sclerosis
Crohn’s disease

Intravenous every 4 weeks

170

Key adverse effects of natilizumab

Infusion reactions
Infection (PML)
Hepatotoxic
Concern re malignancy

171

Mechanism of action of efalizumab

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

Indications for efalizumab

Psoriasis
Withdrawn following fatal cases of PML!!!

173

Key adverse effects of efalizumab

Infusion reactions
Infection (PML)
Concern re malignancy

Withdrawn following fatal cases of PML!!!

174

Mechanism of action of tocilizumab

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

Indications for toxilizumab

Castleman’s disease
Rheumatoid arthritis

IV every 4 weeks

176

Monoclonal antibodies against TNFa

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

177

Target of etancercept

TNF receptor.
Therefore inhibits TNFa and TNFb

178

Allergen desensitization. Maintenance dose frequency and duration of maintenance treatment

Maintenance dose administered monthly for 3-5 years

179

Indications for anti-TNFa monoclonal antibodies

Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis and psoriatic arthritis
Inflammatory bowel disease

Subcutaneous or intravenous

180

Key adverse effects of anti-TNFa monoclonal antibodies

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

181

Indications for etanercept

Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis and psoriatic arthritis

Subcutaneous weekly

182

Key adverse effects of etanercept

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

183

Mechanism of action of ustekinumab

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

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

184

Receptors for IL12 and IL23 found on which cells?

T cells
NK cells

185

Key adverse effects of ustekinumab

Injection site reactions
Infection (TB)
Concern re malignancy

186

Indications for ustekinumab

Psoriasis, psoriatic arthritis

Subcutaneous every 12 weeks

187

Subunits that form IL12 and IL23

IL-12 comprises p40+p35
IL-23 comprises p40+p19

188

Mechanism of action of denosumab

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

Indications for denosumab

Osteoporosis

Subcutaneous every 6 months

190

Key adverse effects of denosumab

Injection site reactions
Infection
Avascular necrosis of jaw

191

Immunosuppression side-effects:
Features of injection site reactions

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

Immunosuppression side-effects:

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

193

Vaccines that cannot be given to immunocompromised patients.

BCG
Measles
Polio
Yellow fever

194

Malignancies linked with immunosupression

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

Most common allergic disorder in adults

Allergic rhinitis

196

Typical symptoms of IgE allergic response

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

197

IgE allergic response occurs within what timeframe

within minutes upto 2 hours

198

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

Serum mast cell tryptase levels

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

199

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

Antihistamines should be discontinued for at least 48 hours beforehand.

200

Indications for specific IgE testing (in allergy)

Patients who can’t stop anti-histamines

Patients with dermatographism

Patients with extensive eczema

History of anaphylaxis

Borderline/equivocal skin prick test results

201

What is component resolved diagnostics?

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

Gold standard for food allergy diagnosis is

Food challenge test

203

Causes of non-IgE mediated mast cell degranulation

Aspirin and NSAID
Intravenous contrast media
Opioid analgesics
Exercise

204

Dose of IM adrenaline anaphylaxis (adults)

IM adrenaline 500ug

205

Emergency management of anaphylaxis

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

206

Dose of adrenaline in an adult epipen

300ug adrenaline

207

Dose of adrenaline in a paediatric epipen

150ug adrenaline

208

Example of food hypersensitivity that is IgE and cell mediated

Atopic dermatitis

209

Best single agent for mild/moderate allergic rhinitis

Steroid nasal spray

210

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

2-4 weeks

211

Viral replication is detected by...

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