Immunology 2 Flashcards
1
Q
What populations are affected by familial Mediterranean fever
A
Sephardic>Ashkenazy Jews
Armenian, Turkish and Arabic people
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)
3
Q
MEFV gene codes for…
A
Pyrin marenostrin
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
5
Q
Treatment of familial mediterranean fever
A
Colchicine 500ug bd
Anakinra (Interleukin 1 receptor antagonist)
Etanercept (TNF alpha inhibitor)
Type 1 interferon
6
Q
List 3 monogenic auto-immune diseases
A
APS-1/APECED
ALPS
IPEX
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
8
Q
Clinical features of autoimmune polyendocrine syndrome
A
Hypoparathyroidism
Addison’s
(autoimmune)
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
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
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
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
13
Q
Gene affected in IPEX
A
foxp3
14
Q
List 5 polygenic auto-inflammatory diseases
A
Crohns disease Ulcerative colitis Osteoarthritis Giant cell arteritis Takayasu’s arteritis
15
Q
Mutations found in Crohn’s disease also found in…
A
Severe psoriasis and psoriatic arthritis
Gene is NOD2/CARD15
16
Q
Crohn’s disease involves dysfunction of which immune system?
A
Innate
17
Q
The temporal artery arises from which artery
A
External carotid
18
Q
The opthalmic artery arises from which artery
A
Internal carotid
19
Q
The most common systemic vasculitis in elderly is…
A
Giant cell arteritis
20
Q
ICAM 1 polymorphism affects
A
Cell migration
21
Q
IL6, IL8 and IL 10 gene promoter polymorphism affects
A
Cytokine expression
22
Q
Toll like receptor 4 polymorphisms affect
A
Dendritic cell activation
23
Q
Nitric oxide synthase polymorphisms can cause…
A
Tissue destruction
24
Q
Clinical features of giant cell arteritis
A
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
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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
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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
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Infusion or injection site reactions
Infection (TB, HBV, HCV)
Lupus-like conditions
Demyelination
Malignancy
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181
Indications for etanercept
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis and psoriatic arthritis
Subcutaneous weekly
182
Key adverse effects of etanercept
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Injection site reactions
Infection (TB, HBV, HCV)
Lupus-like conditions
Demyelination
Malignancy
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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
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Dose of IM adrenaline anaphylaxis (adults)
IM adrenaline 500ug
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Emergency management of anaphylaxis
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IM adrenaline 500ug
Oxygen 100%
Fluid replacement
Inhaled Bronchodilators
Hydrocortisone 100mg IV
Chlorpheniramine 10mg IV ( skin rash)
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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)
