Allergies; Photodermatology; Skin Immunology; Photocarcinogenesis Flashcards
(128 cards)
1
Q
What is the normal cutaneous photosensitivity scale
A
Fitzpatrick Sun-reactive skin prototypes (SPT I-IV)
2
Q
Common “sparing” site in photosensitivity?
A
Behind the ears.
3
Q
Porphyrias
- general description
A
A group of diseases in which PORPHYRINS build up, affecting the skin and the nervous system
4
Q
Main groups of Porphyrias
A
a) Phototoxic skin porphyria - pain and burning (prickly and burny)
b) Blistering and fragility skin porphyria
c) Acute attack porphyria (some with no skin involvement; some causing blistering and fragility)
d) Severe congenital porphyria
5
Q
Example of a photo toxic skin porphyria?
A
Erythropoietic protoporphyria
also can be congenital
6
Q
Porphyria cutanea tarda (PCT) Type 1
Presentation.
A
Blistering Skin fragility Erosions Milia (firm nodules, not as hard as calcium) "Tight" skin
Hyperpigmentation
Hypertrichosis
Solar urticaria
Morphoea
7
Q
Porphyria cutanea tarda
Investigations
A
Woods lamp//
Pink fluorescence of urine if patient has PCT (420nm)
Spectrophotometer
8
Q
Different porphyrias have different…
A
Wavelengths
9
Q
Porphyria cutanea tarda//
Underlying causes
A
Alcohol
Viral hepatitis
Oestrogens
Haemochromatosis
10
Q
Porphyria cutanea tarda//
Management
A
Aims of treatment
- relieve the skin disease
- treat underlying skin disease
- reduce risk of liver cirrhosis
- hepatoma
11
Q
Erythropoietic protoporphyria
A
Deficiency in the Ferrochelatase enzyme
leads to abnormal increase in protoporphyrin (used in formation of haemoglobin and myoglobin)
Acute photoallergy (i think)
626-639nm or so
12
Q
Erythropoietic protoporphyria//
Investigations
A
- Quantitative RBC porphyrins
Fluorocytes
Transaminases
Haemoglobin conc.
Biliary tract USS
Phototesting
13
Q
Erythropoietic protoporphyria
Management
A
Explain diagnosis
Genetic counselling
6 monthly LFTs & RBC porphyrins
Prophylactic TL-01 phototherapy
Anti-oxidants - beta carotene, cysteine, high does vit C
avoid IRON
VISIBLE light photo protection measures
14
Q
What kind of light do sufferers of Erythropoietic protoporphyria need to be careful of?
A
VISIBLE light
15
Q
Photoprotection measures
A
- Behavioural (avoid middle of day sunlight)
- Clothing (DARK CLOTHING)
- Environmental (shade trees, window films)
- Topical sunscreen
(titanium oxide and zinc oxide cream)
16
Q
What should you avoid in Erythropoietic protoporphyria?
A
Iron
17
Q
Liver cirrhosis/ Liver failure related Erythropoietic protoporphyria
Management
A
Oral charcoal
Cholestyramine
ALA synthase inhibition?/
Transplant liver, bone marrow
18
Q
Acute intermittent porphyria
A
Deficiency of porphobilinogen deaminase, affecting the production of heme.
consider in diagnosis //
Acute abdomen
Mononeuritis multiplex
Guillain-Barré syndrome
Psychoses
19
Q
Hypersensitivity
A
Immune response that causes collateral damage to self
Exaggeration of normal immune mechanisms
20
Q
Allergy
A
Hypersensitivity disorder of the immune system
Allergic reactions occur when a person’s immune system reacts to normally harmless substances in the environment
21
Q
Type 1 Allergy
What is it
Routes of exposure
A
IMMEDIATE reaction - occurs within minutes and up to 2 hours after exposure to allergen
Routes: Skin contact, inhalation, ingestion, injection
22
Q
Clinical presentation of Type 1 allergy
A
Urticaria//
very itchy (hives, wheels, nettle rash)
Angioedema// localised swelling of subcut tissue or mucous membranes
Non pitting oedema
Not itchy (unless associated with urticaria)
Wheezing/asthma
- resp function significantly reduced.
23
Q
ANAPHYLAXIS
Clinical presentation
A
Compromised airways (pharyngeal or laryngeal oedema)
Breathing difficulty - bronchospasm w/tachypnoea
Hypotension
Tachycardia
Skin and mucosal changes
24
Q
Type 1 Allergy Investigations
A
Hx
Specific IgE (RAST)
Skin prick or prick prick testing
Challenge test
Serum mast cell TRYPTASE level (during anaphylaxis)
25
When should the challenge test be done?
If skin prick test comes back negative.
26
Type 1 allergy - management
Allergen avoidance
Anti histamines
Anti inflam (CORTICOSTEROIDS)
Adrenaline autoinjector
also...
Mast cell stabiliser - sodium cromoglycate
Immunotherapy
Medic alert bracelet
27
Chemical that can block mast cell activation?
Sodium cromoglycate
28
Adrenaline Autoinjector
Doses
How many pens per patient?
300 µg ADULTS
150µg CHILLUN
All patients should ne prescribed 2 pens
29
Can drugs cause mast cell degranulation?
Yes.
Morphine (opiates)
Aspirin
NSAIDs
30
Type IV allergy
DELAYED hypersensitivity
Antigen specific
T cell mediated
24-48 hrs
31
Allergic contact dermatitis - allergy type/
Type IV
32
Which compound is used to identify nickel? (in nickel allergy)
Dimethylglyoxime
| pink
33
Thiuram
Rubber accelerator
34
Colophony
Adhesive used in bandages/plasters
35
Type IV allergy - Patch testing
GOLD STANDARD
Allergens prepared on Finn chambers
Finn chambers applied on the back
(removed after 48 hours)
36
What other factors could cause dermatitis?
Endogenous
Allergic
Irritant
37
Irritant contact dermatitis
Non-immunological process
Contact with agents that abrade, irritate and traumatise skin directly
Pattern depends on exposure
e.g. Nappy rash
Lip lick dermatitis
38
Endogenous dermatitis
Atopic eczema - dry skin & flexural. Assoc w/ asthma & hay fever
Psoriasis
39
Management of contact dermatitis
Allergen/irritatn avoidance
Allergen/ irritant minimisation
Emollients
Topical steroids
UV phototherapy
Immunosuppressants
40
Normal Immune response
Infection controlled
41
Immunodeficiency
Infection not controlled
tumours may form
42
Keratin layer features
| or stratum corner
- Tough, lipid rich, PHYSICAL barrier
- Formed by terminal differentiation of Keratinocytes to Corneocytes
- Filaggrin/ Involucrin/ Keratin
43
Keratinocytes (in the epidermis)
Structural and functional cells of the epidermis
Sense pathogens via cell surface receptors and help mediate an immune response
Produce cytokines and chemokines
Produce antimicrobial peptides (AMPs) that can directly kill pathogens.
- AMPs have been found at high levels in skin of patients with psoriasis
Produce cytokines and chemokines
- recruit and regulate cell of the adaptive and innate immune system
44
Langerhans cells
> Type of dendritic cell that intersperse with keratinocytes in the epidermis
> Main skin resident immune cell
> Antigen presenting cells
> Act as sentinels in the epidermis
> they process lipid Antigen and microbial fragments and present them to effector T cells
> Help activate T cells
45
What are langerhans cells characterised by?
The BIRBECK granule
46
T Cells in epidermis/dermis
> Large number of T cells in both epidermis and dermis
> MAINLY CD8+ T cells in EPIDERMIS
> CD4+ and CD8+ in the DERMIS
Other subsets of T cells are also found (NK)
47
Which type of T cell is found mostly in the epidermis?
CD8+ T cells
48
Which type of T cell is mostly found in the DERMIS
CD4+ T cells
49
Which type f T helper cell is associated with psoriasis?
TH1
| TH17
50
Which type f T helper cell is associated with atopic dermatitis?
TH2
| TH17
51
T cells
- Produced in bone marrow
- Sensitised in THYMUS
- CELL MEDIATED IMMUNITY
52
What does antigen recognition and T cell activation involve?
Interaction with T Cell receptor (TCR) and the Major Histocompatibility Complex (mHC). Enhanced by co receptors:
CD4+
& CD8+
53
Helper T cells
CD4+
Th1 - activate macrophages to destroy microorganisms
IL2, IFNƔ
TH2 = help B cells to make Ab
IL4, IL5, IL6
Help other cells of the immune system to carry out their roles
The "conductors"
54
Dendritic cells in the dermis
> Dermal dendritic cell
- Ag presenting and secreting city/chemokines
> Plasmacytoid DC (pDC)
- produce IFNα
> APCs (antigen presenting cells)
- transmit info to T &B cells
- Dendritic, langerhans
55
Cell types in dermis.
> Macrophages
> Neutrophils (attracted to tissue by chemokines)
> Mast cells
- found in "barriers"
- IgE mediated immune response effectors
- binding of IgE --> release of inflammatory mediators
- also activated by physical trauma/certain drugs/micro-organisms
56
What are lymphocytes attracted to the injured tissue by?
Chemokines
57
Preformed mediators in mast cells
Tryptase, chymase, TNF, histamine
58
Newly synthesised mediators in mast cells
ILs, TNF, TGFβ, IFNƔ, PGD2, PGE2....
59
Mast cells
- found in "barriers"
- IgE mediated immune response effectors
- binding of IgE --> release of inflammatory mediators
- also activated by physical trauma/certain drugs/micro-organisms
60
Why do you have pain, erythema, oedema in cellulitis?
Cytokines causing dilation of blood vessels
toxins
61
IgE - other main function (organism immunity)
Immunity to helminths (worms/parasites)
62
MHC
- which chromosome?
- classes
Chromosome 6
Class 1
- almost all cells
- present Ag to cytotoxic T cells
- present endogenous Ag
Class 2
- found on Antigen presenting cells (b cells, macrophages)
- present to Th cells
- present Exogenous Ag
Immunolgocial recognition and transplant rejection
Control immune response through recognition of self and non self
63
Koebner phenomenon
Skin lesions on lines of trauma
64
Are psoriasis plaques reversible?
Yes
65
Is psoriasis associated with arthritis?
Yes, psoriatic arthritis can occur (in about 30% of patients)
66
Psoriasis - immunopathogenesis
> Keratinocytes
- release factors that stimulate pDC to produce IFNα
- release IL-1β/IL-6 and TNF
> Chemical signals activate Dendritic cells
- these migrate to skin draining lymph nodes to present to and activate t cells
- TH1 & TH17
> T cells are attracted to the dermis by chemokines and secrete IL-17A/17F/22
stimulates KC proliferation , AMP release and neutrophil attracting chemokines
CD8+ cells
Dermal fibroblasts become involved - release KC and epidermal growth factor
67
Atopic Eczema - immunopathogenesis
Impairment of skin barrier function is a key factor
Mutations in FILAGGRIN gene associated with severe/early onset disease
Decreased AMP in the skin
T cells (TH2), DC, KC, macrophages and mast cells are involved/ found in the lesions
Defective skin barrier allow access/sensitisation to allergen and promotes colonisation by micro organisms
(Block IL4 and it blows away the disease)
68
Autoimmunity in the skin
Lymphocyte abnormalities
Intercell communication
Genetic predisposition
Anatomic alterations
Hormonal influence
Infection
69
Immunodeficiency
INADEQUATE IMMUNE RESPONSE
Primary (genetic)
* inherited defect
- - specific
- - non specific
Secondary (acquired)
* AIDS
* Malignancy
* Aging
* Diabetes, renal malfunction, burns, alcoholic cirrhosis, malnutrition
70
Type 1 hypersensitivity
Antibody mediated - IgE
Early exposure to allergen causes the production of IgE, which binds to FcεR1 receptor on mast cells. Later exposure causes rapid crosslinking of the receptors, signal transduction and degranulation of the mast cell.
Very rapid early response: minutes (wheal & flare)
Late response: hours (cellular infiltration, nodule)
Pollen (birch, oilseed rape)
Drugs (penicillin)
Food (nuts, eggs, seafood)
Insects & animals (bee sting, cat hair)
71
Type II & III hypersensitivity
Antibody mediated: IgG, IgM
Type II mechanisms important in autoimmunity & transplantation
- Haemolytic disease of the newborn
- Blood transfusion recipients
Skin testing in type III hypersensitivity leads to an Arthus reaction, which is slower than a type I skin response, but faster than a type IV skin response
Type III - immune complexes
72
Type IV hypersensitivity
Cell mediated: TH1 cells.
Delayed hypersensitivity is based on a T cell-mediated response, which then recruits other cells to the site.
- Tuberculin reaction
- Contact allergy
Peaks at 24-48h after contact with Ag.
Metals (nickel, chromate), drugs.
73
Factors affecting skin immune response
> Organ transplant
- immunosuppression
> Sunlight/UV
- immunosuppression
- structure
> Ageing
- changes in skin structure
- decreased ability to detect malignant cells
- Decreased ability to detect Ag- Infection risk
- Decreased ability to distinguish “self” from “non-self”(tolerance)- Autoimmunity
74
Cell types involved in skin immunity
EPIDERMIS
> Non immune cells
- Keratinocytes
> Immune cells
- Langerhans cells
- T cells (esp CD8+)
> Others
- melanocytes
DERMIS
> Immune cells
- dendritic cells
- macrophages
- T cells (CD4+ & CD8+)
- NK cells
> Others
- fibroblasts
- lymph/vasculature (transport/access)
75
Defining cancer
An accumulation of abnormal cells that multiply through uncontrolled cell division and spread to other parts of the body by invasion and/or distant metastases via the blood and lymphatic system.
Abnormal malignant cell that can multiply in an uncontrolled fashion.
76
What does the emergence of cancer involve?
Multi-step gene damage
Cancers originate from a single cell.
Genetic mutations (change to normal base sequence of DNA)
A series of mutations accumulate in successive generations in a process known as CLONAL EVOLUTION
Cells accumulate enough mutations to become cancerous
77
Clonal Evolution
The accumulation of mutations in successive generations
78
Evolution of cancer cells
Initiating mutation
--> second mutation (then second clonal expansion)
--> 3rd mutations (then 3rd clonal expansion)
--> 4th mutation (then fourth expansion)
79
Field Cancerisation in skin tumours
Biological process in which large areas of cells at a tissue surface or within an organ are affected by a carcinogenic alteration(s).
80
Dynamic clonal diversification rather than linear clonal succession
Initiating mutation
Second mutation
INCREASED MUTATION RATE
Multiple independent mutations
-->
MULTIPLE PARALLEL CLONAL EXPANSION
81
Hallmarks of cancer
> Sustaining proliferative signalling
> Resisting cell death
> Evading growth suppressors
> Activating invasion and metastasis
> Enabling replicate immortality
> Inducing angiogenesis
82
Emerging hallmark of cancer
Deregulation of cellular energetics
Avoiding immune destruction
83
Enabling characteristics of cancer
Genome instability and mutations
Tumour-promoting inflammation
84
Potential side effects of TNFα blocker
Can perhaps cause malignancies - effectively blocking immune system from blocking the cancer cells.
85
Oncogene
Over-active form of a gene that positively regulates cell division
Drives tumour formation when activity or spy number is increased (accelerator)
e.g. Ras, Raf, growth factor receptors
86
Proto oncogene
The normal, not yet mutated form of an oncogene
87
Tumour suppressor
Inactive or non-functional form of a gene that negative regulates cell division
Prevents formation of a tumour when functioning normally (brake)
e.g. Rb, TP53
88
P53 is important for
Destroying damaged DNA
G1 checkpoint
Apoptosis triggered if repair is impossible.
89
Skin cancer types
> Malignant melanoma
> non melanoma skin cancer (NMSC)
- - BCC
- - SCC
90
Risk factors for skin cancers
```
> UV radiation
> Genetics
> Age
> Chemical exposure
> Immune suppression
```
91
UV radiation
> Chronic/long term
> Intense intermittent
> Burning
> Artificial UV
> Chronic exposure
- - SCC, 77% increased risk
- - Outdoor worker
> Intense intermittent
(i) Holidaing in locations with strong sunlight
ii) Outdoor leisure
i) Melanoma (60%)
ii) BCC (43%)
> Burning
- pain/blistering following exposure
- melanoma & BCC
- double the risk
> Artificia UV
- sunbed
- SCC, Melanoma, BCC (higher risk of melanoma)
92
Genetics
Skin type risk
Predisposition
> Fair skinned with light coloured hair and eyes
Those more likely to burn than tan
Skin types I, II & III
> Genetic predisposition
- albinism
- xeroderma pigmentosum
- Xp associated genes are involved in the repair of DNA damage
- 2000-fold risk of skin cancer before age 20; skin cancers appea in XP children median age 10
93
Chemical exposure - skin cancer risk
Occupational exposure to certain chemicals can increase the risk of non melanoma skin cancer
- coal tar pitch
- soot
- creosote
- petroleum products
- shale oils
- arsenic
94
Immune suppression - skin cancer risk
> Autoimmune conditions
- UC (23% higher risk of malignant melanoma)
- Crohns (80% higher risk of malignant melanoma)
> Immunosuppressants
- azathioprine
- cyclosporine
- adalimumab
> Organ transplant recipients
- NMSC risk 30x higher, esp SCC
- malignant melanoma risk more than double
95
Ultraviolet radiation and skin cancer - UVA & UVB
> UVB (290-320nm) causes DIRECT DNA damage
- 1000x more damaging the UVA when direct sunlight overehead
> UVA (320-400nm) causes INDIRECT oxidative damage
- UVA penetrates more deeply into the skin than UVB
> UV-induced immunosuppression also plays a role
96
UVB induced DNA lesions
2 major types.
> Cyclobutane pyrimidine dimers (CPDs)
> Pyrimidine-pyrimidone (6-4) photo products
TT --> CC UV SIGNATURE
Both are formed by covalent bonding between adjacent pyrimidines on the same DNA strand
97
Repair of UVB induced DNA lesions
Steps
Removal by NER
CPDs and 6-4PPs are relatively stable structures
Removed by NUCLEOTIDE EXCISION REPAIR (NER)
1. Recognition of the damaged DNA
2. Cleavage of the damaged DNA on either
side of the photoproduct
3. DNA polymerase fills in the gap, using
the undamaged strand as a template
4. DNA ligase seals the ends
Sometimes damage is so extensive that it cannot be repaired and leads to genetic mutations.
98
Error prone DNA repair
Unrepaired UV induced photoproducts interfere with base pairing during DNA replication leading to mutations.
In most cases, polymerase will insert the correct bases (A-A)
Polymerase is error prone
so it may not correctly “guess” the structure of the lesion and instead insert G-G opposite the thymidine dimer
99
Indirect damage by UVA
UVA causes indirect damage via oxidation of DNA bases
C --> A point mutation
Esp deoxyguanosine to form 8-oxo-deoxyguanosine
8-oxo-dG can mislaid with deoxyadenosine rather than forming a normal base pari with deoxycytosine
If 8-oxo-dG is NOT removed, when DNA is replicated, dA rather than dC can be incorporated causing GC--> AT point mutation
100
Repair of 8-oxo-dG lesions
Oxodised lesions repair by BASE EXCISION REPAIR (BER)
1. Recognition of the chemically altered base causing slight helix distortion
2. Cleavage of the altered base from the deoxyribose by DNA glycosylase
3. Base-free deoxyribose cleaved away by endonuclease
4. Single nucleotide gap filled by DNA polymerase β
5. DNA ligase seals the ends
101
UV-induced immunosuppression
UV induced DNA damage also leads to immunosuppression:
> Depletion of Langerhans cells in the skin and reduced ability to present antigens
> Generation of UV induced regulatory T cells with immune suppressive activity
> Secretion of anti-inflammatory cytokines e.g. IL-10 by macrophages and keratinocytes.
102
Mutations in PTCH1 are associated with...
BCC development
103
Hedgehog Signalling Pathway
This pathway activate the transcription factors Gli1/2
--> induction of cell proliferation genes (cyclins D/E) and angiogenesis activators.
--> Vismodegib binds to SMO (smoothened) to block hedgehog signalling and prevent cell cycle activation and angiogenesis.
VIDEO
104
Which mutations are common in melanoma?
Mutations in Ras/Raf/MAPK signalling pathway are common melanomas
>50% have B-Raf mutation, mostly V600E,K,R,M & D.
Can produce signalling in uncontrolled fashion --> proliferation --> melanoma formation.
105
Which drugs target mutated form of B-raf?
Vemurafenib and Dabrafenib
106
What drug targets MEK?
Tramatenib
107
Familial melanoma mutations
Two genes.
CDKN2A & CDK4
When these proteins are "turned off" they do not stop the proliferation and mutation of cells.
108
Proteins encoded for by CDKN2A?
p16INK4a and p14ARF
109
CDKN2A
Prevents cells from replicating when they contain damaged DNA by activating the G1/S
Inactivating mutations in p16 permits cell division in presence of unrepaired DNA
110
CDK4
Cyclin dependent kinase 4
Permits cell cycle progression by Phosphorylation of retinoblastoma protein (Rb)
Activating mutations in CDK4 accelerates cell cycle
111
Non melanoma skin cancer
Arise from keratinocytes within the epidermis.
BCC s arise from keratinocytes within the basal layer of the epidermis
SCC arise from supra basal layers.
112
Melanoma survival depends on...
Tumour depth
113
Breslow Thickness
<1mm - 5 yr survival = 95%
>4mm - 50%
Metastases - 5% survival (invading dermis)
EARLY DIAGNOSIS IS ESSENTIAL
114
Diagnose melanoma early
ABCDE
```
A - asymmetry
B - border
C - colour
D - diameter
E - Evolution
```
Multicoloured - abnormal
Light brown/dark brown - normalish
115
Ugly duckling sign
MM often deviates from this nevus pattern.
Multiple myeloma - cancer of plasma cells
116
BCC - Presentation
slow growing lump or non-healing ulcer
painless and often ignored
‘pearly’ or translucent
visible, arborising blood vessels
central ulceration - “rodent ulcer”
can present as scaly plaque - ‘superficial’
can be infiltrative - ‘morphoeic’
locally invasive, but rarely metastasize
> 40 yrs, but can be 3rd or 4th decade
117
"Rodent ulcer"
BCC presentation.
Ulcerated in middle due to poor vascular supply.
118
Pigmented BCC
Simulated melanoma
Treat as a melanoma until you know what the result from the biopsy is.
119
Squamous cell carcinoma
25% of NMSC
hyperkeratotic (crusted) lump or ulcer
arises on sun-damaged skin
grow relatively fast, may be painful &/or bleed
majority - well differentiated low risk SCC
minority - poorly differentiated high risk SCC
risk of metastasis about 5%
poor prognosis once metastatic
precursor lesions - actinic keratoses and Bowen’s disease (carcinoma-in-situ)
Keratoacanthoma - self-resolving
120
Lip and scalp are high risk areas for?
Squamous cell carcinoma
121
Actinic keratoses
Rough, scaly patch. Due to years of sun exposure
Precancerous skin lesions
AK are multiple lesions
Highly associated with risk of developing SCC or BCC.
122
Xeroderma pigmentosum
```
> Photosensitivity
> Skin cancers on UV exposed sites
> Neurological degeneration
> Increased risk of other cancers
> Defect in one of seven Nucleotide Excision Repair (NER) genes
```
123
```
Naevoid BCC
(Gorlin's syndrome)
```
Autosomal dominant familial cancer syndrome
Major features:
- early onset/ multiple BCCs
- palmar pits
- jaw cysts
- ectopic calcification falx
Minor
- skeletal abnormmality
- OFC > 97th centile
- cardiac/ovarian fibroma
- medulloblastoma
124
Butterfly disease
Recessive dystrophic epidermolysis bulls (RDEB)
High risk of skin cancer
125
Hereditary Type VII collagen deficiency
High risk of skin cancers.
126
"Transplant hands"
Pre cancerous lesions
Transplant patients
Red hands, lesions, sores, crusty.
127
Skin cancer prevention
1. Behaviour
- avoid sun at its height (11am-3pm)
- use shade wherever possible
- particular care of babies/children
- avoid sunbeds
2. Clothing
- tightly woven, loose fitting clothing (dark)
- long sleeves, trousers, skirts
3. Sunscreens
- broad spectrum (SPF25+) with UVA protection
4. Regular (self-) surveillance
NO SUNBEDS
128
True sign of anaphylaxis?
Raised serum tryptase
