Immunology of Skin Diseases: Understanding the Skin's Immune System

1
IMMUNOLOGY of
SKIN DISEASES
PROF. DR . IHSAN EDAN ALSAIMARY
ihsanalsaimary@gmail.com
00964 7801410838
Department of microbiology – college of medicine – university of
Basrah- IRAQ

SKIN AND SKIN
DISEASES & SYNDROME
• The skin is often referred to as the largest body organ
and serves as the main protective barrier against damage to
internal tissues from trauma, ultraviolet light, temperature,
toxins and bacteria. The skin is also responsible for sensory
perception, temperature regulation, production of vitamin D
and excretion of waste products.
• The thickness of the skin varies depending on the site, with
thicker skin being present on areas of the body that
experience friction or wear and tear, such as the soles of the
feet and palms of the hand.
• The skin is supported by a layer of fatty tissue, sometimes
known as the hypodermis. This fatty area helps to act as a
cushion to protect the body and is also important for
insulation.

• Skin is composed of two main layers.
Epidermis :
The epidermis (outer layer) contains no blood vessels and is divided
into five layers.
Stratum corneum, lucidium ,granulosum,spinosum,
germinativum(basale).
• Skin containing four layers of Epidermis is called thin skin(present in lips and
eye brows), if Fifth layer Startum Lucidium is present is called as thick skin.
• Thickness : 0.07-0.12 mm thick.
• Epidermis is avascular,means no blood supply.
• Dermis:
Dermis lies under epidermis,This portion is supplied by
• The dermis also contains nerve endings, sweat glands,
sebaceous
glands, hair follicles and blood vessels.
• There are invaginations in Dermis called Dermal papillae and
responsible for Interlocking of epidermis and dermis.

•Sweat glands produce sweat, which contains
some body waste products, water and salt.
Evaporating sweat causes cooling of the body.
Sweat from the axilla and groin areas (apocrine
glands) is more oily in nature and produces a
characteristic odour when digested by the skin
bacteria.
•Sebaceous glands secrete sebum into hair
• follicles. Sebum is an oily substance that keeps
• the skin moist and acts as a barrier against
• foreign substances.

NORMAL SIN STRUCTURE
1
1
 Three functional layers
-epidermis 150 µm
thick
-horny layer
-clear layer
-granular layer
-basal layer
-basal membrane
-dermis or corium
2,800 µm thick
-subcutis
(hypodermis)

NORMAL SKIN
ST RUCTURE
5
1 Horny layer
(stratum corneum)
2 Clear layer
(stratum lucidum)
3 Granular layer
(stratum granulosum)
4 Prickle-cell layer
(stratum spinosum)
5Basal layer
(stratum basale)
6 Basal membrane

NORMAL SKIN STRUCTURE
 1 Epidermis
 2 Dermis
 3 Subcutis
 4 Hair follicle
 5 Sebaceous gland
 6 Sweat gland
1
3

Carole L. Berger.IJBCB 2006;38:1632-1636 1
7
Dendritic cells in cutaneous immunity
The Langerhans ’cells(epidermal DC)
-LC arise in BM
-controversy about whether LC descended from
myeloid or lymphoid progenitor but evidence
suggest myeloid origin
The Langerhans ’cells(cont.)
-can differentiate from monocytes or
CD34 precursors(CD 34
srosrucerp=
fo
hemopoietic cells/endothelium in high endothelial
venules)
-mediators of LC differentiation from periphera
monocytes include TGF-β, GM-CSF, IL-4 and Notch
ligand δ-1

9
The Langerhans’ cells(cont.)
-keratinocyte secrete TGF-β, GM-CSF and δ-1
-LC express CCR6 Rc for MIP-3α )CCL20)
by keratinocytes
-LC that endocytosed Ag and be
activated by inducible innate response may directly
present Ag to skin-resident memory T cells or exit
skin via lymph vessels
N Franklin. Middleton’s allergy 7th edition 2009
-in LNLC process and present Ag peptide to
naïve T cells initial step to develop acquired
immunity
-LC can induce tolerance to self-Ag if
take up apoptotic material through stimulation of T-
regulatory cells which inhibit immune responses

J.Valladeau.Seminars in Immunology 2005;17:273-283
19
Dermal dendritic cells two types of
DDC
1.interstitial DDC
-dermis compose of extracellular matrix (ECM) and
contain fibroblasts,DC,MØ, infiltrating T
lymphocytes
-dermal DC present in ECM & also called type-
I dendrocytes
-expression MHC class II, scavengerRc (CD36),
coagulation factor XIIIa
these 3 markers can find in MØ
-expression of lectin DC-SIGN/CD209 distinguishes
DDC from other dermal cellular populations

20
Dermal dendritic cells(cont.) 2.plasmacytoid DC
-pDC lymphoid origin
-natural IFN-/-producing cells
-present in skin in atopic dermatitis, contact dermatitis, psoriasis, SLE
-immature pDC also described in situ in primary melanoma
-normal skinvery low frequency
-more sensitive than myeloid skin DC
to danger signals  produce typeI-IFN via TLRs
-little is know about pDC trafficking in vivo
-mechanism for recruitment into skin
1.1.pDC express CCR6(Rc of CCL20 that responsible for homing of LC to skin
2.pDC express CXCR3 whose ligrands highly expressed in inflammatory skin
3.pDC express ChemR23 binds chemerin expressed on dermal inflamed vessels

21
Migration of cutaneous DCs
1. TNF- & IL-1 induce migration of LC out of epidermis
2.CCR6 control migration from
blood/dermis to epidermis
3.CCR7 control migration from
epidermis to regional lymphatics (CCR7=Rc of SLC)
4.trafficking is controlled at level of cell adhesion
-LC down-regulate some adhesion molecules to exis
epidermis and
up-regulate other to migrate across
dermal ECM & home to T cell area of region lymphoid tissue

22
-key role of CD44 & 6 integrins in LC
migration was demonstrate
-down-regulation of E-cadherin also
key event in LC migration 5.expression of
matrix metalloproteinases-9
& -2 (MMP) are necessary both for
migration of LC & DDC
-cutaneous DC Ag presentation involve interaction of
-MHC class II-antigenic pepetide
-MHC class I-antigenic peptide
-via CD1 molecules(non-peptide microbial
antigen presented)

B.Spellberg.Life Sciences 2000;67:477-502
23
Epidermis lymphocyte
-about 1% in epidermis
-close proximity to basement membrane
-majority of T cells are memory cell (CD45RO+)
most express CD8 receptor
-50% of epidermal T cell express CLA (cutaneous
lymphocyte Ag) :
Sialyl Lewis-X glycoprotein serve as ligand to
endothelial cell adhesin
(E-selectin)
-T cell do not enter epidermis by random migration,
rather epidermal T cells are special population of
memory cells, which have specific set of instruction
to selectively home to epidermis
-human αβ-T cell : γδ-T cell = 10:1

24
Nerve
-numerous free nerve endings, consist of dendrite
branching of slow conducting nerve fibers
-afferent sensory, unmyelinated, terminate at
epidermal surface of basement membrane
-nerve ending can be found between keratinocytes
through Stratum Granulosum
-able to elaborate neuropeptides which modulate
local immunologic function

24
INNATE IMMUNITY
keratinocyte express epidermal growth factors :
amphiregulin
-induce inflammatory-immune reaction
-recent finding expression amphiregulin by Th2 important
mechanism to clear
intestinal helminth infestation through epithelial shedding
epidermal γδ-T cells,
like B cell, capable directly binding to small phospate
containing Ag with their receptors
-do not require Ag presentation in context of MHC or CD1
-serve as primitive, immediate response element, recognizing
conserved phosphoprotein or phospholipid Ag of microbes
& necrotic human tissues

26

CUTANEOUS IMMUNOLOGY
27
Innate immunity
-first-line defense mechanism
-two separate categories
-constitutive innate immunity
-anatomic barrier -physiologic barrier
-inducible innate immunity
-acute inflammation
-cellular infiltration
-both do not demonstrates acquired specificity or memory for invading pathogen
1. cutaneous constitutive innate immunity consist of
1. normal skin flora
2.cornified keratinocytes 1.3.antimicrobial polypeptides/lipids 1.4.low pH
1.5.normal body temperature

INNATE IMMUNITY
28
Normal flora of skin
-coryneforms and staphylococci
-mush lesser extent, fungi (primarily Malassezia)
Compete with other pathogenic organisms
Cornified keratinocytes
-form impenetrable surface
-outward growth and shedding of cornified keratinocytes eliminate
superficially bound pathogens
-reduced water content & lipid layers of stratum corneum reduce relative
humidity badenvironment
Antimicrobial polypeptides
-β-defensin-1 and -2, dermcidin,
iron-binding proteins, lysozyme, RNases,
DNases, and natural IgM on skin from sweat and from keratinocytes
Reduce skin surface pH
-exhibit antibacterial activity
-lactic acid excreted in eccrine sweat

INNATE IMMUNITY
29
Normal body temperature
-inhibits growth of some pathogens
2. Inducible innate immunity Acute inflammation
1. performed IL-1α stored in cytoplasm of
keratinocyte,released from
itch/scratch
2. TNF-α

INNATE IMMUNITY
Murphy JE. J Invest Dermatol 2000; 114:602-608
30
-IL-1R2
-short cytoplasmic domain
-bind IL-1α & IL-1β efficiently
-but not IL-1ra
-serves to inhibit IL-1 responses
-expression can be upregulated by corticosteroids & IL-4
-receptors
-IL-1R1 can bind both IL-1α & IL-1β
-IL-1ra(IL-1 receptor antagonist) bind to this Rc but does not induce signaling
-mice defcient in IL-1ra show exaggerated & persistent inflammatory
responses
IL-1
-2 forms : α and β
-31 kDa molecules
-IL-1β must be cleaved by ICE
(IL-1β converting enzyme : caspase-1)
-produced by monocyte, MØ, langerhans cells, dendritic cells
-IL-1α biologically active predominates in epithelial cells (keratinocytes, etc)

INNATE IMMUNITY
31
IL-1α induce molecules of typical
cutaneous inflammatory response include :
TNF-α, IL-8(CXCL-8),
nitrous oxide synthase,
PG-producing cyclooxygenase, postcapillary venule
endothelial
cell expression of ICAM-1, VCAM-1, E-seletin
-Moreover,IL-1α & other induced molecules activate most cell types of skin,
alerting and preparing them for further host defense functions including cytokine
and chemokine secretion, wound repair, release of antimicrobial products,
phagocytosis, initiation of acquired immune responses

INNATE IMMUNITY
32
2.3.inducible pathogen-targeted soluble molecules
-inducible antimicrobial polypeptides
-complement-activating a/o opsonin proteins
-complement proteins
Inducible antimicrobial polypeptides
-β-defensin-2 and -3, cathelicidin LL-37
-produced by keratinocytes
-IFN-α, IFN-β, IFN-k another class of antimicrobial polypeptides
(IFN-α produced by plasmacytoid DC, mononuclear phagocytes)
-IFN-β produced by many cell ; fibroblasts sometimes called
fibroblasts IFN)
-protective activities related to antiviral
effect on host cells rather than diract toxic to pathogen

INNATE IMMUNITY
33
2.4.complement activating/opsonin molecules
-members of acute phase proteins (C-reactive protein, serum amyloid protein)
-members of collectin(mannan-binding lectin)
-ficolin lectin families
-C3b fragment, natural IgM
2.4.complement activating/opsonin molecules
-acute phase protein produced by liver & supply to skin via blood
-increase serum concentration in response to IL-1, IL-6, TNF-α from activated MØ
-collectins & ficolins recognize
carbohydrates on bacteria, fungi, viruses then mark them for destruction
-opsonin C3b target pathogen : phagocytosis
-C3a, C5a(anaphylatoxins) : keratinocyte
activating, chemoattractant, mast cell degranulating functions)
-C5b, C6, C7, C8, C9 : MAC(lethal pore)

INNATE IMMUNITY
34
2.5.PRRs host molecules recognize
-PRRs host molecules recognize PAMPs
-PAMPs include
-unmethylated CpGs of bact. DNA
-dsRNA(e.g.influenza)
-mannans
-gram+ bact. lipoteichoic acids
-gram- bact. LPS
-bacterial peptidoglycan
-N-terminal formyl-methionine
-parasitic phosphoglycans
-fungal glucans/zymosan
-MØ & DC ,activated during cutaneous inflammatory response, first
phagocytic host cells utilizing their cell-surface PRRs

INNATE IMMUNITY
35
-inflammation-ass increase chemotactic
factors (chemokines), produced by
keratinocytes stimulated via their TLRs
and postcapillary venule endothelial cell
adhesion molecules (P- & E-selectin,
ICAM-1, VCAM-1) synergiscally mediate
integrin-dependent extravasation of
PRR-expressing leukocytes

INNATE IMMUNITY
N Franklin. Middleton’s allergy 7th edition
-cellular infiltration
-neutrophils earliest infiltrating leukocytes(due to
neutrophil active CXC : IL-8)
-later, monocyte begin extravasate into inflam. site
-assist in phagocytosis &
intracellular destruction of
pathogen with lysozyme, defesins, ROI
-eosinophil less phagocytic than neutrophil, produce ROS at plasma membrane surface,
not intracellularly
 readily degranulate & deposittoxic cationic proteins onto surface of
parasites
-furthermore : basophils, blood Dc, mast cell, T cells, B cell, NK-T cell, NK cells

INNATE IMMUNITY
37
-local defenses are quickly augmented by recruitment of
dermal MØ, just beneath basement membrane
-lymphocyte-/keratinocyte-derived IFN &
growth factors across basement membrane initiates priming
MØ to produce IL-12
-epidermal-derived cytokine & Ag stimuli
 MØ mobilize their cytoskeletons to become mobile & secrete
metalloproteinases and degradative enzymes  allow them to
slice through collagen and other structural components of
basement membrane cross into epidermis
-MØ use ligands expressed on activated keratinocytes,
such as E-cadherin/ICAM-1, to pull themselves
through epidermis and crawl to danger site by
following chemokine gradient to its source

ACQUIRED IMMUNITY
38
-impact of innate to acquired immunity
-chemotactic activity of β-defesin-2 & C5a for DC a/o T
cells
-tissue injury danger signals or engagement of
PRRs(LPS Rc,
mannose binding Rc, TLRs, CD1a) expressed on cutaneous
APC such as Langerhans’ cells, dermal DC, MØ
-inflammation state that continues beyond 24-36 hr induces
onset of adaptive immunity
-IFN-γ in epidermis stimulates leukocytes,
fibroblasts to express CC chemokines, particular MCP-
1, MIP-1, RANTES while suppress production of CXC
chemokines such as IL-8

ACQUIRED IMMUNITY
39
-MIP-1α
-MCP-1
-RANRES
: CCL20;induce chemotaxis of neutrophil and
lymphocytes
: chemotactic for monocytes & lymphocytes
: selectively pro-inflammatory
Th1 lymphocytes, not inflammatory-
suppressive Th2 cells
-Th1 have RANTES Rc : CCR5
-Th1 produce IFN-γ which drive RANTES
production by lymphocytes and MØ
selectively summon additional Th1 cells
to area of danger

ACQUIRED IMMUNITY
40
-endothelial cell adhesins critical to
selection of leukocyte extravasation
-several hour after stimulation lower
their expression of E-selectin(CD62E),
upregulate their ICAM-1 expression,
begin express VCAM diminishneutrophil
across vascular lumen L & Mo are
recruited into area

ACQUIRED IMMUNITY
41
-exposure to IFN-γ endotheliumexpress MHC class II
then presence of IFN-γ, microvascular endothelial cells capable acting as
professional APC to circulating T cells
-In presence in skin of IFN-γ, IFN-α,
TNF-α, microbial particles
(LPS, gram+ cell wall fractions, prokaryotic DNA) induces MØ & DC produceIL-12
-IL-12 induces newly activated T cell to Th1
-keratinocytes unable to express sufficient costimulatory molecules to drive T cell
activation result in T cellanergy/deletion
-keratinocytes able to abort adaptive
response by competing with phagocytes for presentation of Ag to T cells
-if stimulus initiating danger response is too bulky(hyphal fungi, helminths, large
foreign bodies,etc)leukocytes initiate “frutrated phagocyte complex” this induce
production of IL-10 prefentially over IL-12favoring antibody-based Th2

ACQUIRED IMMUNITY
42
-antibody production stimulated by Th2 response  allow leukocytes
to damage large organisms via ADCC
-eosinophil, neutrophil, NK, monocyte/MØ able to use this mechanism
-B cell other key cell for acquired immunity
-B cell recognize relatively intact Ag (contrast T cells)
-plasma cell, memory B cell development,
Ig class switching, somatic hypermutation
all occur in secondary lymphoid geminal center of skin-draining LN
-absence of cutaneous B cells suggests a need for Ag that enter skin to be
transported to B cell as opposed to B cell’s migrating to Ag in skin(but mechanism of B
cell activation remains unclear)
-five classes of Ig have been detected in normal human sweat

ACQUIRED IMMUNITY
43
-sIgA arise from secretory epithelia of eccrine glands, sebum also contain IgA
-exact source of cutaneously secreted Ig remains unresolved
-IgG1 & IgA capable to clear pathogenic
organisms from skin via Fcγ Rc-mediated immune response(ADCC, complement
fixation) and sIgA-coating of bacteria
-in human IgE & IgG4 produced by type 2 cytokine (IL-4, IL-13)
-most antigen-specific IgE supplied via blood(except respiratory mucosa , local
IgE production appear posible)
-IgE can bind to FcεRI-bearing cells(LC,
mast cell, infiltrating basophils)contribute to various allergic skin dz
-Ab specific for FcεRI may contribute to cutaneous dz such as urticaria, Ab against
desmosomal and hemidesmosomal protein provoke immunobullous dz
 increase co-stimulatory molecule expression
(CD80 & CD86) & modulate cytokine expression patterns
-LPS bind to cell surface CD14 of MØ induces IL-12 favor Th1development
-mast cell-produced cytokines such as IL-4,
histamine, keratinocyte-derived thymic stromal lymphopoietin(TSLP)acquire immune
response Th2 profile

75
SUMMARY

Common skin
conditions in adults
1. Acne
2. Cellulitis
3. Psoriasis
4. Shingles (herpes
zoster)
5. Skin cancers
6. Vasculitis

1) Acne
:Acne is a disorder of the pilosebaceous unit which may
present with comedones, inflammatory papules or pustules.
Nodules and scarring can also occur. The precursor lesion of
all acne lesions is the microcomedone which, under the
influence of androgens, develops into non-inflammatory
lesions (comedones) and inflammatory lesions (papules and
pustules). Lesions of acne vary considerably with time, but in
acne vulgaris comedones are always present and are a
diagnostic sign. Most patients notice a fluctuation in the
number and severity of spots. In young women this is often
related to the menstrual cycle.

Sebum
Sebum excretion is increased. However, this alone need not cause acne
Hormonal
Androgens (from the testes, ovaries, adrenals and sebaceous glands themselves) are
the main stimulants of sebum excretion,
Poral occlusion
Both genetic and environmental factors (e.g. some cosmetics) cause the epithelium to
overgrow the follicular surface.
Follicles then retain sebum that has an increased concentration of bacteria and free
fatty acids
Rupture of these follicles is associated with intense inflammation and tissue damage
Bacterial Propionibacterium acnes
normal skin commensal, plays a pathogenic part
Genetic
The condition is familial in about half of those with acne

Presentation:
• Acne occurs on the face, chest and back depending on the
distribution of sebaceous follicles in the individual.
• Type of lesion
i) Non-inflammatory lesions:
• open comedones (blackheads)
.closed comedones (whiteheads).
Inflammatory lesions:
.Papules and pustules – the majority of patients with comedonal acne
develop papules and pustules. They are the well known little red spots or
pustules on a red base. They may be itchy or quite painful.Papules develop
rapidly over a few hours and frequently becomes pustular as they evolve. They
generally resolve over a few days.
•Nodules and cysts – as the inflammation within pilosebaceous unit
progresses and extends deeper into the dermis, the size of visible and
palpable lesions increases, resulting in deep-seated nodules.

•Secondary lesions:
Scars - the inflammatory process of acne can
cause scarring.Characteristically, small, deep “ice-
pick” scars occur, but more severe disease will
leave gross changes with atrophy or keloid
formation.
Individual lesions : usually last less than two
weeks but deeper papules may persist for months.
The average “acne life” is 12 years.
•

• Treatment :
Treatment depends on severity (consider the possibility of
scarring).
• Comedonal acne – topical agents such as: Adapalene;
Benzoyl Peroxide; Isotretinoin; Tretinoin.
• Acne with inflammatory lesions and comedones, topical
agents such as: Benzoyl Peroxide; antibiotics (erythromycin,
tetracycline, clindamycin); Adapalene; Azelaic acid.
• Advice to patient : Squeezing comedones should be
avoided as it convert comedones to an inflammatory lesion
or papule and increases the potential for scarring.

Rosacea affects the face of adults, usuallywomen.
peak incidence is in the thirties and forties, it can also
be seen in the young orold.
It may coexist with acne but is distinct fromit.

The cause is still unknown.
Rosacea is often seen in those who flush easily in
response to warmth, spicy food, alcohol or
embarrassment. No pharmacological defect has been
found that explains these flushingattacks.
Psychological abnormalities, including neuroticism
and depression, are more often secondary to theskin
condition than their cause.
Sebum excretion rate and skin microbiology are
normal

•2) CELLULITIS:
This is an infection of the subcutaneous tissues most
commonly caused by a group A, C or ß-haemolitic
streptococcus. It usually affects a lower limb but can
occur anywhere on the body.
• Approximate age group :
More common in older people but can be seen in all
age
groups.

Treatment
:
•
• Penicillin-based antibiotics are the treatment of choice
(such as benzyl penicillin or flucloxacillin). Oral are allergic to
penicillin. If you have local guidelines on the management of
common bacterial skin infections, their recommendations
should be taken into consideration when prescribing treatment
for cellulitis.
Most patients can be treated at home but intravenous
antibiotics, which may require the patient to be admitted signs
of systemic illness or extensive cellulitis. The co-existing
condition that allowed entry of bacteria into the skin should be
treated.
• Paracetamol may be prescribed for
pain.

•3) Psoriasis :
Psoriais is a common disease which affects about 3%
of the population. Psoriasis typically waxes and wanes with periods of
relapse and remission. It is probably linked to several genes so
occurrence within families varies. It may be precipitated by hormonal
changes, infection such as a streptococcal throat infection or trauma.
Medications and emotional stress can also be a trigger.
• There are several different forms of psoriasis. Here we
describe two of the more common presentations: chronic
plaque psoriasis and guttate or small plaque psoriasis.
Approximate age group:
It can occur at any age but often begins between the
ages of 15 and 25 years.

Treatment:
The majority of individuals with psoriasis can be treated with
topical treatments.
Chronic plaque psoriasis: treatment depends on the type,
size and number of lesions. Topical treatments include:
emollient, vitamin D analogues or vitamin D analogue in
combination with a potent topical steroid; tar preparations;
saliyclic acid Ointments,Dithranol.
• Guttate psoriasis: as the condition usually resolves
spontaneously, reassurance is all that is needed. Complete
emollient therapy (see section 07) is useful if the skin is itchy or
a mild topical steroid or weak tar solution may be indicated to
give symptomatic relief. In some cases, ultra violet light
treatment may be necessary: this would be administered in a
dermatology department.

4) Shingles( Herpes
Zoster):
Shingles occurs in people who have previously had
chickenpox.
The virus lies dormant in the dorsal root ganglion; when
reactivated, it travels down the cutaneous nerves to infect the
epidermal cells.
Can occur at any age.

TREATMENT :
• If the patient is seen in the prodromal phase with pain or
• abnormal sensation, or within 48 hours of the blisters
• appearing, treat with a 7-day course of an oral antiviral
• agents such as Aciclovir, Valaciclovir or Famciclovir.
• Antiviral agents are only effective when the virus is replicating and
should only be given in the early phase of the disease (within 48
hours of the rash appearing).
• Adequate analgesia is important, such as paracetamol 1g every 4
hours,
• or co-dydramol 2 tablets 4 hourly (max 8 in 24hrs). In older people,
• prophylactic amitriptyline 10−25mg at night gradually
• increasing upto 75 mg may help post-herpetic neuralgia if
• started as soon as the rash appears.
Advice to patient
• Reassure the patient that shingles cannot be caught, but
• chickenpox cannbe contracted from a patient with shingles
• by someone who has never had chickenpox.

•5) Skin Cancers:
Excessive exposure to ultraviolet radiation is linked
to non-melanoma type skin cancers and malignant
melanoma. Early recognition is most important.
A good rule of thumb is to seek medical advice
about all lesions which are not healing and may be
enlarging. Here we describe the two most common
forms of skin cancer and malignant melanoma.
Biopsy is usually performed to assess the lesion
histologically.

•Basal Cell
Carcinoma:
This is the commonest skin cancer. It usually occurs in fair-
skinned people who have worked or had hobbies out of doors.
Although due to sun damage, BCC does not occur at the sites
of maximum sun exposure (it rarely appears on bald scalps, the
lower lip or dorsum of the hand). Most occur on the face, with
some on the trunk and limbs. Metastatic spread is rare in BCC.
• Middle age or older.

•Squamous
Cell
Carcinoma :
Although less common than BCC, SCC is an invasive carcinoma
which is faster growing than a BCC and may metastisise if left
untreated. It can arise from previously normal skin or from a pre-
existing lesion (such asBowen’s disease and actinic keratosis). SCC
occur on sun-exposed skin which shows signs of sun damage.
Common sites include bald scalp, lower lip, cheeks, nose, top of ear
lobes and dorsum of the hand. They can also appear on non sun-
exposed sites such as a site of previous radiotherapy or chronic
scarring of burns and leg ulcers.
• Approximate age group : Middle age or older.

Malignant
melanoma :
A malignant melanoma is a malignant tumour of the pigment-
producing cells (melanocytes). Two thirds arise from normal skin
and one third from a pre-existing mole. Numbers are increasing.
It is the most dangerous of the skin cancers as it has the
capability to metastisise through the lymphatic and circulatory
systems.
All age groups, particularly in those with fair or red hair who
burn rather than tan in the sun.

•6) VASCULITIS :
This is the Inflammation of blood vessels in the
skin usually due to the deposit of immune
complexes in the walls of the vessels.

Approximate age group :
Affects all age groups.
Treatment : Identification of the underlying cause and
treating this is the aim. Urinalysis will help identify if there
is renal involvement. If urinalysis identifies protein or blood
in the urine , specilalist help should be sought as the
patient may require systemic steriods or
cyclophosphamide.Treatment is symptomatic (e.g.
analgesia for pain). Where no cause can be found
(idiopathic), the patient should be reassured that the
condition is self limiting and should resolve
within 3−6 weeks.
Advice to patient
Bed rest will stop new lesions .Regular analgesia should
be taken
for pain.

•Common skin conditions in children
•Chicken pox (Varicella)
•Eczema (atopic)
•Henoch-Schönlein purpura
•Impetigo
•Impetiginised eczema
•Miliaria
•Measles
•Napkin dermatitis (nappy rash)
•Rubella (German measles).

• 1) CHICKEN POX :
Varicella zoster virus causes
chickenpox and shingles.
•Approximate age group:
Chickenpox commonly occurs in childhood. By the age of 10
years most children, particularly in urban communities, will
have been infected. Primary infection confers long-term
immunity but the virus remains dormant in the dorsal root
ganglion to be reactivated as shingles.
• Treatment
In most cases, chickenpox does not requirement treatment.However an
antiseptic-based emollient may reduce the risk of secondary infection.
• In adults or immunocompromised patients, aciclovir, valaciclovir or
famciclovir will reduce the severity of the attack. An antiviral agent is not
usually required for healthy children.

•
2) ECZEMA ( ATOPIC
dermatitis
• Atopy means an inherited predisposition
• to eczema, asthma or hay fever and
• atopic individuals may have one or
• all of these conditions.
Eczema usually begins between 3 and 12 months. The
condition tends to be long term, but it will clear by puberty in
90% of individuals.
• Presentation
In an acute reaction, the skin displays the signs of inflammation: heat, erythema
and swelling. Pain is not usually present but itching is severe. The skin lesions
are not sharply demarcated but merge with the surrounding skin. There may be
vesicles or bullae which rupture with oozing of clear fluid.
• Treatment :
To treat effectively consider the following:
• complete emollient therapy
• for eczematouslesions, treat with topicalsteriods.
•if the itch is disturbingsleep,consider a sedative histamine.

LanganSM,et al. Atopic dermatitis. Lancet 2020.

PATHOPHYSIOLOGY AND MECHANISMS OFDISEASE
Atopic Dermatitis
Immunological
dysregulation
and
inflammation
Epidermal
barrier
dysfunction
Skin
microbiome
abnormalities
ALSAIMARY ,IE.ETAL 2006.RECENT FINDINGSABOUT ATOPIC DERMATITIS .
J.INFECT.DIS.20(8)
EDSLEV SM, et al. Skin Microbiome in Atopic Dermatitis. Acta Derm Venereol 20
.
Langan SM, et al. Atopic dermatitis. Lancet 2020
.

PATHOPHYSIOLOGY AND MECHANISMS OFDISEASE
• Genetic risk factors
• Epidermal barrier dysfunction
• Therole of the microbiome
• Immunologicaldysregulation and inflammation
• Roleof allergens
• Immunopathologic features
• Atopic dermatitis hasstrongheritability (75% intwin studies),suggestingthat geneticfactors are an
important contributor
• Genome-wideassociationstudieshave identified 34 loci that cumulativelyaccountfor lessthan
20% of atopic dermatitis heritability
• Thesegenomicregionscontainmultiple geneswith rolesinimmuneresponses
> Type-2 differentiation
> T-cellactivation
> Innate immunity
> Theepidermal differentiation complex
PATHOPHYSIOLOGY AND MECHANISMS OFDISEASE: GENETIC
RISK FACTORS
J.INFECT.DIS.20(8)
EDSLEV SM, et al. Skin Microbiome in Atopic Dermatitis. Acta Derm Venereol2020.
Langan SM, et al. Atopic dermatitis. Lancet 2020.

J.INFECT.DIS.20(8)

PATHOPHYSIOLOGY AND MECHANISMS OF
DISEASE: GENETIC RISK FACTORS >
FILAGGRIN
• Thestrongest genetic risk for atopic dermatitis yet identified is
associated with mutations in the skin barrier protein filaggrin (Encoded
by the FLGgene)
• Loss-of-function mutations in FLGcause a 50% decrease in protein
expression in the heterozygous state and a total lossof protein expression
in the homozygous or compound heterozygous states
• Loss-of-function mutations in FLGcausethe mild, semi-dominant, mendelian
disorder of keratinisation ichthyosis vulgaris
• FLGloss-of-function mutations confer a 3–5 times higher risk of atopic
dermatitis in individuals whohave them
than in individuals whodo not, and predispose these individuals to asthma
and peanut allergy
• FLGmutations were found in European, Japanese, Han Chinese populations
(20-40% of AD patients) ALSAIMARY ,IE.ETAL 2006.RECENT FINDINGSABOUT ATOPIC DERMATITIS .
J.INFECT.DIS.20(8)

PATHOPHYSIOLOGY AND MECHANISMS OF DISEASE:
GENETIC RISK FACTORS > OTHER GENETIC LOCI OF RELEVANCE
•Chromosome 5q31.1
>IL-4
>IL-13
>RAD50
•Chromosome 11q13.5
>EMSY
>LRRC32 ALSAIMARY ,IE.ETAL 2006.RECENT FINDINGSABOUT ATOPIC DERMATITIS .
J.INFECT.DIS.20(8)

PATHOPHYSIOLOGY AND MECHANISMS OFDISEASE:
EPIDERMAL BARRIER DYSFUNCTION
•
Epidermal barrier dysfunctionisconsistentlyobserved in affected and
unaffected skinof patients with atopic dermatitis
Epidermalbarrier dysfunction
Elevatedtransepidermal water lossand pH
Increased permeability
Reduced waterretention
Altered lipid composition
J.INFECT.DIS.20(8)

PATHOPHYSIOLOGY AND MECHANISMS OFDISEASE:
EPIDERMAL BARRIER DYSFUNCTION
•Disruption of barrier function in atopic dermatitis is multifactorial
>Genetic factors (FLG mutations)
>Physical damage (Scratching)
>Microbial dysbiosis (S.aureus,Malassezia)
>Type 2 immuneactivity (Downregulation of skin barrier genes
and stratum
corneum lipids)
> Keratinocytes in the stressed epidermal barrier send
> proinflammatory (Th2 cytokines) and pruritogenic signals
J.INFECT.DIS.20(8)

PATHOPHYSIOLOGY AND MECHANISMS OFDISEASE: THE
ROLE OF THE MICROBIOME
• Atopic dermatitis isassociated with
a disordered microbiome, with S.
aureus being a dominant colonizer
and pathogen
• Colonisation rates onbacterial
cultures
>Non-lesional skin 39%
>Lesional skin 70%
• Thereisa lossof community
diversity preceding flares, and the
microbiome becomesS.aureus
dominant with regression after
treatment and a return to baseline
severity
J.INFECT.DIS.20(8)

EDSLEVSM,et al. SkinMicrobiome inAtopic Dermatitis.Acta DermVenereol 2020.

DISEASE: THEROLE OF THE
MICROBIOME
•Cutaneous yeasts suchas Malassezia species could
trigger or exacerbate cutaneous inflammation in
atopic dermatitis
•Themechanismsare poorly understood

DISEASE: IMMUNOLOGICAL DYSREGULATION
AND INFLAMMATION
ALSAIMARYI.E..ETAL.2007.IGEDEPENDENTATOPIC DERMATITIS
.ALLERGY.154(11)
BoguniewiczM, et al. Atopic Dermatitis. Middleton’s Allergy (9th Edition) 2019.

PATHOPHYSIOLOGY AND MECHANISMS OF DISEASE:
IMMUNOLOGICAL DYSREGULATION AND INFLAMMATION > ROLE OF
IMMUNOGLOBULIN EIN CUTANEOUS INFLAMMATION
.ALLERGY.154(11)
•IgE-dependent biphasic reactions are frequently associated with clinically
significant allergic reactions and may contribute to the inflammatory
process of AD
•Immediate-type reactions related to mediator release by mast cells
bearing allergen-specific IgE may result in the pruritus and erythema
that occur after exposure to relevant allergens
•IgE-dependent late-phase reactions can then lead to more persistent
symptoms
•Epidermal LCs in AD skin express IgE on their cell surface and are
significantly more efficient than IgE-negative LCsat presenting allergen to
Tcells

DISEASE: ROLE OF
ALLERGENS
• Foods
> PatientswithADand positive food allergen skintestscould have negative food
challenges to the implicated allergen
> Double-blind placebo-controlled food challenges canconfirm food allergy
> 33% of infants and young children with ADwill showclinically relevant reactivity
to a food allergen
> Elimination of food allergens resultsin amelioration of skindisease and a
decrease in spontaneousbasophil histamine release
.ALLERGY.154(11)

DISEASE: ROLE OF
ALLERGENS
• Aeroallergens
> Exacerbation of ADcanoccurwith exposureto allergens suchashouse
dustmites,animal danders, andpollens
> Theseverity of ADhasbeen correlated with thedegree of sensitization to
aeroallergens
> Environmentalcontrol measuresaimed at reducing dustmite allergen have
been shownto result in clinical improvementin ADpatients
.ALLERGY.154(11)

DISEASE: ROLE OF
ALLERGENS
•Microbial agents
> Elevated allergen-specific
IgE levels
>> S.aureustoxins
>> Malassezia sympodialis
>> Trichophytonrubrum
.ALLERGY.154(11)

TREATMENT
•Barrier repair and maintenance therapy
•Topical anti-inflammatory therapies
•Phototherapy
•Conventional systemic treatments
•Targeted monoclonal antibodies
•Probiotics

FishbeinAB,et al. Update onAtopic Dermatitis: Diagnosis,SeverityAssessment,and TreatmentSelection.JALLERGYCLINIMMUNOLPRACT2020.

•3) Henoch –Schonlein Purpura :
This is a form of vasculitis (inflammation of
the small blood vessels) i skin and
various other tissues in the body. It may
also be referred to as anaphylactoid
purpura. The precise cause is unknown.
Three-quarters of cases are preceded by
an upper respiratory tract infection, mostly
caused by ß haemolytic streptococci.
Several other associations have been
reported including drugs, food and
various infections.
Mainly seen in children under the age of 10 years, with a slight male
predominance. It may also occur in adults.
• Treatment :
If it follows a streptococcal infection, treat with phenoxymethyl penicillin.Otherwise,
bed rest will stop new lesions occurings and most cases will get better in 3–6
weeks. Paracetamol syrup will help with joint and abdominal pain.

• 4) IMPETIGO :
• A superfacial infection of the epidermis
Staphlococcus aureus, a group A beta-
haemolitic streptococcus or a mixture of
both. Entrance is gained through broken skin
such as cuts and grazes. The condition is
highly contagious.
Approximate age group : Childhood.
• Treatment
• Impetigo can be a self-limiting condition but antimicrobials are usually prescribed to hasten a clinical
cure and to interrupt spread to other areas.
• Topical antibiotics (e.g. fusidic acid) are as effective as systemic antibiotics, but where there is concern
about fusidic acid resistance, topical 1% hydrogen peroxide cream is an alternative.
If there is a thick crust, this can be removed by applying oil for 20 minutes. This will soften crusting crust
has been removed, apply the topical treatment to the affected area, ensuring that the treatment is applied
to the nares at the same time.If the patient has widespread lesions or impetiginised eczema, systemic
antibiotics, such as flucloxacillin or erythromycin if allergic to penicillins are advised.
• Advice to parent/carer
• Encourage good basic hygiene practices to limit contact and spread of the condition: this includes
advice to avoid sharing towels and face cloths
• and encouraging good handwashing technique after contact. As scratching may
spread the lesions so keeping the nails,short is advisable.

• 5) IMPETIGINZED ECZEMA :
• Secondary infection, most commonly
with Staphlococcus aureus or
streptococcal isolates, can occur in the
broken skin caused by scratching in
atopic eczema.
• Approximate age group : Childhood.
• Treatment :
• Topical antibiotics should not be prescribed as the patient may
be self medicating on an ad hoc basis, promoting antibiotic
resistance. Localised areas may be treated with either a topical
antiseptic (e.g. 1% hydrogen peroxide cream or chlorhexidine)
or a topical antiseptic combined with a corticosteroid. If the
lesions are widespread, treat with oral anti staphylococcal
antibiotic clarithromycin or flucloxacillin
• Consider skin swab if non responsive.

•
6) Miliaria :
Miliaria (sweat rash) arises from
obstruction of the sweat glands. It is
most commonly found in hot, humid
conditions.
Miliaria crystalline is caused by
obstruction of the sweat ducts and
appears as tiny superficial clear b
Miliaria rubra (prickly heat) occurs deeper
in the epidermis and results in
itchy red plaques.
• Miliaria profunda results from sweat leaking into the dermis causing deep, intense, uncomfortable, prickling red lumps.
• Miliaria pustulosa describes pustules due to bacterial infection.
Common in infancy, but may occur at any age.
• Treatment :
Antiseptics can reduce bacterial growth. Mild topical steroids can give reasonable symptomatic relief.
• Advice to parent/carer
•avoid excessheat which predisposesto thecondition
•avoid excessivesoapusage
•cool water compresseswillsoothe

•
7) Measles
:
Measles is a highly contagious disease
caused by the RNA morbillivirus.
Immunisation can prevent measles but the
disease is becoming more common with
reduced uptake of vaccination.
•
Approximate age group :Childhood.
• Treatment :
• Treatment is symptomatic as affected children get better
spontaneously. Bed rest is advisable if the child is sick and
pyrexia can be treated with paracetamol elixir.
• Advice to parent/carer :
Adequate fluid intake to avoid dehydration.

8) NAPKIN Dermatitis (nappy rash) :
•
The common type of nappy rash is an irritant
contact dermatitis, caused by urine and faeces
being held next to the skin under occlusion.
Bacteria in the faeces break down the urea in the
urine into ammonia which irritates the skin.
Treatment :
Nappies should be changed as soon as they are wet or soiled and the skin gently
cleaned and patted dry. A barrier moisturiser such as zinc and castor oil cream
should then be applied to the area covered by the nappy. Disposable nappies are
more suitable than towelling ones while skin is affected as they are more effective
at drawing liquid away from the skin.
Avoid plastic pants.
Advice to parent/carer
In a child over nine months, 60–80mls of cranberry juice daily may help by
altering the pH of the urine.
If the rash does not improve after taking these simple measures, a weak topical
steroid such as 1% hydrocortisone can be applied twice a day for 3–5 days.

•9) Rubella( German Measles) :
Rubella, caused by a rubivirus, is a common viral illness in
children.
It is spread by inhalation of infected droplets.
Approximate age group :Childhood.
• Treatment :
• If the diagnosis is suspected, rubella antibody titres should be
measured immediately and after 10 days so that diagnosis can be
confirmed. Treatment is symptomatic as affected children get
better spontaneously.
Paracetamol elixir will ease pain.
• Advice to parent/carer:
• Adequate fluid intake to avoid dehydration.

• Common skin conditions in Both Adults and
Children :
• Bites (insect)
• Eczema herpeticum
• Pruritus
• Urticaria (acute)
• Scabies

• 1) BITES (INSECTS) :
• The presentation of the bite will help determine the causative insect.
• Presentation
• Insect bites present as itchy papules with a central punctum. If there are groups
or rows of 3 or 4, think of flea bites; bed bug bites produce sin very large lesions
on the hands or face, with new lesions usually being found each morning.
Numerous other insects can bite humans, including midges, mosquitoes, flies,
wasps, tics, bees, ants, moths and butterflie centipedes, ladybirds and spiders.
Sometimes large blisters will appear following an insect bite.
• Treatment :
Itch can be relieved by the application of 10% crotamiton cream, a topical steroid for short-term use. If
itch keeps the patient awake at night, a sedating night-time antihistamine can be prescribed.
• Advice to patient
If there is a family pet (cat or dog) and fleas bites are suspected
,the animal, rather than the human, should be treated. Advise to take
the animal to the vet for treatment.

•
2) Eczema Herpeticum:
• Atopic eczema which has become secondarily
infected with herpes
simplex virus.
Affects all age groups.
• Treatment :
A viral swab should be taken from o diagnosis. Treat adults with a 7- day course of
an oral antiviral agent such as aciclovir, valaciclovir or famciclovir. In children,
topical aciclovir can be prescribed if infection is mild, and oral aciclovir if severe.
These drugs are only effective when the virus is replicating so should only be
given in the early phase of the disease (within 48 hours of the rash appearing).
Adequate analgesia, such as paracetamol is important.
Advice to patient/parent
• Good hygiene: avoiding the sharing of towels and good handwashing techniques
are important to minimis the risks of spreading the Infections to others.
• DO NOT apply topical steroids if viral infection is suspected.

•
3) Pruritus :
Pruritus is a medical term for itchy skin.
• Approximate age group : All ages.
Treatment
If no cause can be found, treatment should be symptomatic. Start with
10% crotamiton cream twice a day. Complete emollient therapy should
also be prescribed. If this does not help, a moderately potent topical
steroid should be considered. If the itch is not settling and is interfering
with sleep, a sedative antihistamine should be prescribed to be taken an
hour before going to bed. Advise adults to be careful about driving the
next day.
0.5% menthol in aqueous/hydrophilic cream may also be useful to
relieve the itch.

•
4) Urticaria :
Urticaria refers to a group of disorders
caused by the release of chemicals such as
histamine from the mast cells in the skin. This
causes small blood vessels to leak, which results
in tissue swelling.
Approximate age group :
• This disorder affects both adults and children.
• Treatment:
Antihistamines until rash settles.There is no need for specific
inves the following tests may be helpful in some cases:
•FBC – identify eosinophillia caused by allergen or parasitic infestation; low white
blood count for systemic lupus erythematosis.
• thyroid antibodies and function – in chronic urticaria if autoimmune
origin is considered
• skin-prick test and blood tests for specific allergens.
• skin biopsy – if weals are prolonged, to identify vasculitis.

•
5) SCABIES :
Scabies is an infestation with the sarcoptes
scabie mite. It is transmitted by prolonged skin-to-
skin contact with someone who is infected.
• A fertilised female has to be transferred for
infestation to occur. The female mite will then burrow
into the skin to lay the eggs: 4−6 weeks later,a
hypersensitivity rash will appears.
• Approximate age group : Affects all age groups.
• Presentation :
• The rash is made up of excoriated papules scattered over the
trunk and limbs but sparing the face (except in infants). The
patient will experience intense itch, especially at night,
Identification of one or more burrow will confirm the diagnosis.
Burrows are most commonly found on the hands and feet in the
sides of the finger and toes.In Infants burrows are often present
on the palms of the hands and soles of the feet.
•

Allergy  A misguided reaction to foreign
substances by the immune
system, the body system of
defense against foreign
invaders, particularly pathogens
(the agents of infection).
The allergic reaction is misguided
in that these foreign substances
are usually harmless.
The substances that trigger
 allergy are called allergen.
 Examples include pollens, dust
mite, molds, danders, and
certain foods. People prone to
allergies are said to be allergic
or atopic.

Types of Allergies
Types
:-
 An allergy occurs when your body’s
immune system sees a certain
substance as harmful. It reacts by
causing an allergic reaction.
Substances that cause allergic
reactions are allergens.
 Drug Allergy
 Food Allergy
 Insect Allergy
 Latex Allergy
 Mold Allergy
 Pet Allergy
 Pollen Allergy

True allergies to drugs (medicines) occur in only a small
number of people. Most drug reactions are not allergic, but
are side effects of the properties of the medicine. A diagnosis
of the cause of the drug reaction is usually based only upon
the patient’s history and symptoms.
Sometimes skin testing for drug allergy is also done.
A food allergy occurs when the body’s immune system sees a
certain food as harmful and reacts by causing allergic symptoms.
Immunoglobulin E (IgE) mediated. The body’s immune system
makes antibodies called immunoglobulin E (IgE). These IgE
antibodies react with a certain food and cause symptoms. the most
common causes of food allergy :Milk ,Egg,Peanut,Tree
Nut,Soy,Wheat,Fish,Shellfish.
Non-IgE mediated. Other parts of the body’s immune system
react to a certain food. This reaction causes symptoms, but does
not involve an IgE antibody. Someone can have both IgE mediated
and non-IgE mediated food allergies.

A latex allergy is an allergic reaction to natural rubber latex. Natural
rubber latex gloves, balloons, condoms and other natural rubber
products contain latex. An allergy to latex can be a serious health
risk.
Bees, wasps, hornets, yellow jackets and fire ants are the most
common stinging insects that cause an allergic reaction.
Non-stinging insects can also cause allergic reactions. The
most common are cockroaches and the insect-like dust mite.
Allergies to these two insects may be the most common cause
of year-round allergy and asthma.
Mold and mildew are fungi. Since fungi grow in so many places, both
indoors and outdoors, allergic reactions can occur year round.
The symptoms of mold allergy are very similar to
the symptoms of other allergies, such as sneezing, itching, runny
nose, congestion and dry, scaling skin.
Outdoor molds may cause allergy symptoms in summer and fall (or
year-round in some climates)
Indoor molds may cause allergy symptoms year-round

Pollen is one of the most common triggers
of seasonal allergies. Many people know
pollen allergy as “hay fever.” Experts
usually refer to pollen allergy as “seasonal
allergic rhinitis.”
Symptoms:
•Runny nose and mucus production
•Sneezing Itchy nose, eyes, ears and
mouth
•Stuffy nose (nasal congestion)
Allergies to pets with fur are
common. It is important to know
that an allergy-free
(hypoallergenic) breed of dog or
cat does not exist.

Psoriasis Definition
A Chronic (long
lasting) skin disease
characterized by scaling
and inflammation.
Scaling occurs when cells
in the outer layer of skin
reproduce faster than
normal and pile upon the
skin’s surface.

Psoriasis is a chronic, autoimmune d
i
s
e
a
s
ethat appears on the skin. It
occurs when the immune system
sends out faulty signals speed up growth cycle of skin cells.
T h e scaly patches commonly caused by psoriasis, called
psoriatic plaques.
F i n g e r n a i l s and toenails arefrequentlyaffected and can seen as an
isolated symptom.
N o n p u s t u l a r psoriasis
Plaque psoriasis ( psoriasis vulgaris ) is the most common form of psoriasis.
Erythrodermic psoriasis involves the widespread inflammation of the skin.
P u s t u l a r psoriasis
Other Psoriasis Guttate psoriasis Psoriatic
arthritis Nail psoriasis
Classification

Sings and symptoms
Nail psoriasis
Piaque of psoriasis

Quality of life
It shows affect health-related quality of life to an extent
similar to the effects of other chronic as depression,
myocardial infarction, hypertension congestive heart failure
or type 2 Diabetes.
Severity
Psoriasis is usually graded as mild,moderate severe.
Genetic factors
Many genes are associated with it. Most of them involve the immune
system, particularly. the major histocompatibility complex and
T cells.
Immunological factors
In psoriasis, immune cells move from the dermis to the epidermis,
where they stimulate skin cells to proliferate.

Diagnosis
A diagnosis of psoriasis is usually based on
the appearance of the skin. There are no
special blood tests or diagnostic procedures for
psoriasis. Sometimes a skin biopsy, or
scraping, may be needed to rule out other
disorders and to confirm the diagnosis.

Management
Cognitive behaviourtherapy
Tr o p i c a l treatment
P h o t o therapy treatment
P h o t o chemotherapy
S y s t e m i c treatment
Alternative therapy

Prongosis
Psoriasis is a lifelong condition. There is
currently no cure but various treatments can
help to control the symptoms.
Epidemiology
Psoriasis affects both sexes equally and can
occur at any age, although it most commonly
appears for the first time between the ages of 15
and 25 years.

Aetiopathogenesis of psoriasis
Genetic factors Environmental factors
e.g. streptococci
Defects in
epidermal function,
innate/acquired immunity

Pathological hallmarks of psoriasis
Abnormal differentiation and hyperproliferation of keratinocytes
Infiltration of inflammatory cells
Increased dermal blood vessels

Previous hypothesis (pre 1990)
-
Primary activation of keratinocytes
-
Subsequent release of cytokines and antigen-independent activation of Tcells
Where is the primary defect?
Current understanding (post 1990)
-
Persistent T-cell stimulation (antigen?) which drives abnormal keratinocyte proliferation
-
Exaggerated innate immune response
(DC, macrophages, IFNs, TNF
, IL-12/IL-23)
- Alteration of transcription factors in keratinocytes

Boyman et al. J Exp Med. 2004;199: 731
Role of T cells in psoriasis
CD3
Day 56
Xenotransplantation models:
AGR-/- xenograft model1
non-lesional human skin engrafted onto AGR129 mice
spontaneous development of psoriatic phenotype

Infiltrate:
- memory-effector T cells
CD4 DC, macrophages CD8
keratinocytes
•T cells are activated
- CD69, CD25, HLA-DR
•clonal T cell expansions
- antigen-specific stimulation
Krueger JG. J Am Acad Dermatol 2002; 46: 1
Nickoloff et al. J Invest Dermatol. 1998; 110, 459-460
Role of T cells in psoriasis
CD4 > CD8
CD8 > CD4
CD 69
TCR
TCR
TCR
TCR
T
C
TR
cell

Putative antigen(s) ?
• -haemolytic streptococci can trigger psoriasis
• Superantigens stimulate a skin-homing
molecule (CLA) on T cells
• T cells cross-react with epitops whichare
common to streptococcal M protein and
keratins 1,2
.1
Gudjonsson et al. Clin Exp Immunol 2004; 135:1
.2
Baker et al. Scand J Immunol 2003; 58: 335
TCR
TCR
TCR
TCR TCTRcell

DC
Signal 1: Antigen
Innate immunity is critical for T cell activation
Signal 2:
-
Co-stimulatory molecules
-
Adhesion molecules
CD28
CD2
CD80
LFA3
LFA1
ICAM1
Signal 3:
- Cytokines (IL-2, IL-12, IL-23,…)
T cell

• Psoriatic skin is highly infiltrated
by dendritic cells (DC)
Abrams et al. J Exp Med. 2000; 192: 681
Lowes et al. PNAS. 2005; 102: 19057
Zaba et al J Invest. Dermatol 2009;129:79
-
plasmacytoid DC (BDCA-2)
-
myeloid DC (CD11c, BDCA-1-)
Innate immunity in psoriasis

DC
- plasmacytoid DC (BDCA-2)
- myeloid DC (CD11c)
Activation of DC and production of cytokines
IFN-
TNF-
, IL-12, IL-23
IL-23
IL-12
IFN
TNF
„stress“
infection, trauma
„danger signals“
cytokines, HSP, LL-37
+ antigen ?

Day 0
Day 35
Nestle et al. J Exp Med. 2005; 202: 135
Anti-BDCA-2
Key cytokines in psoriasis: IFN
- Psoriasis is inhibited by anti–BDCA-2
- fully restored by the addition of
recombinant human IFN-
Xenotransplantation models:
AGR-/- xenograft model1
Anti-BDCA-2 + IFN

• Enhanced expression in
-skin
-joints
-serum (correlates with activity)
• Produced by multiple cells
- DC, macrophages
- T cells
- mast cells
- keratinocytes, endothelial cells
Key cytokines in psoriasis: TNF

Key cytokines in psoriasis: TNF
TNF
Stimulation of
cytokines/ chemokines
Keratinocyte
activation
Adhesion molecules
Neovascularisation
Recruitment of further
leucocytes

Modulation of key cytokines
TNF
•
TNFAntagonists
Etanercept, ENBREL
Adalimumab, HUMIRA
Infliximab, REMICADE

IL-12 IL-23
Lee et al. Exp Med. 2004; 199:125
Yawalkar et al. J Dermatol Science 2009; 54: 99
Key cytokines in psoriasis: IL-12 and IL-23

1. Blauvelt A. J Invest Dermatol. 2008;128: 1064
•
IL-12 and IL-23 bind tospecific
receptors on T cells and natural
killer cells
•
Strongly influence T celldifferentiation
and activation
IL-12 and IL-23 are heterodimers with a
common p40 subunit

IL-12 and IL-23 drive development of Th1
and Th17 cells
Th17
IL-17,IL-22,
TNF
IL-12
IL-23
Th 1
IFN ,TNF
Th17
Th17
Th1
Th1
DC

Th1 cytokines drive inflammatory processes
in the psoriatic plaque
Th1
IFN
TNF
Adapted from: Lowes MA, et al. Dermatol Clin. 2004; 22:349
iNOS (NO)
IL-8
MIG, IP-10
VEGF
MHC Class II
ICAM-1
VCAM-1
Neovascularisation
Keratinocyte and
endothelial cell
activation
T cell influx
Neutrophil influx
Vasodilation

Th17 cytokines drive inflammation and
keratinocyte hyperplasia in the psoriatic plaque
Th17
IL-17
IL-22
TNF
Aggarwal S, Gurney AL. J Leukoc Biol. 2002; 71:1
Monocyte and
neutrophil recruitment
Neovascularisation
Vasodilatation
T cell influx
Keratinocyte
hyperplasia
MCP-1
Gro-
IL-8
G-CSF
GM-CSF
IL-6
PGE2
ICAM-1
VCAM-1

Modulation of key cytokines
•
Anti-IL-12/Il-23 p40
Ustekinumab, STELARA®
Briakinumab, ABT-874

Activation of DC and Tcells
•
Stimulation of keratinocytes
Summary:
Key steps in the immunopathogenesis
Th17
Th1
IL-12
IL-23
Perpetuation of inflammation
•
Neovascularisation
•
Recruitment of further leucocytes
IFN
TNF

URTICARIA: THE BASICS
 Urticaria (hives) is a vascular reaction of the skin
characterized by wheals surrounded by a red halo
or flare (area of erythema)
 Cardinal symptom is PRURITUS (itch)
 Urticaria is caused by swelling of the upper dermis
 Up to 20% of the population experience urticaria at
some point in their lives

ANGIOEDEMA: THEBASICS
 Angioedema can be caused by the same pathogenic
mechanisms as urticaria, but the pathology is in the deep
dermis and subcutaneous tissue and swelling is the major
manifestation
 Angioedema commonly affects the face or a portion of an
extremity
Involvement of the lips, cheeks, and periorbital areas is common,
but angioedema also may affect the tongue, pharynx, larynx and
bowels
 May be painful or burning, but not pruritic
 May last several days

URTICARIA & ANGIOEDEMA
 Urticaria and angioedema may occur in any
location together or individually.
 Angioedema and/or urticaria may be the
cutaneous presentation of anaphylaxis, so
assessment of the respiratory and
cardiovascular systems is vital!

URTICARIA: CLINICAL FINDINGS
 Lesions typically appear over the course of
minutes, enlarge, and then disappear within hours
 Individual wheals rarely last >12hrs
 Surrounding erythema will blanch with pressure
 Urticaria may be acute or chronic
• Acute = new onset urticaria < 6 weeks
• Chronic = recurrent urticaria (most days) > 6 weeks
 Most urticaria is acute and resolves

COMMON CAUSES OF ACUTE URTICARIA

Idiopathic

Infection
•
Upper respiratory,
streptococcal
infections,
helminthes
 Food reactions
• Shellfish, nuts, fruit, etc.
 Drug reactions
 IV administration
• Blood products, contrast agents

ETIOLOGY OF CHRONIC URTICARIA
 Idiopathic: over 50% of chronic urticaria
 Physical urticarias: many patients with chronic urticaria have
physical factors that contribute to their urticaria
• These factors include pressure, cold, heat, water (aquagenic),
sunlight (solar), vibration, and exercise
• Cholinergic urticaria is triggered by heat and emotion
• The diagnosis of pure physical urticaria is made when the sole
cause of a patient’s urticaria is a physical factor
 Chronic autoimmune: possibly a third or more of patients
with chronic urticaria
 Other: infections, ingestions, medications

DERMATOGRAPHISM
 Most common form of
physical urticaria
 Sharply localized
edema or wheal within
seconds to minutes
after the skin has been
rubbed
 Affects 2-5% of the
population

URTICARIA: PATHOPHYSIOLOGY
 Non-Immunologic Urticaria: not dependent
on the binding of IgE receptors
• For example, aspirin may induce histamine
release through a pharmacologic mechanism
where its effect on arachidonic acid metabolism
causes a release of histamine from mast cells.
• Physical stimuli may induce histamine release
through direct mast cell degranulation

ALLERGY TESTING
 Allergy testing is not routinely performed in
patients with chronic urticaria.
• Skin prick testing may reveal sensitivities to a
variety of allergens that may not be relevant to
the patient’s urticaria.
• Laboratory tests may identify the 1/3 of patients
with chronic urticaria who have an autoimmune
pathogenesis. This adds additional costs and
may not change the management.

NATURAL HISTORY AND PROGNOSIS
 Symptoms of chronic urticaria can be severe
and impair the patient’s quality of life (QOL)
 In most patients, chronic urticaria is an episodic
and self-limited disorder
 Average duration of disease is two to five years
 In patients with idiopathic chronic urticaria,
there is a rate of spontaneous remission at one
year of approximately 30 to 50 percent
 However, symptoms extend beyond five years
in nearly one-fifth of patients

TREATMENT: ANTIHISTAMINES

Oral H1 antihistamines are the first-line treatment for
acute and chronic urticaria

1st-generation H1 antihistamines are less well-tolerated
due to sedation
•
e.g. 10-50 mg hydroxyzine 1-2 hours beforebedtime
•
Can start with smaller doses (10 mg) to allow the patientto
manage the sedation effects
•
Remember to warn patient not to drive a car or operate
other dangerous machines within 4-6 hours of taking this
medication
•
Do not take with other sedating medications

TREATMENT: ANTIHISTAMINES

2nd-generation H1 antihistamines (e.g. Loratadine)
are better tolerated with fewer sedative and
anticholinergic effects and may be used in patients
intolerant of or inadequately controlled by 1st-
generation agents

Certain populations, including children, the elderly,
and patients with renal or hepatic impairment may
require dosage adjustments when using H1
antihistamines

Also used with caution in patients with glaucoma,
prostatic hyperplasia, and respiratory disease

ANTIHISTAMINES
 The following are examples of H1 antihistamines:
• 1st Generation
• Diphenhydramine (OTC)
• Hydroxyzine (Rx, generic)
• Chlorpheniramine (OTC)
• 2nd Generation
• Cetirizine (OTC)
• Loratadine (OTC)
• Fexofenadine (OTC)

URTICARIAL LESIONS
Not all patients with urticarial eruptions have
urticaria. Which of the following patients has
ordinary urticaria?

URTICARIAL LESIONS
Urticarial
Vasculitis
Ordinary
Urticaria
Bullous
Pemphigoi
d

BEYOND ORDINARY URTICARIA
 The appearance of the hives does not tell
you the underlying cause
 The presence of systemic symptoms should
signal the possibility that an urticarial rash is
not ordinary urticaria but rather a systemic
syndrome with urticaria-like skin lesions

REFERRAL TODERMATOLOGY
 Referral to a dermatologist and biopsy should be
performed in patients with one or more of the
following features:
• Individual lesions that persist beyond 48 hours, are
painful rather than pruritic, or have accompanying
petechial characteristics
• Systemic symptoms
• Lack of response to antihistamines
• Lesions that leave pigmentation changes upon
resolution

ANAPHYLAXIS
 Anaphylaxis is a serious allergic reaction that is rapid in
onset and may cause death
 Patients with anaphylaxis may have no skin lesions,
lesions of angioedema, and/or typical urticarial wheals
 Morphology of the skin lesion does not matter
• Patients with angioedema are not more likely to have
anaphylaxis compared to patients with urticaria
 ABC’s first!
 Recruit more help. May need to triage to higher level of
care (in clinic this means calling 911).

ANAPHYLAXIS: TREATMENT
 First-line therapy for anaphylaxis includes
epinephrine, IV fluids and oxygen
 Administer 0.3-0.5ml in 1:1000 epinephrine
dilution IM repeating every 10-20min as
necessary
 Make sure airway is patent or else intubation
may be emergently necessary
 Patients who have severe reactions requiring
epinephrine should be monitored in the hospital

SYNOPSIS
 Urticaria (hives) is a vascular reaction of the skin
characterized by wheals surrounded by a red halo or
flare.
 Urticaria is classified as acute or chronic. Acute urticaria
is defined as periodic outbreaks of urticarial lesions that
resolve within six weeks.
 Over 50% of chronic urticaria is idiopathic.
 Oral H1 antihistamines are first-line treatment for acute
and chronic urticaria.
 1st generation H1 antihistamines can cause sedation.
 The presence of systemic symptoms should signal the
possibility that an urticarial rash is not ordinary urtica

SYNOPSIS
 Anaphylaxis is a serious allergic reaction that is
rapid in onset and may cause death.
 Remember to ask about symptoms of
anaphylaxis, including: chest tightness or
difficulty breathing, hoarse voice or throat
tightness, nausea, vomiting, abdominal pain,
lightheadedness.
 The 1st step in management of a patient with
signs and symptoms of anaphylaxis is to assess
airway, breathing, circulation, and adequacy of
mentation.
 Call for help if you suspect a patient has
anaphylaxis

Hyperkeratotic
disorders
Hypertrophy of the horny layer of the
skin (excessive development of keratin)

Callus
Skin lesions
Over a broad
area of skin
caused by
Excess friction

Callus
Hand
callus
Feet callus
Repeated handling of an object
that puts pressure on the hand
Pressure from footwear
Lack a central core

Warts
Skin growth HPV
caused by
Very contagious
Go away on their own within months or years

Warts
Common Plantar
Grow most often on the hands
Grow on the soles of the feet
Rough, shaped like a
dome, and greyish-brown
in color.
Hard, thick patches of skin with
dark specks

Immunology of Skin Diseases: Understanding the Skin's Immune System

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