week 3 lec 1 Flashcards
atopic dermatitis causes
familial transmitted skin disease
–> genetic, immune, environmental risk factors
when does atopic dermatitis usually begin
childhood
hallmark symptom of atopic dermatitis
itch (can effect sleep, cause excoriations and infections)
co-morbidities with atopic demaitits
allergic asthma and allergic rhinitis
major features of atopic dermatitis
chronic or chronically relapsing
- Pruritus
- Eczematous dermatitis (acute, subacute, or chronic) -
- Facial and extensor involvement in infancy
- Flexural eczema or lichenification in children and adults
atopic dermatitis is commonly associate qith
family history of atopy (allergic rhinitis, Asthma, AD)
xerosis or skin barrier dysfunction
IgE reactivity
pathogenesis of atopic dermatitis is driven by
skin barrier defect (FLG gene)
environment
altered immunologic responses in T cells, antigen processing, inflammatory cytokines, host defense proteins, allergen sensitivity, and infection.
types of atopic dermatitis
eczema
contact dermatitis
seborrheic dermatitis
atopic dermatitis etiology
3x prevalence since 1960s
more in industrialized countries 10-20%
more females
acute lesion characteristics in a topic dermatitis
erythematous papulovesciles (small red bumps or blisters)
surface changes; pinpoint crusting or weeping from exudation
sxz: prurits –> itchy
subacute or chronic lesions in atopic dermatitis
dry, scaly plaques
excoriation and lichenification
pruritis, less erythema than acute
atopic dermatitis lesions
can have acute and chronic lesions
multiple areas
indistinguishable clinically or historically from other eczematous conditions like allergic contact dermatitis and nummular dermatitis
patients with darker skin and atopic dermatitis
follicular accentuation
flat-topped papule in lichenified areas
hyperpigmentation
(rare) vitiligo like depigmentation
infancy - which area on body for atopic dermatitis
face, scalp, extensors
adolescent with atopic dermatitis is usually on which area
flexural folds
(lichenification and chronic)
adults primary location for atopic dermatitis
hand eczema
also more flexural and around neck
1/3 of patients with atopic dermatitis have features of _____ deficiency
filaggrin deficiency
–> ichthyosis vulgaris, keratosis pilaris, and hyperlinear palms.
other features in atopic dermatiits
allergic shiners below eyes
conjunctivitis
elevated IgE
facial pallor
etc
comorbidities of atopic dermatitis
Th2 immune activation
high IgE
eosinophilia
predisposed to other allergies
psychosocial (anxiety/depress)
complications of atopic dermatitis
Bacterial, Viral, Fungal infections
Ocular Issues (eyelid dermatitis, etc)
Hand dermatitis
Exfoliative dermatitis
what is exfoliative dermatitis (complication of AD)
generalized (90% of body) redness, scaling, weeping, crusting, systemic toxicity, lymphadenopathy, and fever. Although this complication is rare, it is potentially life threatening
skin barrier function decreased in atopic dermatitis
-downregulate cornified enveloped genes (keratin, filaggrin, loricrin)
-reduced ceramide levels
-increase endogenous proteolytic enzyme activity
-enhance trans-epidermal water loss
scratching and exogenous proteases (ie. dust mites and s. aureus) impact barrier too
increase allergen absorption
lack endogenous protease inhibitors
soap and detergents effect skin barrier in AD
raise pH, increase endogenous protease activity –> further breakdown of epidermal barrier function
genes in atopic dermatitis
loss of function in filaggrin (chromosome 1q21)
–> effect barrier function: increase trans-epidermal water load, increase allergen and chemical entry, inflammatory response
filaggrin mutation in
Atopic dermatitis but also can be in normal people and be fine
3 characterizations of AD lesions
non-lesional AD
acute AD lesions (3 or fewer days after onset),
chronic skin lesions (>3 days’ duration)
non lesiona atopic dermatitis immunopathology
mild epidermal hyperplasia (thicken)
sparse perivascular T cell infiltrate in dermis
acute lesions in atopic dermatitis immunopathology
epidermal spongiosis (intracellular edema in epidermis disrupts keratinocytes)
T cell activation and skin-homing cutaneous lymphocyte- associated antigen (CLA)
sometimes mast cells (degranulation), eosinophils, basophils, neurophils
nonlesional and lesion atopic dermatitis have which dendritic antigen presenting cells
langerhan cells
inflammatory dendritic epidermal cells
macrophages
difference between non lesional and lesional atopic dermatitis for dendritic cells
non lesional has dendritic cells with fewer surface bound IgE
chronic lichenified lesions in atopic dermatitis
hyperplastic epidermis with elongation of rate ridges
hyperkeratosis
minimal spongiosis (reduced intercellular edema)
immune cells in chronic lichenified lesions of atopic dermatitis
increase langerhans cells with IgE
macrophages dominante dermis
mast cells
are there neutrophils and eosinophils in atopic dermatitis
no neutrophils - even if staph aureus infects
eosinophils: increased
allergic inflammation in atopic dermatitis from
- cytokine and mediator secretion
-ROS intermediates
-toxic granule proteins
atopic dermatitis epidermis vs normal epidermis differences
-thymic stromal lymphopoeitin (TSLP) increased in AD which activates dendritic cells and cause Th2 response
IL-33 released by damaged keratinocytes causes type 2 immunity
normal keratinocytes lack something that is seem in atopic dermatitis and cause inflammation
Normal keratinocytes lack significant levels of TSLP and IL-33
TSLP and IL-33 is secreted by _____ and induces _____ to have a _____ response
secreted by epithelial cells
induce dendrite cells to drive Th0 cells into Th2
cytokines in nonlesional and acute atopic dermatitis
IL-4, IL-5, IL-13, IL-25, IL-31, IL-33.
cytokines in all stages of atopic dermatitis
and what cells their secreted by
type 2 cytokines
innate lymphoid type 2 cells
mast cells
basophils
key functions of type 2 cytokines in atopic dermatitis
Elevated IgE responses.
Eosinophilia.
Skin barrier dysfunction.
Allergic skin inflammation
Itching.
other cytokines outside of Th2 in atopic dermaatitis
IL-22, IL-17, IL-4, IL-13: inhibit terminal keratinocyte differentiation and inhibit filaggrin expression
IL-22, IL-17, IL-4, IL-13: inhibit what
inhibit terminal keratinocyte differentiation and inhibit filaggrin expression
IL-4 and IL-13 also enhance IL-23 from dendritic cells
IL-23 in atopic dermatitis is from what cell and enhances what
Dendritic cell–derived IL-23 enhances IL-22–IL-17 differentiation.
when going from acute to chronic atopic dermatitis what cytokines and IL’s increase
Th1 cytokine increases with IFN-y
IL-5 (promotes eosinophil survival)
TSLP in early atopic dermatitis
can be detected in infants before AD onset
TSLP-Th2-ILC2 pathway initiates AD
which chemokine are in atopic dermaitits
CTACK (CCL27)
CCR4 and CCL17
CTACK (CCL27) chemokine in atopic dermatitis
Attracts skin-homing CLA+ CCR10+ T cells into the skin.
CCR4 and CCL17 chemokine in atopic dermatitis
CCR4, expressed on skin-homing CLA+ T cells, binds to CCL17 on cutaneous venules.
Facilitates targeted T-cell migration into inflamed skin.
CCR4 expressing Th2 cells are recruited by what in AD
Macrophage-derived chemokine (MDC).
Thymus and activation-regulated cytokine (TARC).
severity of atopic dermatitis is correlated with
levels of thymus and activation-regulated cytokine (TARC).
Th1 cell migration in chronic AD is driven by which upregulated keratinocyte chemokines
Fractalkine
IFN-γ–inducible protein 10 (IP-10)
Monokine induced by IFN-γ (MIG)
immune cell infiltration in AD from which elevated CC chemokine
Macrophage chemoattractant protein-4 (MCP-4)
Eotaxin
RANTES (regulated on activation, normal T-cell expressed and secreted)
Recruit macrophages, eosinophils, and T cells into skin lesions.
immune effects on epithelial differentiation complex (in AD)
dry skin increases transepidermal water loss
minority of patient have filaggrin null mutations
most patients have immune mediated reduction in epidermal differentiation
activate proteases and lipases
defective epidermal barrier
allergens and microbes can penetrate
effects of reduced epidermal differentiation in atopic dermatitis
Decreased production of:
Epidermal structural proteins.
Filaggrin breakdown products.
Epidermal lipids.
Antimicrobial peptides (AMPs).
cytokines that downregualte filagrin expression in AD
TSLP, IL-4, IL-13
synergistic cytokines to IL-4 and IL-13: IL-17, IL-22, IL-25, and IL-33
minority and majority of patients with AD have which changes that cause pathophysiology
minority of patient have filaggrin null mutations
most patients have immune mediated reduction in epidermal differentiation
most prominent feature of AD
pruritus (itch)
pruritus in AD is worse after
allergen exposure, humidity changes, excessive sweating, low concentrations of irritants
pruitits in AD and mechanical injury from scratching can induce
pro- inflammatory cytokine and chemokine release
what can cause pruritis in AD possibly?
histamine from mast cell
but H1 antihistamines dont help
topical corticosteroid and calcineurin inhibitor help so histamine may play a role
molecules implicated in pruritis
histamine
IL-31 (cytokines from T cells)
stress-induced neuropeptides (substance P, CGRP)
proteases (act on protease-activated receptors; PAR-2)
eicosanoids (lipid mediator from arachidonic acid- i.e. prostaglandins, leukotrienes)
eosinophil derived proteins (major basic protein, eosinophil derived neurotoxin)
activate sensory nerves and inflame
allergic contact dermatitis is a cell mediated ______ reaction
hypersensitivity; Type IV (delayed)
what triggers allergic contact dermatitis
skin contact with environmental allergen
how does allergic contact dermatitis work
immune system exposed to allergen
allergen/ hapten binds skin proteins and forms complex = foreign
sensitization leads to T cell activation and inflammatory response upon subsequent exposure
(prior sensation required)
clinical presentation of allergic contact dermatitis
eczematous dermatitis
red, itch, swell, vesicles
chronic: lichenifcation and scaling
acute phase of allergic contact dermatitis sx
where area was exposed:
pruritus
erythema
edema
vesicles
chronic allergic contact dermatitis with repeated exposure to allergens causes lichenified erythematous plaques with
Hyperkeratosis.
Fissuring.
Pigmentary changes.
Lesions may spread beyond areas of direct exposure.
key features of allergic contact dermatitis
itch and swell
diagnose allergic contact dermaitits
patch testing is gold standard
treat allergic contact dermatitis
avoid allergen
provide alternatives
examples of allergens for allergic contact dermatitis
nickle, nail polish, fragrance, cosmetics, textiles, rubber related chemicals, adhesives, …
allergic contact dermatitis presentation
pruritic, eczematous dermatitis @ site of allergen
geometric, linear or focal patterns (i.,e. poison ivy is linear)
acute vs subacute vs chronic lesions in allergic contact dermatitis
acute: edema, erythema, vesicles or papules
subacute: rupture vesicle ooze, scaly juicy papule with weeping and crusting
chronic: scale, fissure, lichenification
**SLIDE 57 chart for different types of allergic contact dermatitis
pigmented ACD on clothed portions of body from textile dyes and fragrances
i.e. eryhtema multiform like ACD on site of allergen from woods, medicament
etc
allergic contact dermatitis is what type of hypersensitivity rxn
type IV; delayed
features of allergic contact dermatitis
Erythema, edema, and papulovesiculation.
2 phases of allergic contact dermatitis
- sensitization phase
- elicitation phase
sensitization and elicitation phase of allergic contact dermatitis
sensitization: initial contact with allergen activates immune system to develop memory
elicitation: subsequent re-exposure triggers a complex inflammatory rxn
what are haptens? how do they become activated in allergic contact dermatitis?
unprocessed allergen that need modification to become immunogenic
form hapten-protein complex –> hapten penetrate skin barrier and bind epidermal carrier proteins –> forms complete antigen that can trigger immune response
how is the innate immune system activated in allergic contact dermatitis?
what cytokines do keratinocyte release when theres hapten exposure?
IL-1, IL-8, IL-18
TNFalpha
GM-CSF
which cells uptake the hapten protein complex (“antigen”) and express on surface bound to HLA in allergic contact dermatitis
Langerhans cells (LCs) and dermal dendritic cells
APC migration in allergic contact dermatitis
migrate via lymphs
present HLA-antigen complex (with hapten) to naive T cell
Naive T cell differentiate into memory T cells which expand clonal and aqeuire skin-specific homing antigens and go into circulation and act on cells with antigen in future exposure
sensitization phase in allergic dermatitis lasts how long and sx
The sensitization phase lasts 10–15 days and is typically asymptomatic
elicitation phase in allergic contact dermatitis
subsequent exposure to an allergen that the px is already sensitized to
inflam + TLR activation + nucleotide binding oligomerization domain like receptors
leads to neutrophil then T cell recruitment
what happens when T cells get recruited in allergic contact dermatitis
antigen specific effector T cells go to skin
interact with APCs (PCs and dendritic cells) around post capillary venules
Inducible Skin-Associated Lymphoid Tissue (iSALT) in allergic contact dermatitis elicitation phase
induced by inflammation
what do T cells release to amplify the immune response in allergic contact dermatitis
IFN-y
TNF-a
which then recruit more inflammatory cells, stimulate macrophages, and keratinocytes to release more cytokines
what suppresses the allergic contact dermatitis elicitation phase
regulatory T cells
Las can help develop reg T cells
if px presents with eczematous dermatitis they might have
allergic contact dermatitis
allergic contact dermatitis misconceptions
not alway bilateral even if antigen exposure is bilateral
even if exposure to allergen is uniform the eczematous manifestation can still be patchy
ACD can effect palms and soles
irritant dermatitis if from
wet-to-dry cycling in cold seasons
what is a predisposition to allergic and atopic dermatitis
Innate immune signals from irritant dermatitis
how to help irritant dermatitis
decrease duration and frequency of irritant contact
while allergic contact dermatitis needs complete avoidance
what helps irritant dermatitis
emollients
but emollient on normal skin over long periods of time can cause irritant dermatitis
hardening and sx disappear with continued irritate exposure without treatment
what is it called when sx disappear in irritant dermatitis and prevent progression to allergic or atopic dermatitis
hardening
when does irritant dermatitis manifest and resolve vs allergic contact dermatitis
irritant dermatitis manifests within hours of the causative exposure, and resolves within days of cessation of exposure.
In contrast, allergic contact dermatitis may manifest days after exposure and persist for weeks
dermatitis definition
inflammatory disruption of the epidermis related to physical or immunologic provocation.
dermatitis and ____ are used interchangeably
eczema
histology of dermatitis
spongiosis
dermatitis in general had impairment in what
barrier functions of the skin, which results in increased transepidermal water loss.
irritant dermatitis from
bacteria, yeast, chemicals
combination of factors
I,e, detergent, rubber gloves, candida, malassezia, food, staph
irritant dermatitis is caused by
physical damage to epidermis
severe irritant dermatitis have what type of keratinocytes
necrotic keratinocytes
variables influencing irritant dermatitis
climate and season, occlusion, frequency of exposure to the irritant, and concentration of the irritant
common irritants for irritant dermatitis
solvents including water
detergents
disinfectants
anti-wrinkle medicaments
risk factors for irritant dermatitis
wet work, detergents, gloves occlusion, occupation, water occlusion, solvents
3 steps in irritant dermatitis pathogenesis
- epidermal insult
- danger signals
- potential fro allergic sensitization
atopic dermatitis from what mutatitons
filaggrin
kids will get irritant dermatitis in which areas (which leads to allergic contact dermatitis usually)
flexural areas
step 1- epidermal insult in irritant dermatitis
solvents diminish epidermal barrier and remove lipids or desiccate stratum corneum from repeated rapid drying
genetic- filaggrin mutations lowers threshold to minor friction damaging epidermis
step 2- danger signals in irritant dermatitis
damaged keratinocytes release alarmins (danger signals) (i.e. defensins and uric acid)
alarmins bind TLRs and promote inflammatory pathways like nuclear factor-KB that links to adaptive immune response and leads to allergic dermatitis
step 3- potential for allergic sensitization in irritant dermatitis
chemical allergens and microorganism stimulate innate immune system and TLRs
predispose to allergic contact dermatitis
complications of irritant dermatitis
food allergy
allergic contact dermatitis
seborrheic dermatitis features and location
greasy, scaling patches and plaques appear on scalp, face, ears, chest, and intertriginous areas.
cause of seborrheic dermatitis
abnormal immune mechanism, Malassezia, sebaceous glands, and individual susceptibility.
who is seborrheic dermatitis most common in
adolescent and young adults from hormones increasing sebaceous gland activity
also > 50yoa
3 month of infants
-more in males
-seasonal (cold and dry)
-sun may decrease severity
causes of seborrheic dermatitis
many….
sebaceous glands
immune status (I.e. AIDS and Parkinson, immunosuppressed)
malassezia (antifungals)
seasonal changes and sun
immune system in seborrheic dermatitis
defective CD4+ and CD8+ T cells caused SD in mice
increase IgA and IgG
decrease B cells
increase NK cells
which cytokines in seborrheic dermatitis
IL-1α, IL-1β, IL-4, IL-12, tumor necrosis factor-α, and interferon (IFN)- γ
histamine
dandruff in seborrheic dermatitis
induced inflammatory genes and repressed lipid metabolism genes
oxidative stress
microbe for seborrheic dermatitis
malassezia globosa and malassezia restricta
Pityriasis versicolor and Pityrosporum folliculitis, both induced by Malassezia, are often associated with SD
key features of malazzesia in seborrheic dermatitis
lipase and phospholipase enzymes that make them lipophilic
these enzymes metabolize lipids into fatty acids for fungal cell wall formation
what enzymes in malassezia and their effect in seborrheic dermatitis
lipase and phosphilpase contribute to
invading skin layers
dissemination across affected areas
malassezia furfur effects in seborrheic dermatitis
disrupt protective skin barrier and induce inflammation
malassezin is made by which malassezia and does what in serborrheci dermatitis
what does this receptor do
Malassezin, generated by M. furfur or M. restricta, acts as an agonist to the aryl hydrocarbon receptor (AhR).
AhR: differentiate Th-17 cells and mediate contact sensitivity (TH-17)
what does aryl hydrocarbon receptor (AhR) via malassezia do in seborhhersic dermatitis
differentiate Th-17 cells
what can cause dandruff in susceptible individuals
Oleic acid, produced by Malasseiza globosa lipase
hyper or hypo proliferation in seborrheic dermatitis>
increased epidermal turnover; hyperproliferation
DDX for seborrheic dermatitis
psoriasis
seborrheic dermatitis treatment
here are case reports that keratolytics and antiinflammatory medications were successful in the treatment of the patients with SD whose treatment with amphotericin B had failed.
what might alter epidermis and cause hyperproliferation in seborrheic dermatitis
increased activity of calmodulin
