Patofyziologie

Příčiny

• Defekt kožní bariéry se považuje za primární. [6]
• Mutace genů pro
• Filagrin
• Ivolukrin
• Lorikrin [6]
• Mutace vedou k:
• Poruše maturace keratinocytů
• X integrity kožní bariéry
• Změněný profil spektra ceramidů
• Snížené funkci intercelulárních lipidů [6]
• Vysoká koncentrace kožních serinových proteáz
• Předčasné ztrátě soudržnosti keratinocytů a deskvamaci
• Zvýšená náchylnost ke kolonizaci kmeny Staphylococcus aureus [6]
• Kolonizace S. aureus
• Přispívá ke vzniku, intenzitě a udržování atopického zánětu
• K sensibilizaci [6]
• V nepostižené kůži atopiků
• Reziduální, minimální dermatitida vždy přítomna
• Opodstatňuje význam udržovací léčby [6]
• Porušená bariéra
• Vstupní branou pro vznik senzibilizace
• Vývoj atopického zánětu [6]
• Psychogenní složka
• Stresující životní události často předcházejí počátek exacerbace AD (Kodama et al., 1999, Pikardi et al., 2001) [6]
• Psychická zátěž ovlivňuje AD interakcí centrálního nervového systému a imunitního systému [6]
• Kolísání neurotransmiterů v neuroendokrinním a autonomním systému související se stresem
• Ke změně imunologické reaktivity a rozvoji alergického zánětu [6]
• Mohou ovlivňovat rovnováhu epidermální permeabilní bariéry, což následně vede k zánětu a svědění [6]
• Dospělí pacienti s AD jsou více úzkostní a depresivní ve srovnání s kontrolními skupinami (Ehlers et al., 1995, Hashiro a Okumura, 1997) [6]
• Přícina a následek ? Souvislost s metabolismem MK omega-3 ?

Dry, irritable skin

• Reduces the skin's ability to be an effective barrier

A gene variation

• Affects the skin's barrier function

Immune system dysfunction

Bacteria

• Such as Staphylococcus aureus, on the skin
• Creates a film that blocks sweat glands [2]

Environmental conditions

Histopathology

The skin

• Dry
• Greater irritant skin response
• Sparse perivascular T-cell infiltrate in unaffected AD skin [4]
• Not seen in normal healthy skin [4]

Atopické léze

• Marked infiltration of CD41 activated memory T cells in acute AD
• Antigen-presenting cells -APC (v menším rozsahu i v kůži bez lézí)
• Langerhans cells [LCs]
• Inflammatory dendritic epidermal cells [IDECs]
• Macrophages
• Bear IgE molecules [4]
• Mast cell degranulation can be observed [4]

Chronic AD skin lesions

• Tissue remodeling caused by chronic inflammation
• Thickened plaques with increased skin markings (lichenification)
• Increased collagen deposition in the dermis [4]
• Dry fibrotic papules
• Macrophages dominate the dermal mononuclear cell infiltrate
• Eosinophils also contribute to the inflammatory response
• T cells remain present [4]
• In smaller numbers than seen in acute AD [4]

Cytokines and chemokines

• Local tissue expression of proinflammatory cytokines and chemokines

TNF-alfa and IL-1 from resident cells

• From keratinocytes, mast cells, and DCs
• Binds to receptors on the vascular endothelium [4]
• Activating cellular signaling [4]
• Including the nuclear factor (NF) B pathway
• Inducing expression of vascular endothelial cell adhesion molecules
• Extravasation of inflammatory cells [4]
• Once the inflammatory cells have infiltrated into the tissue
• Respond to chemotactic gradients
• Play a central role in defining the nature of the inflammatory infiltrate [4]

The onset of acute AD

• Strongly associated with the production of TH2-produced cytokines [4]

IL-4 a IL-13

• Significantly higher in AD individuals compared with control subjects
• switching to IgE synthesis [4]
• Upregulating expression of adhesion molecules on endothelial cells [4]
• Implicated in the initial phase of tissue inflammation [4]

TH2 cytokine IL-5

• Involved in eosinophil development and survival
• Predominates in the chronic form [4]

GM-CSF

• Increased production is reported to inhibit apoptosis of monocytes
• Contributing to the chronicity - also:
• TH1-like cytokines
• IL-12
• IL-18 [4]
• Remodeling-associated cytokines (in chronic forms of the disease)
• IL-11
• TGF-beta 1 [4]

Increased expression of C-C chemokines

• monocyte chemoattractant protein 4
• eotaxin
• RANTES [4]

• Contributes to infiltration into acute and chronic AD skin lesions:
• Macrophages
• Eosinophils
• T cells [4]

Cutaneous T cell–attracting chemokine (CCL27)

• Highly upregulated in AD
• Preferentially attracts cutaneous lymphocyte antigen–positive T cells into the skin [4]

Selective recruitment of CCR4-expressing TH2 cells

• Mediated by macrophage-derived chemokine, thymus and activation-regulated cytokine
• Increased in patients with AD
• Severity of AD linked to magnitude of thymus and activation-regulated cytokine levels [4]

TH1 cell migration toward the epidermis

• Strongly upregulated in keratinocytes
• Fractalkine
• IFN-gamma–inducible protein 10

IgE and IgE receptors

• Cca 80% of adult patients with AD IgE levels >150 kU/L
• sensitization against aeroallergens and food allergens
• Concomitant allergic rhinitis and asthma
• 20% of adult patients with AD have normal serum IgE levels
• Often has a late onset (>20 years of life)
• Lack of IgE sensitization against inhalant or food allergens
• Might have IgE sensitization against microbial antigens
• Staphylococcus aureus enterotoxins
• Candida albicans
• Malassezia sympodialis - Pityrosporum ovale
• Some have positive reactions on the atopy patch test (APT)

Transient form of AD

• Low IgE serum levels in children
• Without any detectable sensitizations
• Develops into the extrinsic variant of AD with increasing IgE serum levels
• Developing sensitizations against aeroallergens and food allergens later in life [4]

Expression of IgE receptors

• high-affinity receptor for IgE [Fc RI]
• Can be found in the epidermal skin lesions
• Higher IgE-binding capacity of DCs in the skin and in the peripheral blood of patients with AD
• Fc RI is regulated distinctly on DCs of atopic and non-atopic subjects [4]

Skin barrier dysfunction

• dry skin
• Even involving nonlesional skin [4]
• Increased transepidermal water loss
• reduced content of ceramides in the cornified envelope of both lesional and nonlesional skin
• Major water-retaining molecules in the extracellular space of the cornified envelope [4]
• Matrix of structural proteins
• Bound to ceramides [4]
• Changes in stratum corneum pH levels
• Might impair lipid metabolism in the skin
• Overexpression of stratum corneum chymotryptic enzyme
• Likely to contribute to the breakdown of the AD epidermal barrier [4]
• Penetration of irritants and allergens
• Trigger an inflammatory response
• Contributing to the cutaneous hyperreactivity [4]

T cells

• Key role of immune effector
• Primary T-cell immunodeficiency disorders frequently have increased serum IgE levels and eczematous skin lesions
• Disappear after successful bone marrow transplantation [4]
• In animal models of AD, the eczematous rash does not occur in the absence of T cells
• treatment with topical calcineurin inhibitors (TCIs)
• Specifically target activated T cells
• Significantly reduces the clinical skin rash present in AD [4]

TH1 and TH2 play

• Transgenic mice with overexpress IL-4 in their skin
• Inflammatory pruritic skin lesions similar to those seen in patients with AD
• Local skin expression of TH2 cytokines may be a critical role in AD [4]
• Allergen-sensitized skin from IL-5–deficient mice
• no detectable eosinophils
• Decreased thickening [4]
• Skin from IL-4–deficient mice
• Normal thickening of the skin layers
• Reduction in eosinophil counts [4]
• Patients with AD
• activated T cells with skin-homing properties
• Express high levels of IFN-gama
• Predominantly undergo apoptosis in the circulation
• Skewing the immune response to surviving TH2 cells
• In the affected skin these T cells switch on effector cytokines
• Induce the activation and apoptosis of keratinocytes [4]
• T regulatory (TReg) cells
• Further subtype of T cells
• Immunosuppressive function
• Cytokine profiles distinct from those of either TH1 or TH2
• Able to inhibit the development of both TH1 and TH2 responses
• Mutations in a nuclear factor expressed in TReg cells, Foxp3
• Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome
• Hyper-IgE
• Food allergy
• Eczema [4]
• staphylococcal superantigens
• Subvert TReg cell function
• Might thereby augment skin inflammation [4]

DCs

• Two types of Fc RI-bearing myeloid DCs
• Found in the lesional skin
• LCs and IDECs [4]

LCs

• Predominant role in the initiation of the allergic immune response
• Prime naive T cells into T cells of the TH2 type with high IL-4–producing capacity
• Predominate in the initial phase of AD
• Stimulation of Fc RI on the surface of LCs by allergens
• Induces the release of chemotactic signals
• Recruitment of precursor cells of IDECs and T cells in vitro [4]

IDECs

• Stimulation of Fc RI on IDECs leads to
• Release of high amounts of proinflammatory signals
• Contribute to the amplification of the allergic immune response [4]

Plasmacytoid DCs (pDCs)

• In contrast to other inflammatory skin diseases
• Allergic contact dermatitis
• Psoriasis vulgaris
• only very low numbers
• Major role in the defense against viral infections
• PDCs in the peripheral blood of patients with AD
• Bear the trimeric variant of Fc RI on their cell surface
• Occupied with IgE molecules
• Modified immune function of pDCs in patients with AD after Fc RI-mediated allergen stimulation might contribute to
• The deficiency of pDCs in patients with AD
• Produce type I IFNs
• High susceptibility of patients with AD toward viral skin infections
• Herpes simplex–induced eczema herpeticum [4]
• Undergoing apoptosis
• Spongioform morphology in the epidermis
• Hallmark of eczematous lesions
• Suppression of keratinocyte activation and apoptosis
• Potential target for the treatment of AD [4]

Eosinophils

• Major role in AD
• activated eosinophils in the peripheral blood and in the lesional skin
• Psychosocial stress
• Important trigger for the increase of eosinophil counts in the peripheral blood [4]
• Inhibition of eosinophil apoptosis in AD
• Autocrine release of IL-5 and GM-CSF
• Recruited to, and activated at, tissue sites by TH2 cytokines
• IL-5
• IL-13 [4]
• Chemokines (eotaxin and RANTES)
• Contribute to eosinophil chemotaxis and activation
• eosinophil extravasation and activation
• Eosinophil surface molecules
• Endothelial cells vascular cell adhesion molecule 1
• Intercellular adhesion molecule 1 [4]
• switching the TH1 response in AD
• Production of significant amounts of IL-12 on activation
• Activated
• Releasing an armory of potent cytotoxic granule proteins and chemical mediators
• Role in neuroimmunologic interactions

Pathophysiology of pruritus in AD

• Mediátory pruritu
• Zároveň mediátory zánětu i vazoaktivními látkami
• Působí na volná nervová zakončení
• Mohou vyvolávat až pocity bolesti [6]
• Reduced threshold for pruritus
• Cutaneous hyperreactivity
• Scratching after exposure to allergens, changes in humidity, excessive sweating, and low concentrations of irritants
• Usually worse at night
• Frequently disrupting the patient's sleep and overall quality of life
• Allergen-induced release of histamine from skin mast cells
• Not an exclusive cause of pruritus in AD
• Antihistamines are not effective in controlling the itch of AD unless there is associated urticaria
• TCIs and corticosteroids
• Effective at reducing pruritus
• Inflammatory cells play an important role in driving pruritus
• Cytokines
• Neuropeptides
• Proteases
• Eicosanoids
• Eosinophil-derived proteins

Dysbalance of skin microbiota

Resident flora

• Constantly present on body surfaces
• May prevent colonization by pathogens and possible disease
• Restoring the ecological skin niches [16]

Commensal microorganisms

• Mutualistic symbiosis
• Contribute to human health and welfare
• Production of defense molecules
• Natural antibiotics [16]

Transient skin flora

• Temporarily colonize the skin
• Unable to remain in the body for a long period of time
• Due to competition from resident microbes [16]

Meconium microbes

Presence of enterobacteria

• Associated with a history of atopic eczema in the mother [16]

Presence of lactobacilli

• Was associated with respiratory disorders in the baby [16]

Infant skin microbiome

• Different from that of an adult
• Differences in skin structure and function [16]
• Early colonization is dominated by Staphylococci
• Stratum corneum is better hydrated than that of an adult
• Site specific [16]
• Firmicutes
• Predominate on infant skin [16]
• Similar to an adult organism by the age of 12–18 months [16]

Kožní oblasti a různá mikroflora

• Density of sebaceous glands
• Dry, moist, or sebaceous

High density of sebaceous glands

• Face, chest, and back
• Encourage the growth of lipophilic microorganisms [16]
• Near the top of hair follicles - sebum
• Promotes the growth of facultative anaerobes
• Propionibacterium acnes
• Hydrolyzing the triglycerides present in sebum, releases free fatty acids
• Maintenance of the acidic epidermal pH
• Anoxic environment
• Hosts anaerobic microorganisms
• Cathelicidin LL37
• Defensin (HBD-2)

Eccrine sweat glands - main sweat glands

• water and NaCl
• Natural antibiotic, dermcidin [16]

Apocrine sweat glands

• Larger than eccrine sweat glands
• Underarms (axillae)
• Under the breasts
• Around the nipples
• In the groin and genital region [16]
• Secretions into the hair follicles
• Thick, milky fluid
• Can easily be turned into smelly body odour by germs
• Contains pheromones
• Respond to adrenaline
• Related to sexual attractiveness [16]

Komáři

• Individuals that are highly attractive to Anopheles gambiae s.s.
• Higher abundance, but lower diversity, of bacteria on their skin
• Volatile metabolites released by Staphylococcus spp. are attractive to A. gambiae females [16]

Antimicrobial peptides (AMPs)

Z kůže

• Cathelicidin LL37
• Beta-defensins [16]

AMPs from commensal microbes

-able to increase the production of AMPs by keratinocytes [16]

Staphylococcus epidermidis

• AMPs
• Phenol-soluble modulin (PSM)gamma
• Could be beneficial to the host
• Additional AMPs on normal skin surface [16]
• Exhibited bactericidal activity against skin pathogens
• Staphylococcus aureus
• Group A Streptococcus (GAS)
• Escherichia coli [16]
• Gram-positive bacterium
• More than 90% of the aerobic resident flora
• Mutualistic organism
• Many strains of S. epidermidis produce lantibiotics
• Lanthionine containing antibacterial peptides
• Bacteriocins
• Epidermin
• Epilancin K7
• Epilancin 15X
• Pep5
• Staphylococcin 1580 [16]
• Host-bacterium relationship one of mutualism
• Produce antibacterial peptides that amplify the keratinocyte response to pathogens via TLR2
• Influencing the innate immune response of keratinocytes through Toll-like receptors (TLRs) signaling
• Activation of TLR-2 by S. epidermidis
• Enhances the expression of tight junctions [16]
• Decreases the production of proinflammatory cytokines via TLR3 in the keratinocyte cultures [16]
• Keratinocytes are able to respond more effectively and efficiently to pathogenic insults [16]
• Colonization of body surfaces (especially in the nose) by S. epidermidis
• Impairs the establishment of S. aureus [16]
• Two different strains of S. epidermidis
• Strain JK16
• Inhibits biofilm formation by S. aureus
• Esp-secreting S. epidermidis
• Eliminates S. aureus nasal colonization [16]
• serine protease Esp inhibits biofilm formation and nasal colonization by S. aureus
• Correlates with the absence of S. aureus [16]
• Destroys preexisting S. aureus biofilms [16]
• Enhances the susceptibility of S. aureus in biofilms to immune system components through human beta-defensin-2 (hBD2) [16]
• Strain JK11
• Noninhibitory type

S. aureus

• Nonmotile
• Nonspore forming
• Catalase and coagulase positive
• Typical colonies
• Yellow to golden yellow
• Smooth, entire, slightly raised
• Hemolytic on 5% sheep blood agar [16]
• Extremely prevalent in people with atopic dermatitis.
• Predominantly localized in the anterior nares (vestibulum nasi)
• 20% of individuals are persistent S. aureus carriers
• 60% are intermittent carriers
• 20% are persistent noncarriers [16]
• Activates local inflammatory processes through the release of delta-toxin [16]
• There is a strong association between worsening disease severity and lower skin bacterial diversity [16]
• S. aureus is observed during disease flares [16]
• Increases in the proportion of Staphylococcus and reductions in microbial diversity precede the worsening of AD disease severity as observed in no-treatment flares [16]

Glucocorticoid receptor (GR) gene polymorphisms

• Associated also with variation in glucocorticoid sensitivity
• Changes in glucocorticoid sensitivity
• May predispose to or protect from microbial colonization or infection
• Novel environmental factor can influence
• The ability of S. aureus to bind to nasal mucosa
• Biocide triclosan
• Commonly found in the nasal secretions of healthy adults
• Presence of triclosan has a positive trend with nasal colonization by S. aureus [16]

Imunita kůže a Th2 reakce

• Microorganisms are recognized by innate immune receptors such as Toll-like receptors on the keratinocyte surface
• Keratinocytes produce antimicrobial molecules
• HBD-2, HBD-3, and NO
• IL-8 (neutrophil chemokine) is also produced
• Drive neutrophils from the bone marrow pool into inflamed skin [16]
• In a Th2 environment
• IL-4 and IL-13
• Induce the phosphorylation of STAT6
• Inhibits INF-gamma and TNF-alpha
• Inhibits the production of HBD-2 and HBD-3
• Reduction of IL-8
• Defective neutrophil accumulation in the skin
• Contribute to allowing microbes to grow in the Th2 environment of AD skin [16]

Allergic immune reactions

• Globally attenuated
• Differentially polarized in patients with AD
• Significant decreases in levels of TH1 products
• Some increases in levels of TH17 products
• Inconsistent upregulation in levels of TH2 products
• The overall hyporesponsiveness in skin from patients with background AD might be explained
• Baseline immune abnormalities
• Increased TH2, TH17
• Negative regulator levels

AD kontra psoriaza

• T-cell infiltration characterizes both diseases
• T-cell polarization differs
• Psoriasis
• IL-23/TH17 polarized
• AD
• Testing of targeted therapeutics against various immune axes
• TH2, TH22, and IL-23/TH17 [18]

Triggers of AD

Stress-induced immunomodulation - neuroimmunologic factors

• Epidermal nerve fibers in close association with epidermal LCs-
• neuropeptides
• Increased levels in the plasma:
• nerve growth factor
• substance P
• Correlate positively with the disease activity
• brain-derived growth factor
• Reduce eosinophil apoptosis
• Enhancing chemotaxis of eosinophils in vitro [4]

Allergens

Food allergens

• Can induce eczematoid skin rashes in a subset of infants and children with AD
• Positive immediate skin test responses
• Or serum IgE directed to various foods, particularly:
• Egg
• Milk
• Wheat
• Soy
• Peanut [4]
• Food allergen– specific T cells
• Cloned from the skin lesions
• Direct evidence [4]
• Food can exacerbate AD
• Through allergic
• Nonallergic hypersensitivity reactions [4]
• Direct contact with the skin
• Preparation of meals or when feeding infants
• Might be an important factor for the aggravation of eczema [4]

Aeroallergens

• Pruritus and skin lesions after intranasal or bronchial inhalation
• Epicutaneous application of
• House dust mites, weeds, animal danders, and molds, Dermatophagoides pteronyssinus (Der p 1)
• Eczematoid reactions in a subset of patients
• Effective house dust mite reduction measures has been reported to improve AD [4]

Microorganisms

• Colonized with S. aureus
• Exacerbation of their skin disease after infection with this organism
• Antistaphylococcal antibiotics can result in reduction of skin disease
• Secreting toxins called superantigens
• Stimulate activation of T cells and macrophages [4]
• Most patients with AD make specific IgE antibodies directed against staphylococcal superantigens
• Correlate with skin disease severity [4]
• Superantigens
• Induce corticosteroid resistance [4]
• Deficient in antimicrobial peptides needed for host defense against bacteria, fungi, and viruses
• Underexpressed
• Because of the upregulation of TH2 cytokines [4]
• lower levels of proinflammatory cytokines, such as TNF-alfa and IFN-gamma
• Increased susceptibility to skin infections [4]
• Disseminated infections with herpes simplex or vaccinia virus
• Susceptibility to severe viral infections
• Smallpox vaccination is contraindicated in patients with AD unless there is imminent danger of exposure to smallpox [4]

Binding of S. aureus to skin

• Enhanced by AD skin inflammation
• Treatment with topical corticosteroids or tacrolimus reduces S. aureus counts in AD [4]

Yeasts

• Opportunistic yeast Malassezia species
• Contributing factor in AD
• Presence of specific serum IgE
• Positive skin prick test (SPT) response
• Positive APT response against Malassezia species in adults with AD [4]
• IgE sensitization to Malassezia species
• Specific for patients with AD [4]
• Not seen in patients with asthma or allergic rhinitis [4]

Autoantigens

• Autoreactivity of patients with AD to human proteins
• IgE against autoantigens could stimulate type 1 hypersensitivity reactions and DCs
• Induce the proliferation of autoreactive T cells
• IgE against manganese superoxide dismutase (MnSOD) from the skin-colonizing yeast M sympodialis cross-reacts with human MnSOD
• Patients reacting to human MnSOD were sensitized against the M sympodialis MnSOD
• Sensitization most likely occurs primarily by exposure to the environmental fungal MnSOD [4]

Irritant factors

• Rough or woolly clothing
• Mechanical irritation [4]
• Chemical irritants [4]