Immunologiczne ścieżki rozwoju zmian skórnych u chorych na AZS

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Tabela 2. Wzajemne zależności pomiędzy zaburzeniami immunologicznymi oraz strukturalnymi w obrębie bariery naskórkowej u chorych na AZS

W przypadku chorych na AZS o wysokich stężeniach surowiczej IgE w obrębie skóry niezmienionej chorobowo obserwuje się selektywną ekspansję limfocytów Th2 o lokalizacji okołonaczyniowej (tabela 2).[64] Ostre, naciekowe zmiany skórne charakteryzuje aktywacja komórek Th2, Th22 oraz Th17, czego wyrazem jest synteza i uwalnianie cytokin prozapalnych, typowych dla tych linii komórkowych. Równocześnie dochodzi do rozwoju odpowiedzi naskórkowej (S100), wyrażonej wybitnie wzmocnioną ekspresją genów S100A (S100A7-9), które są częścią prozapalnego kompleksu różnicowania naskórka, co jak wiadomo, podlega regulacji cytokinowej (IL-22 oraz IL-17).[74] Natomiast w przypadku chorych o przewlekłym przebiegu AZS aktywacja typu Th2 i Th22 przebiega równocześnie z istotnym elementem Th1-zależnym, przy czym nie obserwuje się „kompletnego przełączenia” w kierunku Th1.[17] Pomimo że profil cytokinowy typu Th2 rejestrowany jest nadal w fazie przewlekłego stanu zapalnego w AZS, typowy jest wzrost stężenia IFN-γ odpowiedzialnego m.in. za apoptozę keratynocytów.[70]

Na przestrzeni ostatniej dekady stwierdzono, że cytokiny Th2- i Th22-zależne w istotnym zakresie modulują barierę naskórkową w AZS, w tym ograniczają różnicowanie keratynocytów, hiperplazję, apoptozę keratynocytów oraz syntezę białek przeciwdrobnoustrojowych.[39-41,50,71-74]

Do działań niepożądanych cytokin należą:

  • hamowanie genów dla białek końcowego różnicowania keratynocytów (np. FLG, lorykryna, inwolukryna) poprzez cytokiny profilu Th2 (IL-4, IL-13 oraz IL-31) oraz cytokiny profilu Th22/IL-22,
  • hamowanie syntezy białek przeciwdrobnoustrojowych przez cytokiny profilu Th2 (IL-4, IL-13),
  • wzmocnienie S100As przez IL-17 i IL-22,
  • wzmocnienie hiperplazji naskórka przez cytokiny profilu Th22/IL-22.[69]


Aktywność procesu chorobowego u pacjentów z AZS (ocena w skali SCORAD) pozostaje w dodatniej korelacji z ekspresją mediatorów o charakterze Th2 oraz Th22 w obrębie zapalnych zmian skórnych oraz w zależności ujemnej z markerami różnicowania końcowego keratynocytów.[62,71-74] Pomimo że aktywacja immunologiczna w obrębie zapalnych zmian skórnych jest istotnie wyższa w porównaniu ze skórą niezmienioną w AZS, ekspresja szerokiego zakresu genów różnicowania naskórkowego (czyli lorykryna, periplakina oraz inwolukryna wraz z filagryną) charakteryzuje zarówno skórę objętą procesem chorobowym, jak i pozornie zdrową. Ponieważ cytokiny profilu Th2 (IL-4/IL-13), jak też Th22 (IL-22) mają zdolność hamowania ekspresji produktów końcowego różnicowania keratynocytów, podwyższone stężenie krążących cytokin o wspomnianym profilu może warunkować ograniczenie ekspresji białek bariery naskórkowej, jak też podwyższać stężenie S10As, które obserwowane jest w momencie rozwoju ostrych, zapalnych zmian skórnych.[17]

Zatem nadal pozostaje wiele elementów niejasnych i co prawda możliwych do logicznej interpretacji, ale dylematem pozostaje pytanie, czy interpretacja ta jest faktycznie prawidłowa.

ABSTRACT
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. It often precedes the development of food allergy and asthma.
Recent insights into AD reveal abnormalities in terminal differentiation of the epidermal epithelium leading to a defective stratum corneum that allows enhanced allergen penetration and systemic IgE-sensitization. Atopic skin is also predisposed to colonization or infection by pathogenic microbes, most notably Staphylococcus aureus and herpes simplex virus. The causes of this abnormal skin barrier in AD are complex and driven by a combination of genetic, environmental and immunologic factors. These factors likely account for heterogeneity of AD onset, severity and natural history of the disease.
Recent studies suggest that prevention of AD can be achieved through early intervention to protect the skin barrier. Onset of lesional AD requires effective control of local and systemic immune activation for optimal therapeutic strategy. Early intervention might improve long-term outcomes for AD and reduce the systemic allergen sensitization that leads to associated allergic diseases in the gastrointestinal and respiratory tract.

KEYWORDS: atopic dermatitis, eczema, epidermis, immune system, infection, filaggrin.

Zdjęcia: archiwum prywatne (2)

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