Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis

Abstract

Background Atopic dermatitis (AD) is classified as extrinsic (ADe) and intrinsic (ADi), representing approximately 80% and 20% of patients, respectively. While sharing a similar clinical phenotype, only ADe is characterized by high serum IgE. Since most AD patients exhibit high IgE, an “allergic”/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly Th2/Th22 polarization, and epidermal barrier defects. Objective To define if both variants share a common pathogenesis. Methods We stratified 51 severe AD patients as ADe (42) and ADi (9) (with similar mean disease activity/SCORAD), and analyzed the molecular and cellular skin pathology of lesional and non-lesional ADi and ADe using gene-expression (RT-PCR) and immunohistochemistry. Results A significant correlation between IgE levels and SCORAD (r=0.76, p<10−5) was found only in ADe. Marked infiltrates of T-cells and dendritic cells and corresponding epidermal alterations (K16, Mki67, S100A7/A8/A9) defined lesional skin of both variants. However, higher activation of all inflammatory axes (including Th2) was detected in ADi, particularly Th17 and Th22-cytokines. Positive correlations between Th17-related molecules and SCORAD were only found in ADi, while only ADe showed positive correlations between SCORAD and Th2-cytokines (IL-4, IL-5), and negative correlations with differentiation products (loricrin, periplakin). Conclusions Although differences in Th17 and Th22 activation exist between ADi and ADe, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a Th2 bias is not the sole cause of high IgE in ADe, with important implications for similar therapeutic interventions. Clinical Implications Both extrinsic and intrinsic AD variants might be treated with T-cell targeted therapeutics or agents that modify keratinocyte responses.

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

“…We have also found increased expression of Defb4, Cxcl1, S100a7, S100a8, and S100a9 in Tg KLK5 skin, which are genes known to be induced by Il 17 and Il 22. A similar inflammatory profile is found in atopic dermatitis in which, in addition to Th2, Th22 and Th17 play important roles in the pathogenesis of the dis ease Suárez Fariñas et al, 2013). These observations support the contribution of Th17 and Th22 cells to skin inflammation in the Tg KLK5 murine model.…”

Contact hypersensitivity to nickel in patients with atopic dermatitis

“…Numerous reports point to a more complex immune response where both Th1 and Th2 lymphocytes play an important role [34,35]. Additionally, the Th17 response [36] and Th2-mediated IL-31 expression in the skin of patients with AD and ACD [37] is what these two dermatoses may have in common.…”

Atopic Dermatitis: New Aspects of Treatment

“…Другое уникальное свой-ство ТИК состоит в том, что с восстановлением барьер-ной функции кожи абсорбция препаратов снижается. В то же время абсорбция мази такролимуса через кожу превышает проникающую способность пимекролимуса в форме крема [5][6][7]. По данным J. Meingassner и соавт., оба ТИК проникали в воспаленную кожу, предвари-тельно обработанную ТГК, в большей степени (до 6 раз интенсивнее) по сравнению со здоровой кожей [8].…”

“…Для обоих патогенетических путей развития АтД дефект эпидермального барьера функции кожи признан наи-более характерным и значимым звеном [1][2][3][4][5]. C другой стороны, не менее сложные иммунологические процессы активации Т лимфоцитов, дисбаланс врожденной и адап-тивной иммунной системы до конца не изучены.…”

“…Во-первых, ученые предложили новую концепцию -т. н. проактив-ную терапию АтД с помощью топического ингибитора кальциневрина (ТИК) такролимуса, что подразумевает его длительное использование. Во-вторых, более чем десяти-летний опыт применения ТИК в клинической практике в сочетании с экспериментальными данными позволяет ученым с высокой долей вероятности считать «закрытым» т. н. черный ящик -риск развития опухолевых болезней, связанный с применением наружных ингибиторов каль-циневрина [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. …”