One of the most typical characteristics of patients with Atopic Dermatitis is dry skin or xerosis.
The xerosis is a consequence of alterations of the epidermal barrier, which, in turn, depend on an altered metabolism of lipids in keratinocytes.
PATHOGENESIS OF XEROSIS
A series of studies in humans and in animal models has clearly demonstrated that alterations of the epidermal barrier, in addition to causing the appearance desquamante dry skin, it is itself cause of inflammation.
Causes of barrier loss
In fact, the keratinocytes increase the production of a series of enzymes involved in lipid synthesis and autocrine growth factors that stimulate cell proliferation, such anfiregulina (AR), nerve growth factor (NGF), transforming growth factor α (TGF-α) and granulocyte / macrophage colony-stimulating factor (GM-CSF). In parallel however, the epidermal cells synthesize and release greater amounts of cytokines and chemokines, including interleukin 1α (IL-1α), IL-1β, IL-6, tumor necrosis factor, and these chemochines can stimulate the synthesis of other chemokynes like TNF-α (TNF -α), IL-8 and RANTES IL-1 lipic;All of these cytokynes and chemokynes, together with GM-CSF and IL-8, are also potent inducers of inflammation .
Moreover, the same cytokines activate mast cells which, in turn, release pro-inflammatory factors. IL-1β, TNF-α and GM-CSF are important for the survival and maturation of Langerhans cells (and usually of all dendritic cells.), mature dendritic cells increases the ability to activate T lymphocytes, acquire migratory capacity, and, in turn, produce pro-inflammatory cytokines and chemokines (RANTES, IP-10, IL-8, Mig).
It is so easly understandable how in the skin of patients with AD vicious circles can be established to encourage the development and persistence of the inflammation and of the allergic reactions. These considerations explain why the apparently healthy skin of patients with AD show histological signs of epidermal hyperplasia and inflammation, and suggest why therapeutic approaches that restore the integrity of the skin barrier may have a preventive and curative significance on the process of inflammation.
Histopathology of acute injury with epidermal spongiosis, exocytosis and lympho-monocyte infiltration in the superficial dermis
Histopathology of chronic lesion with epidermal hyperplasia, minimal spongiosis and inflammatory infiltrate in the superficial dermis
THE ROLE OF ACTIVATED T LIMPHOCYTES
The tendency of atopic keratinocytes to produce increased quantities of growth factors, chemokines and cytokines is particularly important in influencing the activities of dendritic cells, which are the main cells that are able to activate T lymphocytes . The histopathology of the skin lesion of AD shows an inflammatory infiltrate in which predominate activated T lymphocytes , monocytes-macrophages and activated dendritic cells .
Dendritic cells present in these lesions are particularly efficient in presenting allergens to specific T cells, as shows the expression on their surface of elevated levels of high (FcεRI) and low (FcεRII) affinity receptors for IgE. The functional consequence of the expression of these receptors on an increased number of deputies to the antigen-presenting cells in the skin is that the response of lymphocytes in situ with small amounts of allergen is greatly amplified.
Moreover, while acute injuries of the DA are characterized by the predominance of cytokines produced by lymphocytes activated by allergen-specific Th2 type (including IL-4, IL-5 and IL-13), chronic lesions show a significant presence of lymphocytes Th1 able to release IFN-γ.
Acquisitions on the role of chemokines in selective recruitment of inflammatory cells are contributing to a better understanding of the molecular and cellular mechanisms involved articulated in the onset of this disease.
THE ROLE OF EOSINOPHILS AND MACHROFAGES
In acute DA, keratinocytes are also the most important source of macrophage migration inhibitory factor (MIF), a protein factor whose blood concentration reflects the state of disease activity. Through mechanisms not yet identified, MIF contributes to the imbalance in the Th2 direction, characteristic of atopic dermatitis.
In situ hybridization experiments conducted on atopic skin have also shown the appearance in the dermis of mRNA for RANTES and MCP-3 in the hours immediately following intradermal injection dell'allergene trigger. High levels of RANTES protein were measured in lesional skin scales and patients' serum. Finally, patients with AD, but not patients with bronchial asthma, have genetic variants in the promoter region of RANTES gene affecting an exaggerated transcriptional activity and thus increased production of the chemokine itself.
If RANTES is one of the most powerful chemoattractors for eosinophils and T cells, MCP-3 is involved in the attraction of dendritic cells, macrophages and T lymphocytes.
It was demonstrated that IL-4, one of the predominant cytokines in inflamed atopic skin, is an effective stimulus to induce the production of eotaxin and MCP-4 by the fibroblasts of the dermis, and these molecules are potent chemokines to eosinophils.
The skin lesion of atopic dermatitis express high levels of the receptor CCR3: many population of inflammatory cells strongly represented in the atopic lesions, including eosinophils and Th2 cells express CCR3 on their surface.
CCR3 is the receptor for chemokines as eotaxin, RANTES, MCP-3 and MCP-4, whose
expression levels are significantly increased in atopic lesions.
From these observations, we can assume that the use of antagonists of RANTES or MCP-3 / 4 (or their receptors) may represent an effective therapy in atopic dermatitis.