Skin contact irritation conditions the development and severity of allergic contact dermatitis.

Irritant contact dermatitis (ICD) is a frequent inflammatory skin disease induced by skin contact with low molecular weight chemicals such as haptens endowed with proinflammatory properties. Allergic contact dermatitis (ACD) is a frequent complication of ICD and is mediated by hapten-specific T cells primed in lymph nodes by skin emigrating dendritic cells. The aim of this study was to analyze the relationship between ICD and ACD to 2,4-dinitrofluorobenezene (DNFB) in C57BL/6 and BALB/C mice, which develop a severe and a moderate skin inflammation, respectively. Upon a single skin painting with DNFB, C57BL/6 developed within hours a more severe dose-dependent ICD response as compared to BALB/C mice, which was associated with enhanced upregulation of IL-1beta, IL-6, and IL-10. Skin exposure to a low dose of DNFB resulted, in both strains, in a low ICD that resolved in a few hours. Alternatively, skin painting with either an intermediate or a high DNFB concentration induced an ICD that subsequently gave rise to an ACD reaction whose intensity was proportional to the magnitude of the ICD response and was more severe in C57BL/6 mice than in BALB/C mice. In conclusion, the hapten-induced skin contact irritation conditions the development and the severity of ACD.

CD8+ T cells are effector cells of contact dermatitis to common skin allergens in mice.

Allergic contact dermatitis (ACD) to strong experimental haptens is mediated by specific CD8+ T cells. Here, we show that similar mechanisms occur for weak haptens, which comprise the vast majority of chemicals responsible for human ACD. We used a model of ACD, that is, the contact hypersensitivity reaction, to test for the allergenicity of three weak haptens involved in fragrance allergy. ACD to weak haptens could not be induced in normal mice. In contrast, mice acutely depleted in CD4+ T cells developed a typical ACD reaction to the three weak fragrance allergens that peaked 24 hours after challenge. Priming of CD8+ T cells was observed in draining lymph nodes 5 days after sensitization and development of ACD was associated with the infiltration of activated CD8+ T cells in the challenged skin. CD8+ T cells were effectors of the ACD reaction as in vivo treatment with depleting anti-CD8 mAbs abrogated the ACD responses and as purified CD8+ T cells could adoptively transfer ACD to naive recipients. In conclusion, our data demonstrate a dominant role of CD8+ T cells as initiators of ACD to weak haptens, and suggest that CD8+ T cells may represent potential targets for preventing or treating ACD.

[Allergic contact dermatitis: how to re-induce tolerance?]. / Eczéma allergique de contact: comment ré-induire une tolérance?

Allergic contact dermatitis (ACD) is a skin inflammatory disease mediated by activation of CD8+ cytotoxic T cells specific for haptens in contact with the skin. CD4+ T cells behave as both regulatory and tolerogenic cells since they down-regulate the skin inflammation in patients with ACD (regulation) and prevent the development of eczema (tolerance) in normal individuals. Thus, ACD corresponds to a breakdown of immune tolerance to haptens in contact with the skin. Several regulatory CD4+ T cell subsets (Treg), especially CD4+CD25+ natural Treg cells, are involved in immunological tolerance and regulation to haptens through the production of the immunosuppressive cytokines IL-10 and TGF-beta. Ongoing strategies to re-induce immune tolerance to haptens in patients with eczema include improvement of existing methods of tolerance induction (oral tolerance, low dose tolerance, allergen-specific immunotherapy, UV-induced tolerance) as well as development of new drugs able to activate IL-10 producing Treg cells in vivo. Ongoing and future progress in this area will open up new avenues for treatment of eczema and more generally autoimmune and allergic diseases resulting from a breakdown of tolerance to autoantigens and allergens, respectively.

Fisiopatologia da dermatite de contato alérgica: papel das células T CD8 efetoras e das células T CD4 regulatórias / Update on the pathophysiology with special emphasis on CD8 effector T cells and CD4 regulatory T cells

A dermatite de contato alérgica (DCA), também conhecida como hipersensibilidade de contato (HSC) é uma das dermatoses inflamatórias mais freqüentes, sendo caracterizada por eritema, pápulas e vesículas, seguidas de ressecamento e descamação. A DCA é induzida pelo contato da pele com substâncias químicas não protéicas denominadas haptenos, e corresponde a uma reação de hipersensibilidade cutânea do tipo tardio, mediada por células T hapteno-específicas. Durante a fase de sensibilização, tanto os precursores de células T CD4+ quanto os de CD8+ são ativados nos linfonodos de drenagem através da apresentação de peptídeos conjugados a haptenos pelas células dendríticas (CD) da pele. A subseqüente exposição de pele ao hapteno em um local a distância induz o recrutamento e ativação de células T específicas no local de provocação, levando à apoptose dos queratinócitos, recrutamento de células inflamatórias e desenvolvimento de sintomas clínicos. Estudos experimentais dos últimos 10 anos demonstraram que, em respostas normais de HSC a haptenos fortes, as células T CD8+ do tipo 1 são efetoras da HSC através de citotoxicidade e produção de IFNgama, enquanto que as células T CD4+ são dotadas de funções de regulação negativa. Estas últimas podem corresponder à população de células T regulatórias CD4+ CD25+ recentemente descritas. Entretanto, em algumas situações, especialmente naquelas em que há um pool deficiente de células T CD8, as células T CD4+ podem ser efetoras da HSC. Estudos em andamento deverão confirmar que a fisiopatologia da DCA em humanos é semelhante à HSC em camundongos, e que a resposta de HSC a haptenos fracos comuns, mais freqüentemente envolvidos na DCA em humanos, é semelhante à descrita para haptenos fortes.

Deficient contact hypersensitivity reaction in CD4-/- mice is because of impaired hapten-specific CD8+ T cell functions.

Mice deficient in the CD4 molecule (CD4-/-) are widely used to evaluate the requirement for CD4+ T cell help in viral, tumoral, and transplantation immunity. Previous studies, showing that CD4-/- mice develop impaired contact hypersensitivity (CHS) responses, have suggested that CD4+ T cells are required for the optimal induction of this skin inflammatory reaction. other studies have, however, demonstrated that CHS was mediated by CD8+ T cells, without the need for CD4+ T cell help. Here, we show that CD4-/- mice develop a normal delayed-type hypersensitivity response to protein antigen, which is mediated by major histocompatibility molecules class II-restricted CD4-CD8- T cells, but a decreased CHS response to 2,4-dinitro-fluorobenezene. Analysis of the hapten-specific T cell pool demonstrates that priming of CD8+ T cells occurred normally in CD4-/- mice, as assessed by specific proliferative responses and interferon-gamma (IFN-gamma) production of purified CD8+ T cells. Furthermore, CD8+ T cells were able to adoptively transfer a normal CHS reaction. In contrast, total lymph node cells from CD4-/- mice showed decreased IFN-gamma production and diminished specific cytotoxic T lymphocytes (CTL) activity, which could be reversed by in vitro restimulation with hapten-pulsed class II-deficient antigen-presenting cells. These data confirm that class I-restricted CD8+ T cells can fully develop in effectors of CHS in the absence of CD4+ T cell help and suggest that the impaired CHS in CD4-/- mice is because of the presence of a class II-restricted T cell subset, which controls CHS by inhibiting hapten-specific CTL responses.

Contribution of CD4(+ )and CD8(+) T-cells in contact hypersensitivity and allergic contact dermatitis.

Allergic contact dermatitis, also referred to as contact hypersensitivity, is one the most frequent inflammatory skin diseases, and is characterized by redness, papule and vesicles, followed by scaling and dryness. Allergic contact dermatitis is elicited upon skin contact with nonprotein chemicals, haptens, and corresponds to a cutaneous delayed type hypersensitivity reaction, mediated by hapten-specific T-cells. During the sensitization phase, both CD4(+) and CD8(+) T-cell precursors are activated in the draining lymph nodes by presentation of haptenated peptides by skin dendritic cells. Subsequent hapten painting on a remote skin site induces the recruitment and activation of specific T-cells at the site of challenge. This leads to apoptosis of keratinocytes, recruitment of inflammatory cells and development of clinical symptoms. Experimental studies from the last 10 years have demonstrated that, in normal contact hypersensitivity responses to strong haptens, CD8(+) type 1 T-cells are effector cells of contact hypersensitivity through cytotoxicity and interferon-gamma production, while CD4(+) T-cells are endowed with downregulatory functions. The latter may correspond to the recently described CD4(+)CD25(+) regulatory T-cell population. However, in some instances, especially when there is a deficient CD8(+) T-cell pool, CD4(+) T-cells can be effector cells of contact hypersensitivity. Ongoing studies will have to confirm that the pathophysiology of human allergic contact dermatitis is similar to the mouse contact hypersensitivity and that the contact hypersensitivity response to common weak haptens, most frequently involved in human allergic contact dermatitis, is similar to that reported for strong haptens.

Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo.

Psychological stress affects the pathophysiology of infectious, inflammatory, and autoimmune diseases. However, the mechanisms by which stress could modulate immune responses in vivo are poorly understood. In this study, we report that application of a psychological stress before immunization exerts an adjuvant effect on dendritic cell (DC), resulting in increased primary and memory Ag-specific T cell immune responses. Acute stress dramatically enhanced the skin delayed-type hypersensitivity reaction to haptens, which is mediated by CD8(+) CTLs. This effect was due to increased migration of skin DCs, resulting in augmented CD8(+) T cell priming in draining lymph nodes and enhanced recruitment of CD8(+) T cell effectors in the skin upon challenge. This adjuvant effect of stress was mediated by norepinephrine (NE), but not corticosteroids, as demonstrated by normalization of the skin delayed-type hypersensitivity reaction and DC migratory properties following selective depletion of NE. These results suggest that release of NE by sympathetic nerve termini during a psychological stress exerts an adjuvant effect on DC by promoting enhanced migration to lymph nodes, resulting in increased Ag-specific T cell responses. Our findings may open new ways in the treatment of inflammatory diseases, e.g., psoriasis, allergic contact dermatitis, and atopic dermatitis.