Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines.

Abstract

Introduction Psoriasis is a common, well-defined skin disease featuring the interplay of genetic, environmental, and immunological factors (1). Psoriasis is listed among other chronic diseases believed to be of autoimmune origin, such as multiple sclerosis (2). While it shares clinical features with multiple sclerosis such as spontaneous remissions and exacerbations, the cellular and molecular basis for targeting T cell involvement in the skin remains unknown (2). Unlike multiple sclerosis in which a specific "antigen" has been identified (i.e., myelin basic protein) and a reproducible animal model exists (i.e., experimental allergic encephalitis), psoriasis research has been hampered by the absence of an identifiable self-antigen or animal model. Perhaps the strongest evidence supporting an autoimmune basis for psoriasis are reports that eradication of a psoriatic patient's bone marrow, and replacement with a genetically different nonpsoriatic donor, can completely cure the skin lesions (3, 4).The predominant investigative pathway into autoimmunity and psoriasis has primarily been in the direction of studies of T lymphocytes (5-7), with little or no regard for the potential importance of the antigen-presenting cell populations in the dermis that possess a dendritic morphology. Members of the dendritic cell system possess an extremely potent capacity to stimulate resting T cell proliferation and cytokine release (8)(9)(10). Rather than focusing on T cells, we asked whether dendritic cells isolated from skin of active untreated psoriatic lesions possess the capability of stimulating resting, autologous peripheral blood T cells. Dermal dendritic cells (DDCs)' are increased in psoriatic lesions (11, 12), and we pointed out previously the potential importance of dendritic cell/T cell interaction in the pathophysiology of psoriasis ( 13). To determine whether psoriatic plaque (PP) DDCs possessed the capacity to stimulate spontaneous proliferation of autologous T cells, a method for isolating DDCs from both PP and normal skin (NN) was devised. Comparisons were made between such skin-derived as well as psoriatic blood-derived dendritic cells in autologous T cell proliferation assays measured with and without the addition of other T cell mitogenic stimuli such as bacterialderived superantigens (SA) (staphylococcal enterotoxins A and B) and PHA. Studies involving superantigens were included because bacterial infections are frequent triggering factors for psoriatic lesion formation, and superantigens have been implicated in the pathogenesis of psoriasis ( 1,14). Our data indicate that PP DDCs do possess a potent autostimulatory capacity to induce proliferation of resting T cells which is mediated by involvement of HLA-DR, B7, and lymphocyte function associated antigen-I (LFA-1) molecules and associated with high 1. Abbreviations used in this paper: DDCs, dermal dendritic cells; LFA-1, lymphocyte function associated antigen-l; NN, normal skin; PP, psoriatic plaques; SA, superantigens.

CD56brightCD16– NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation

“…In addition, activated NK cells are cytotoxic for immature but not mature dendritic cells, thus providing a critical checkpoint for induction of efficient immune responses. Dendritic cells are greatly increased in number in psoriatic skin [57][58][59][60][61]. In addition, psoriatic dendritic cells display maturation markers, such as abundant MHC class II, CD86 and CD83 [60,61].…”

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

“…Research using AGR129 mice demonstrated that retained T cells in tissue uninvolved by psoriasis could proliferate, leading eventually to the development of psoriatic plaques (8). Studies demonstrating increased activity of lesional APCs (9,10), their apposition to psoriatic T cells undergoing activation (2), their reduction during cyclosporine A therapy (11), and the efficacy of intralesional cyclosporine A (12) all attest to the ongoing and critical role of intralesional T cell activation.…”

Monomethylfumarate affects polarization of monocyte‐derived dendritic cells resulting in down‐regulated Th1 lymphocyte responses

“…T cells producing type-1 cytokines, like IFN-+ and IL-2, predominate in these skin lesions [1,2] and most likely the majority of DC in these lesions are of the type that promotes Th1-mediated immune responses.…”

“…Insight into the role of DC in psoriasis [1] led to the suggestion that FAE may influence DC differentiation and/or maturation. In this connection, Zhu et al [13] recently showed that both DMF and MMF dose-dependently inhibited the in vitro differentiation of monocytes into immature (i)DC via, at least in the case of DMF, the induction of apoptosis.…”