Impaired Responses of Peripheral Blood Mononuclear Cells to Staphylococcal Superantigen in Patients with Severe Atopic Dermatitis: A Role of T Cell Apoptosis

Abstract

Staphylococcus aureus colonization is an almost universal feature of atopic dermatitis. In order to investigate the role of staphylococcal enterotoxin B in the pathogenesis of atopic dermatitis, we assessed the correlation between clinical disease severity and proliferative response of peripheral blood mononuclear cells to staphylococcal enterotoxin B in patients with atopic dermatitis. Peripheral blood mononuclear cells from patients with mild atopic dermatitis showed significantly increased proliferative responses to staphylococcal enterotoxin B compared to controls. In contrast, peripheral blood mononuclear cells from patients with severe atopic dermatitis showed markedly suppressed proliferative responses. Additionally, longitudinal evaluation of peripheral blood mononuclear cell samples from the same patient demonstrated that proliferative responses were suppressed only at times of severe disease exacerbation. Mixing experiments, using autologous T cells and antigen presenting cells that were isolated at different time points from the same patient, demonstrated that T cells of severe atopic dermatitis patients were dysfunctional, but their antigen presenting cell function remained intact. We found no significant differences of interleukin-2 levels in the culture supernatants between healthy controls and atopic dermatitis groups. Fluorescence-activated cell sorter analysis for APO2.7 antigen, an early apoptosis cell marker, demonstrated that approximately 60% of staphylococcal-enterotoxin-B-stimulated T cells expressed APO2.7 antigen in severe atopic dermatitis cases. By contrast, 5%-20% of T cells expressed APO2.7 after staphylococcal enterotoxin B stimulation in cases of mild atopic dermatitis and in healthy controls. Nuclear staining with Hoechst 33258 also showed approximately 40% apoptotic cells in the CD19-CD16-PBMC of severe atopic dermatitis patients, compared with only 5%-10% in the mild atopic dermatitis group and in healthy controls. Blocking monoclonal antibody to Fas ligand partially prevented the staphylococcal-enterotoxin-B-induced apoptosis detected by APO2.7 expression and Hoechst 33258 staining. Suppressed proliferation of peripheral blood mononuclear cells in severe atopic dermatitis patients may be secondary to T cell death by apoptosis. These results suggest that an infection of S. aureus producing staphylococcal enterotoxin B may play a role in aggravation of atopic dermatitis by inducing apoptosis in T cells.

The Role of Immune Response to <i>Staphylococcus aureus </i>Superantigens and Disease Severity in Relation to the Sensitivity to Tacrolimus in Atopic Dermatitis

“…On the other hand, Yoshino et al [29 ]assessed the correlation between clinical disease severity and proliferative response of PBMCs to SEB in vitro in AD. They found that PBMCs from their severe patients showed a markedly suppressed proliferative response to SEB.…”

Staphylococcal Enterotoxin B Upregulates Fas‐Mediated Apoptosis of Peripheral Blood Mononuclear Cells in Childhood Atopic Dermatitis

“…Recently, Akdis et al [9] reported that dysregulated apoptosis of effector cells plays a role in the pathogenesis of AD, with these mechanisms involving increased eosinophil survival, T-cell induced keratinocyte apoptosis and different T-cell lifespan in the peripheral blood and skin as a result of the intralesional cytokine microenvironment. Yoshino et al [10] also suggested that an infection of S. aureus, producing SEB, might play a role in the aggravation of AD by inducing apoptosis in T cells.…”

"Avaliação da resposta proliferativa das células mononucleares do sangue periférico às enterotoxinas A e B do Staphylococcus aureus e dos níveis de interleucina-18 na dermatite atópica do adulto"

“…Além disto, tem sido evidenciado que SEB induz uma supressão da resposta proliferativa nas PBMC de doentes atópicos, associada a uma diminuição na secreção de IFN-γ e aumento da produção de IL-4 (Yudate et al, 1996;Tanaka et al, 1996;Campbell, Kemp, 1997;Yoshino et al, 2000). A persistência do S. aureus na pele poderia contribuir com a inflamação da mesma, causando ativação contínua de células T e macrófagos.…”

“…Devido à grande variabilidade de doses utilizadas nos vários ensaios de proliferação encontrados na literatura, houve necessidade de realizar uma curva dose-resposta para as enterotoxinas A e B do S. aureus e escolha de uma dose adequada para realização do ensaio de proliferação (König et al, 1995;Tanaka et al, 1996;Yudate et al, 1996;Yoshino et al, 2000).…”

“…O grupo de doentes atópicos adultos avaliados neste estudo expressaram uma supressão na resposta proliferativa das PBMC às enterotoxinas estafilocócicas (SEA e SEB), sugerindo que na DA ocorra uma deficiência da resposta imune celular. Yoshino et al (2000) descreveram um aumento na resposta proliferativa e da apoptose das células T para SEB em doentes com DA , enquanto que Yudate et al (1996) mostraram que as PBMC eram mais responsivas tanto para SEA quanto para SEB, com uma resposta mais elevada para SEA. Kedzierska et al (2005) proliferação, sugerindo um estado de imunossupressão na DA.…”