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1.
J Autoimmun ; 40: 1-8, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22890025

ABSTRACT

Lupus erythematosus (LE) is an autoimmune disease with evidence for an IL-23- and IL-17-induced immunopathology. Little is known about the type of dendritic cells supporting this immune response. We recently demonstrated the strong Th1- and Th17-T-cell inducing capacity of human 6-sulfo LacNAc-dendritic cells (slanDCs), and identified slanDCs as inflammatory dermal dendritic cells in psoriasis locally expressing IL-23, TNF-α and inducible nitric oxide synthase (iNOS). In this study, we investigated the role of slanDCs in LE. Using immunohistochemistry, we identified slanDCs at increased frequency in affected skin lesions of cutaneous and systemic LE. slanDCs were found scattered in the dermal compartment and also clustered in lymph follicle-like structures. Here, they colocalized with T cells in the periphery but not with B cells in the center. The positive staining of dermal slanDCs for TNF-α indicated their pro-inflammatory status. In vitro the production of TNF-α was induced when slanDCs were cultured in the presence of serum from patients with LE. Stimulatory components of LE serum were previously identified as autoimmune complexes with ssRNA binding to TLR7 and TLR8. We found that slanDCs express mRNA for TLR7 and TLR8. slanDCs stimulated with ssRNA, selective TLR7 or TLR8 ligands responded with high-level TNF-α and IL-12 production. In contrast to slanDCs, the population of CD1c(+) DCs and plasmacytoid DCs (pDCs) expressed either TLR7 or TLR8, and their production of TNF-α and IL-12 to respective ligands was far less pronounced. We conclude that slanDCs have molecular and functional features of a pro-inflammatory myeloid DC type relevant for the immunopathogenesis of LE.


Subject(s)
Amino Sugars/immunology , Dendritic Cells/immunology , Lupus Erythematosus, Cutaneous , Lupus Erythematosus, Systemic , Cells, Cultured , Dendritic Cells/metabolism , Humans , Inflammation/immunology , Interleukin-12/biosynthesis , Lupus Erythematosus, Cutaneous/blood , Lupus Erythematosus, Cutaneous/immunology , Lupus Erythematosus, Cutaneous/metabolism , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , RNA, Messenger/biosynthesis , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/genetics , Toll-Like Receptor 8/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/metabolism
2.
Curr Opin Allergy Clin Immunol ; 11(5): 445-50, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21841470

ABSTRACT

PURPOSE OF REVIEW: Dendritic cells are essential for the generation of innate and adaptive immune responses, which makes them stay on center stage when studying the immuno pathogenesis of atopic dermatitis. This review will discuss recent findings on the role of dendritic cells subsets in atopic dermatitis and will report novel findings on how the microenvironment conditions dendritic cells to fuel atopic dermatitis. RECENT FINDINGS: Several microenvironmental factors characteristic for atopic dermatitis and with direct relevance for the disease have been defined. We now increasingly understand how thymic stromal lymphopoietin and histamine contribute to the disease by modulating the function of dendritic cells. We have learned much about the pathogenesis of atopic dermatitis by the studies on inflammatory dendritic epidermal cells. However, the current analysis on the functional and phenotypic heterogeneity of dendritic cells in eczematous skin lesions may lead to the definition of additional dendritic cell types relevant in the pathogenesis of atopic dermatitis. In this respect, it appears interesting to further discuss the parallels and differences in atopic dermatitis and psoriasis. SUMMARY: Understanding the heterogeneity of dendritic cells and their functional alteration by local factors in the inflamed skin will provide essential clues to the immunopathogenesis of atopic dermatitis.


Subject(s)
Dendritic Cells/immunology , Dermatitis, Atopic/immunology , Langerhans Cells/immunology , Psoriasis/immunology , Skin/immunology , Adaptive Immunity , Animals , Antigen Presentation , Cell Differentiation , Cytokines/immunology , Histamine/immunology , Humans , Immunity, Innate , Inflammation , Interleukins/immunology , Thymic Stromal Lymphopoietin
3.
J Allergy Clin Immunol ; 127(3): 787-94.e1-9, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21377044

ABSTRACT

BACKGROUND: Psoriasis is a chronic inflammatory skin disease that is considered to result from activated T cells stimulated by a population of inflammatory dermal dendritic cells (DCs). The origin and identity of these inflammatory dermal DCs are largely unknown. OBJECTIVE: We previously identified slanDCs (6-sulfo LacNAc) DCs as a rich source of TNF-α and as the early major source of IL-12. Here we studied the relevance of slanDCs as inflammatory dermal DCs in psoriasis. METHODS: Psoriasis skin samples were stained for the presence of activated slanDCs. Functional studies were carried out to determine the cytokine production of slanDCs, their T(h)17/T(h)1 T-cell programming, and their migration behavior. RESULTS: Large numbers of IL-23, TNF-α, and inducible nitric oxide synthase expressing slanDCs were found in psoriatic skin samples, which can be recruited by C5a, CX3CL1, and CXCL12. SlanDCs isolated from blood produced high levels of IL-1ß, IL-23, IL-12, and IL-6. Compared with classic CD1c(+) DCs, slanDCs were far more powerful in programming T(h)17/T(h)1 T cells that secrete IL-17, IL-22, TNF-α, and IFN-γ, yet CD1c(+) DCs induced a higher IL-10 production of T cells. Self-nucleic acids complexed to cathelicidin LL37 trigger endosomal Toll-like receptor (TLR) signaling (TLR7, TLR8, TLR9) and are key factors for the activation of DCs in psoriasis. We show that slanDCs respond particularly well to complexes formed of self-RNA and LL37. Similarly, slanDCs stimulated with a synthetic TLR7/8 ligand produced high levels of proinflammatory cytokines. CONCLUSION: Our study defines slanDCs as inflammatory dermal DCs in psoriasis and identifies their strong capacity to induce T(h)17/T(h)1 responses.


Subject(s)
Amino Sugars , Langerhans Cells/immunology , Psoriasis/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Adult , Aged , Amino Sugars/immunology , Female , Flow Cytometry , Humans , Immunohistochemistry , Male , Middle Aged
4.
Immunity ; 24(6): 767-777, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16782032

ABSTRACT

Early and high-level production of IL-12 is crucial for effective immune responses against pathogens. Up until now, the cells providing this initial IL-12 have remained elusive. Here we show that a subset of human blood dendritic cells (DC) is the principal and primary source of IL-12p70 when blood leukocytes are stimulated with the TLR4-ligand LPS or with CD40-ligand. These so-called slanDC are characterized by the 6-sulfo LacNAc modification of PSGL-1, which is identified by the mAb M-DC8. The IL-12 response of slanDC requires a few hours of in vitro maturation, which is completely blocked in the presence of erythrocytes. This inhibition of maturation depends on the expression of CD47 on erythrocytes and of its ligand SIRPalpha on DC. While strictly controlled in the blood by erythrocytes, the high IL-12- and TNF-alpha-producing capacity of slanDC in tissues may be critical in fighting off pathogens; if uncontrolled, it may lead to adverse inflammatory reactions.


Subject(s)
Dendritic Cells/immunology , Erythrocytes/immunology , Interleukin-12/metabolism , Lipopolysaccharides/immunology , Amino Sugars , Antigens, Differentiation/analysis , Antigens, Differentiation/metabolism , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , CD40 Ligand/pharmacology , CD47 Antigen/analysis , CD47 Antigen/metabolism , Coculture Techniques , Dendritic Cells/drug effects , Humans , Ligands , Lipopolysaccharides/pharmacology , Membrane Glycoproteins/immunology , Psoriasis/immunology , Psoriasis/pathology , Receptors, Immunologic/analysis , Receptors, Immunologic/metabolism , Th1 Cells/immunology , Toll-Like Receptor 4/agonists
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