Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a).
We find that CD11c(+) cells with many markers of dendritic cells (DCs) are a major cell type in the skin lesions of psoriasis. These CD11c(+) cells, which are evident in both epidermis and dermis, are the sites for the expression of two mediators of inflammation, inducible nitric oxide synthase (iNOS) and TNF-alpha in diseased skin. These cells express HLA-DR, CD40, and CD86, lack the Langerin and CD14 markers of Langerhans cells and monocytes, respectively, and to a significant extent express the DC maturation markers DC-LAMP and CD83. Treatment of psoriasis with efalizumab (anti-CD11a, Raptiva) strongly reduces infiltration by these DCs in patients responding to this agent. Disease activity after therapy was more related to DC infiltrates and iNOS mRNA levels than T cell infiltrates, and CD11c(+) cells responded more quickly to therapy than epidermal keratinocytes. Our results suggest that a type of DC, which resembles murine "Tip-DCs" that can accumulate during infection, has proinflammatory effects in psoriasis through nitric oxide and TNF-alpha production, and can be an important target for suppressive therapies.
Lowes
Michelle A
MA
Laboratory for Investigative Dermatology and Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA.
Chamian
Francesca
F
Abello
Maria Veronica
MV
Fuentes-Duculan
Judilyn
J
Lin
Shao-Lee
SL
Nussbaum
Rachel
R
Novitskaya
Inna
I
Carbonaro
Henrietta
H
Cardinale
Irma
I
Kikuchi
Toyoko
T
Gilleaudeau
Patricia
P
Sullivan-Whalen
Mary
M
Wittkowski
Knut M
KM
Papp
Kim
K
Garovoy
Marvin
M
Dummer
Wolfgang
W
Steinman
Ralph M
RM
Krueger
James G
JG
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D039521:CD11c Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D007150:Immunohistochemistry; D007249:Inflammation; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008856:Microscopy, Fluorescence; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism / Q000502:physiology*; D011565:Psoriasis / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D000097802:CD83 Antigen
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D051940:B7-2 Antigen; D039521:CD11c Antigen; D019013:CD40 Antigens; D006684:HLA-DR Antigens; D007136:Immunoglobulins; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C472181:efalizumab