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-␣ 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 (antiCD11a, 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-␣ production, and can be an important target for suppressive therapies.autoimmune disease ͉ CD11c ͉ Tip-DC

Myeloid dermal dendritic cells (DCs) accumulate in chronically inflamed tissues such as psoriasis. The importance of these cells for psoriasis pathogenesis is suggested by comparative T cell and DC cell counts, where DCs outnumber T cells. We have previously identified CD11c+BDCA-1+ cells as the main resident dermal DC population found in normal skin. We now show that psoriatic lesional skin has two populations of dermal DCs: 1) CD11c+BDCA-1+ cells which are phenotypically similar to those contained in normal skin, and 2) CD11c+BDCA-1− cells which are phenotypically immature and produce inflammatory cytokines. While BDCA-1+ DCs are not increased in number in psoriatic lesional skin compared to normal skin, BDCA-1− DCs are increased 30-fold. For functional studies, we FACS-sorted psoriatic dermal single cell suspensions to isolate these two cutaneous DC populations, and cultured them as stimulators in an allo-MLR. Both BDCA-1+ and BDCA-1− myeloid dermal DC populations induced T cell proliferation, and polarized T cells to become Th1 and Th17 cells. In addition, psoriatic dermal DCs induced a population of activated T cells that simultaneously produced IL-17 and IFN-γ, which was not induced by normal skin dermal DCs. As psoriasis is believed to be a mixed Th17/Th1 disease, it is possible that induction of these IL-17+IFNγ+ cells is pathogenic. These cytokines, the T cells that produce them, and the inducing inflammatory DCs may all be important new therapeutic targets in psoriasis.

The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood. Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months. Histological response, inflammatory gene expression, and cellular infiltration in psoriasis plaques were evaluated. There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes. The observed decreases in IL-8, IFN-γ-inducible protein-10 (CXCL10), and MIP-3α (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively. DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein. Decreases in T cell-inflammatory gene expression (IFN-γ, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation. Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes. This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques.

We studied the frequency, location, clinical and histopathological features, associated manifestations, and prognosis of vasculitides in a cohort of 667 SLE patients. Exclusion of patients with previous vasculitis or insufficient information left 540 patients, 194 of whom has vasculitis (incidence density: 0.053 new cases/person/year, cumulative incidence of 0.051 at one year, 0.232 at 5 years and 0.411 at 10 years). Vasculitis was confirmed by biopsy in 46 cases, by arteriography in five, and by both in three. A single episode of vasculitis occurred in 119 and two or more in 75 patients. Vasculitis was cutaneous in 160, visceral in 24, both in 10. In the first episode of cutaneous vasculitides, 111 had punctuate lesions, 32 palpable purpura, 6 urticaria, 6 ulcers, 8 papules, 5 erythematous plaques or macules confirmed with biopsy, 2 erythema with necrosis, and 1 panniculitis (plus small vessel vasculitis). Of 29 with visceral vasculitis in the first episode, 19 had mononeuritis multiplex, 5 digital necrosis, 3 large artery vasculitis of limbs, one mesenteric, and one coronary, more than one type could appear simultaneously or in subsequent episodes. Patients with vasculitis had longer disease duration and followup, younger age of onset of SLE, and were more frequently males than those without. Lupus manifestations associated with vasculitis in univariate logistic regression included myocarditis, psychosis, Raynaud's phenomenon, serositis, leukopenia, lymphopenia and pleuritis. Vasculitis also associated with the antiphospholipid syndrome. The strength of this association increased when patients with vasculitis confirmed by biopsy and/or arteriography were considered separately. Visceral vasculitis associated with increased mortality when controlled for age of onset and nephropathy.