The dendritic cell (DC) system of antigen-presenting cells controls immunity and tolerance. DCs initiate and regulate immune responses in a manner that depends on signals they receive from microbes and their cellular environment. They allow the immune system to make qualitatively distinct responses against different microbial infections. DCs are composed of subsets that express different microbial receptors and express different surface molecules and cytokines. Our studies lead us to propose that interstitial (dermal) DCs preferentially activate humoral immunity, whereas Langerhans cells preferentially induce cellular immunity. Alterations of the DC system result in diseases such as autoimmunity, allergy, and cancer. Conversely, DCs can be exploited for vaccination, and novel vaccines that directly target DCs in vivo are being designed.

high pDCs secrete higher levels of IL12p40, express higher levels of costimulatory molecule CD80, and are more efficient in triggering proliferation of naive allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions.

SummaryImmunity results from a complex interplay between the antigen-nonspecific innate immune system and the antigen-specific adaptive immune system. The cells and molecules of the innate system employ non-clonal recognition receptors including lectins, Toll-like receptors, NOD-like receptors and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. Here we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines.

Infiltration of various types of leucocytes has been shown to play a crucial role in the pathogenesis of rheumatoid arthritis (RA). Macrophage inflammatory protein‐3α (MIP‐3α) is a recently identified chemokine which is a selective chemoattractant for leucocytes such as memory T cells, naïve B cells and immature dendritic cells. In this study, we investigated the expression of MIP‐3α and its specific receptor CCR6 in the inflamed joints of patients with RA. Increased amounts of MIP‐3α were found by ELISA in synovial fluids (SF) of patients with RA. MIP‐3α was apparently detected in all synovial tissue specimens of RA patients (n = 6), but it could not be detected in that of osteoarthritis (OA) patients (n = 4). Expression of MIP‐3α was detected especially in the sublining layer, and infiltrating mononuclear cells in RA synovial tissue. Gene expression of MIP‐3α was also found in six out of 11 RA‐synovial fluid cells by RT‐PCR. Cultured synovial fibroblasts derived from either RA or OA patients were capable of producing MIP‐3α in response to IL‐1β and TNFα in vitro. Furthermore, expression of CCR6 was found in infiltrating mononuclear cells in the cellular clusters and around the vessels of RA synovial tissue. These findings indicate that increased production of MIP‐3α may contribute to the selective recruitment of CCR6‐expressing cells in RA.

Objective. Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear hormone receptor superfamily and functions as a key regulator of lipid and glucose metabolism, atherosclerosis, and inflammatory responses. This study was undertaken to evaluate the biologic role of PPAR␥ in self-limiting episodes of acute gouty arthritis. To do this, we investigated PPAR␥ expression by monosodium urate monohydrate (MSU) crystal-stimulated monocytes, and we studied the effects of PPAR␥ ligands on crystal-induced acute inflammation.Methods. PPAR␥ expression by MSU crystalstimulated human peripheral blood mononuclear cells was determined by reverse transcription-polymerase chain reaction and immunostaining. Expression of CD36 on monocytes was detected by flow cytometric analysis. The effects of PPAR␥ ligands on in vitro crystal-induced cytokine production and on in vivo cellular infiltration during crystal-induced acute inflammation were also investigated.Results. MSU crystals rapidly and selectively induced PPAR␥ expression by monocytes. Gene expression was detected as early as 2 hours, and maximum expression was observed at 4 hours after stimulation. The induced PPAR␥ was functional, since a PPAR␥ ligand was able to up-regulate CD36 expression on monocytes. A natural ligand of PPAR␥, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15deoxy-PGJ 2 ), significantly reduced the crystal-induced production of cytokines by monocytes. Indomethacin inhibited cytokine production only at high concentrations, and an antidiabetic thiazolidinedione (troglitazone) failed to exert significant effects. Administration of troglitazone and 15deoxy-PGJ 2 significantly prevented cellular accumulation in a mouse air-pouch model of MSU crystal-induced acute inflammation.Conclusion. Rapid induction of PPAR␥ expression on monocytes by MSU crystals may contribute, at least in part, to the spontaneous resolution of acute attacks of gout.