Uptake of Leishmania major by dendritic cells is mediated by Fcgamma receptors and facilitates acquisition of protective immunity.

Uptake of Leishmania major by dendritic cells (DCs) results in activation and interleukin (IL)-12 release. Infected DCs efficiently stimulate CD4- and CD8- T cells and vaccinate against leishmaniasis. In contrast, complement receptor 3-dependent phagocytosis of L. major by macrophages (MPhi) leads exclusively to MHC class II-restricted antigen presentation to primed, but not naive, T cells, and no IL-12 production. Herein, we demonstrate that uptake of L. major by DCs required parasite-reactive immunoglobulin (Ig)G and involved FcgammaRI and FcgammaRIII. In vivo, DC infiltration of L. major-infected skin lesions coincided with the appearance of antibodies in sera. Skin of infected B cell-deficient mice and Fcgamma-/- mice contained fewer parasite-infected DCs in vivo. Infected B cell-deficient mice as well as Fcgamma-/- mice (all on the C57BL/6 background) showed similarly increased disease susceptibility as assessed by lesion volumes and parasite burdens. The B cell-deficient mice displayed impaired T cell priming and dramatically reduced IFN-gamma production, and these deficits were normalized by infection with IgG-opsonized parasites. These data demonstrate that DC and MPhi use different receptors to recognize and ingest L. major with different outcomes, and indicate that B cell-derived, parasite-reactive IgG and DC FcgammaRI and FcgammaRIII are essential for optimal development of protective immunity.

Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis.

OBJECTIVES: To study the role of interleukin 22 (IL-22) in rheumatoid arthritis (RA). METHODS: IL-22 serum levels were measured in patients with early, treatment-naive RA (n=49) and in 45 age- and sex-matched healthy individuals as controls. Patients were assessed clinically and radiographically at baseline and followed up for 2 years. Correlations of IL-22 serum levels were sought with parameters of disease activity, serological markers, demographic factors and the incidence of erosions. IL-22 production by peripheral blood T cells was investigated by intracellular flow cytometry. RESULTS: 24 of 49 patients with RA demonstrated elevated IL-22 levels compared with the range of healthy controls. At baseline, a high percentage of these patients (8/24, 33%) demonstrated bone erosions, whereas only one patient (4%) from the group with normal IL-22 had erosions. During the 2 years of follow-up, six additional patients with increased IL-22 at baseline developed erosions. In contrast, none of the patients in whom IL-22 levels were normal developed erosions despite similar treatment regimens. Multivariate regression analysis accounting for other parameters predictive for erosions, such as the presence of rheumatoid factor or anti-cyclic citrullinated peptide antibodies and disease activity, showed that elevated IL-22 baseline levels were independently and significantly associated with erosive RA. Cellular analysis demonstrated enhanced expression of IL-22 from CD4 T cells in RA. CONCLUSION: IL-22 is elevated in the serum of half of the patients with RA. Elevated serum IL-22 allows discrimination between patients with different radiographic progression and indicates a possible involvement of IL-22 in the pathophysiology of RA.

Ultrasound of synovitis in rheumatoid arthritis: advantages of the dorsal over the palmar approach to finger joints.

OBJECTIVE: To compare the dorsal and palmar ultrasound (US) examination of finger joints in early rheumatoid arthritis (RA) with regard to the concurrence of greyscale (GSUS) and power Doppler (PDUS) positivity, and to correlate both approaches with clinical variables. METHODS: Patients with newly diagnosed RA were assessed by clinical examination and US. GSUS and PDUS of metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints were performed using the dorsal and palmar approach. Findings of synovitis in GSUS and PDUS were graded semiquantitatively from 0 to 3. Clinical and sonographic reevaluation was performed after 6 months. RESULTS: With 44.6% versus 32.2% positive findings, palmar GSUS identified significantly more joints with synovitis than did dorsal GSUS. With 22.1% versus 8.9%, PDUS abnormalities were detected significantly more often from the dorsal side. With 71.2% versus 21.8% for the MCP and 57.5% versus 17.4% for the PIP joints, significantly more GSUS and PDUS double-positive joints were found with the dorsal as opposed to the palmar approach. These differences remained significant at Month 6. Both palmar and dorsal GSUS and PDUS correlated with comparable strength with clinical variables such as the Disease Activity Score 28, Clinical Disease Activity Index, and Simple Disease Activity Index. CONCLUSION: Although the dorsal approach detected fewer GSUS findings than the palmar approach, PDUS signals were significantly more frequently detected by dorsal US. In addition, the prevalence of double-positive joints with concurrent GSUS and PDUS findings was significantly higher with the dorsal approach. These data argue in favor of the dorsal US approach to finger joints in RA.

Dendritic cell-derived IL-12p40 homodimer contributes to susceptibility in cutaneous leishmaniasis in BALB/c mice.

Protection against Leishmania major in resistant C57BL/6 mice is mediated by Th1 cells, whereas susceptibility in BALB/c mice is the result of Th2 development. IL-12 release by L. major-infected dendritic cells (DC) is critically involved in differentiation of Th1 cells. Previously, we reported that strain differences in the production of DC-derived factors, e.g., IL-1alphabeta, are in part responsible for disparate disease outcome. In the present study, we analyzed the release of IL-12 from DC in more detail. Stimulated DC from C57BL/6 and BALB/c mice released comparable amounts of IL-12p40 and p70. In the absence of IL-4, BALB/c DC produced significantly more IL-12p40 than C57BL/6 DC. Detailed analyses by Western blot and ELISA revealed that one-tenth of IL-12p40 detected in DC supernatants was released as the IL-12 antagonist IL-12p40 homodimer (IL-12p80). BALB/c DC released approximately 2-fold more IL-12p80 than C57BL/6 DC both in vitro and in vivo. Local injection of IL-12p80 during the first 3 days after infection resulted in increased lesion volumes for several weeks in both L. major-infected BALB/c or C57BL/6 mice, in higher lesional parasite burdens, and decreased Th1-cytokine production. Finally, IL-12p40-transgenic C57BL/6 mice characterized by overexpression of p40 showed increased levels of serum IL-12p80 and enhanced disease susceptibility. Thus, in addition to IL-1alphabeta, strain-dependent differences in the release of other DC-derived factors such as IL-12p80 may influence genetically determined disease outcome.