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.

ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.

Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2 (NRF2)-dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3(-/-) mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3(-/-) mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3(-/-)Il6(-/-) mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3(-/-) mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.

Nodular malignant melanoma and multiple cutaneous neoplasms under immunosuppression with azathioprine.

Immunosuppressed patients are at increased risk of skin cancer. A 67-year-old renal transplant recipient developed a nodular malignant melanoma after 30 years of immunosuppression with azathioprine and prednisolone. The patient died of metastatic disease 3 months after the diagnosis was made. The function of the renal graft was not affected at all. Renal transplant recipients are at high risk of developing nonmelanocytic skin tumors when on immunosuppressive therapy with cyclosporine A. Less common is the development of skin cancer during immunosuppression with azathioprine. Latest reports show the increased incidence of malignant melanoma in immunosuppressed patients. Our case illustrates the necessity of close dermatological surveillance of allograft recipients, to assure an early recognition of any malignant skin tumor and to reduce the risk of systemic metastatic disease.