ABSTRACT
Cell surface receptor internalization can either terminate signaling or activate alternative endosomal signaling pathways. We investigated here whether endosomal signaling is involved in the function of the human receptors for Fc immunoglobulin fragments (FcRs): FcαRI, FcγRIIA, and FcγRI. All these receptors were internalized after their cross-linking with receptor-specific antibodies, but their intracellular trafficking was different. FcαRI was targeted directly to lysosomes, while FcγRIIA and FcγRI were internalized in particular endosomal compartments described by the insulin esponsive minoeptidase (IRAP), where they recruited signaling molecules, such as the active form of the kinase Syk, PLCγ and the adaptor LAT. Destabilization of FcγR endosomal signaling in the absence of IRAP compromised cytokine secretion downstream FcγR activation and macrophage ability to kill tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Our results indicate that FcγR endosomal signaling is required for the FcγR-driven inflammatory reaction and possibly for the therapeutic action of monoclonal antibodies.
ABSTRACT
Antigen (Ag)-trimming aminopeptidases belong to the oxytocinase subfamily of M1 metallopeptidases. In humans, this subfamily contains the endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and 2) and the insulin-responsive aminopeptidase (IRAP, synonym oxytocinase), an endosomal enzyme. The ability of these enzymes to trim antigenic precursors and to generate major histocompatibility class-I ligands has been demonstrated extensively for ERAP1, less for ERAP2, which is absent in rodents, and exclusively in the context of cross-presentation for IRAP. During 20 years of research on these aminopeptidases, their enzymatic function has been very well characterized and their genetic association with autoimmune diseases, cancers, and infections is well established. The mechanisms by which these proteins are associated to human diseases are not always clear. This review discusses the Ag-trimming-independent functions of the oxytocinase subfamily of M1 aminopeptidases and the new questions raised by recent publications on IRAP and ERAP2.
Subject(s)
Aminopeptidases , Cystinyl Aminopeptidase , Humans , Aminopeptidases/genetics , Aminopeptidases/metabolism , Cystinyl Aminopeptidase/genetics , Antigens , Minor Histocompatibility Antigens/geneticsSubject(s)
Cell Survival , Endosomes/metabolism , Interleukin 1 Receptor Antagonist Protein/metabolism , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/physiology , Animals , Humans , Lymphocyte Activation , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Lymphoid Tissue/cytology , Lymphoid Tissue/metabolism , Mice , Signal Transduction , T-Lymphocytes/immunologyABSTRACT
As case management is under development in France for elderly people, this study sets out to identify and analyse key situations responsible for ethical dilemmas for French case managers. We based our study on the analyses of individual interviews made with case managers and focus-group discussions, bringing together all case managers working in local organisations running for at least a year. We identified three situations giving rise to ethical dilemmas: in the order of importance, the refusals of care, the practicalities of collecting and sharing personal data and the allocation of resources. These three situations can lead to conflict between the principle of beneficence and those of respect for autonomy, non-maleficence and justice. We describe here how French case managers practically deal with these situations.
Subject(s)
Administrative Personnel/psychology , Case Management/ethics , Health Services for the Aged , Outcome and Process Assessment, Health Care/ethics , Conflict, Psychological , Focus Groups , France , Humans , Interviews as Topic , Outcome and Process Assessment, Health Care/methods , Resource Allocation , Treatment RefusalABSTRACT
In France, the national public health plan proposes a group of innovations including the initiation of case management for older adults in complex situations, particularly those with cognitive disorders. In this context, public authorities asked case managers to use a standardized multidimensional evaluation tool. The results of a qualitative study on the pertinence of such a tool relative to the emergence of this new professional field are described. Early use of an evaluation tool seems to be linked to the emergence of a new professional identity for recently recruited case managers. Factors determining the strength of this link are training tool standardization, computerization, and local structure's involvement. Our results contribute to identifying one of the ways by which professional identity can be changed to become a case manager.
