Dynamics and Function of Langerhans Cells In Vivo: Dermal Dendritic Cells Colonize Lymph Node Areas Distinct from Slower Migrating Langerhans Cells

Langerhans cells (LCs) are prominent dendritic cells (DCs) in epithelia, but their role in immunity is poorly defined. To track and discriminate LCs from dermal DCs in vivo, we developed knockin mice expressing enhanced green fluorescent protein (EGFP) under the control of the langerin (CD207) gene. By using vital imaging, we showed that most EGFP(+) LCs were sessile under steady-state conditions, whereas skin inflammation induced LC motility and emigration to lymph nodes (LNs). After skin immunization, dermal DCs arrived in LNs first and colonized areas distinct from slower migrating LCs. LCs reaching LNs under steady-state or inflammatory conditions expressed similar levels of costimulatory molecules. Langerin and EGFP were also expressed on thymic DCs and on blood-derived, CD8alpha(+) DCs from all secondary lymphoid organs. By using a similar knockin strategy involving a diphtheria toxin receptor (DTR) fused to EGFP, we demonstrated that LCs were dispensable for triggering hapten-specific T cell effectors through skin immunization.

Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.

Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (Lat(Y136F) mice) develop a fast-onset lymphoproliferative disorder involving polyclonal CD4 T cells that produce massive amounts of Th2 cytokines and trigger severe inflammation and autoantibodies. We analyzed whether the Lat(Y136F) pathology constitutes a bona fide autoimmune disorder dependent on TCR specificity. Using adoptive transfer experiments, we demonstrated that the expansion and uncontrolled Th2-effector function of Lat(Y136F) CD4 cells are not triggered by an MHC class II-driven, autoreactive process. Using Foxp3EGFP reporter mice, we further showed that nonfunctional Foxp3(+) regulatory T cells are present in Lat(Y136F) mice and that pathogenic Lat(Y136F) CD4 T cells were capable of escaping the control of infused wild-type Foxp3(+) regulatory T cells. These results argue against a scenario where the Lat(Y136F) pathology is primarily due to a lack of functional Foxp3(+) regulatory T cells and suggest that a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity. This abnormal status confers Lat(Y136F) CD4 T cells with the ability to trigger the production of Abs and of autoantibodies in a TCR-independent, quasi-mitogenic fashion. Therefore, despite the presence of autoantibodies causative of severe systemic disease, the pathological conditions observed in Lat(Y136F) mice unfold in an Ag-independent manner and thus do not qualify as a genuine autoimmune disorder.

Acoustic, volumetric, compressibility and refractivity properties and Flory’s reduction parameters of some homologous series of alkyl alkanoates from 298.15 to 333.15 K

The speeds of sound u in, densities ? and refractive indices nD of some homologous series, such as n-alkyl ethanoates, n-alkyl propionates, methyl alkanoates, ethyl alkanoates, dialkyl malonates, and alkyl haloalkanoates, were measured in the temperature range from 298.15 to 333.15 K. Molar volume V, isentropic and isothermal compressibilities ?S and ?T, molar refraction Rm, Eykman’s constant Cm, molecular radius r, Rao’s molar function R, thermal expansion coefficient a, thermal pressure coefficient ?, and Flory’s characteristic parameters image, P*, V*, and T* have been calculated from the measured experimental data. Applicability of Rao theory and Flory–Patterson–Pandey (FPP) theory have been examined and discussed for these alkanoates.

The postmodernist war on evidence-based practice

In this paper, we examine the war of words between those who contend that health care practice, including nursing, should primarily be informed by research (the evidence-based practice movement), and those who argue that there should be no restrictions on the sources of knowledge used by practitioners (the postmodernists). We review the postmodernist interventions of Dave Holmes and his colleagues, observing that the postmodernist style to which they adhere, which includes the use of continental philosophy, metaphors, and acerbic delivery, tends to obscure their substantive arguments. The heated nature of some responses to them has tended to have the same effect. However, the substantive arguments are important. Five main postmodernist charges are identified and discussed. The first argument, that the notion of ‘best evidence’ implies a hierarchical and exclusivist approach to knowledge, is persuasive. However, the contention that this hierarchy is maintained by the combined pressures of capitalism and vested interests within academia and the health services, is less well founded. Nevertheless, postmodernist contentions that the hierarchy embraced by the evidence-based practice movement damages health care because it excludes other forms of evidence that are needed to understand the complexity of care, it marginalizes important aspects of clinical knowledge, and it fails to take account of individuals or their experience, are all seen to be of some merit. However, we do not share the postmodernist conclusion that this adds up to a fascist order. Instead, we characterize evidence-based practice as a necessary but not sufficient component of health care knowledge.