Recent advances in the diagnosis and treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.     

Extending, changing, and explaining the brain

This paper addresses concerns raised recently by Datteri (Biol Philos 24:301–324, 2009) and Craver (Philos Sci 77(5):840–851, 2010) about the use of brain-extending prosthetics in experimental neuroscience. Since the operation of the implant induces plastic changes in neural circuits, it is reasonable to worry that operational knowledge of the hybrid system will not be an accurate basis for generalisation when modelling the unextended brain. I argue, however, that Datteri’s no-plasticity constraint unwittingly rules out numerous experimental paradigms in behavioural and systems neuroscience which also elicit neural plasticity. Furthermore, I propose that Datteri and Craver’s arguments concerning the limitations of prosthetic modelling in basic neuroscience, as opposed to neuroengineering, rests on too narrow a view of the ways models in neuroscience should be evaluated, and that a more pluralist approach is needed. I distinguish organisational validity of models from mechanistic validity. I argue that while prosthetic models may be deficient in the latter of these explanatory virtues because of neuroplasticity, they excel in the former since organisational validity tracks the extent to which a model captures coding principles that are invariant with plasticity. Changing the brain, I conclude, is one viable route towards explaining the brain.     

The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits

Background  

Transplant rejection has been considered to occur primarily because donor antigens are not present during the development of the recipient's immune system to induce tolerance. Thus, transplantation prior to recipient immune system development (pre-immunocompetence transplants) should induce natural tolerance to the donor. Surprisingly, tolerance was often not the outcome in such 'natural tolerance models'. We explored the ability of natural tolerance to prevent immune responses to alloantigens, and the reasons for the disparate outcomes of pre-immunocompetence transplants.