The origins and longevity of IgE responses as indicated by serological and cellular studies in mice and humans.

The existence of long-lived IgE antibody-secreting cells (ASC) is contentious, with the maintenance of sensitization by the continuous differentiation of short-lived IgE+ ASC a possibility. Here, we review the epidemiological profile of IgE production, and give an overview of recent discoveries made on the mechanisms regulating IgE production from mouse models. Together, these data suggest that for most individuals, in most IgE-associated diseases, IgE+ ASC are largely short-lived cells. A subpopulation of IgE+ ASC in humans is likely to survive for tens of months, although due to autonomous IgE B cell receptor (BCR) signaling and antigen-driven IgE+ ASC apoptosis, in general IgE+ ASC probably do not persist for the decades that other ASC are inferred to do. We also report on recently identified memory B cell transcriptional subtypes that are the likely source of IgE in ongoing responses, highlighting the probable importance of IL-4Rα in their regulation. We suggest the field should look at dupilumab and other drugs that prohibit IgE+ ASC production as being effective treatments for IgE-mediated aspects of disease in most individuals.

Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan.

Antibodies produced by antibody-secreting plasma cells (ASCs) underlie multiple forms of long-lasting immunity. Here we examined the mechanisms regulating ASC turnover and persistence using a genetic reporter to time-stamp ASCs. This approach revealed ASC lifespans as heterogeneous and falling on a continuum, with only a small fraction surviving for >60 days. ASC longevity past 60 days was independent of isotype but correlated with a phenotype that developed progressively and ultimately associated with an underlying "long-lived" ASC (LL ASC)-enriched transcriptional program. While some of the differences between LL ASCs and other ASCs appeared to be acquired with age, other features were shared with some younger ASCs, such as high CD138 and CD93. Turnover was unaffected by altered ASC production, arguing against competition for niches as a major driver of turnover. Thus, ASC turnover is set by intrinsic lifespan limits, with steady-state population dynamics governed by niche vacancy rather than displacement.

It takes a sec(22b) to accrue plasma cells.

A recent study shows that the SNARE protein Sec22b plays a key role in antibody-secreting plasma cell accrual. Without Sec22b, antibody titres were diminished, and plasma cells rare to undetectable. The few plasma cells that were detected were functionally compromised, with altered organelle morphology and deficient antibody production.

When will individuals meet their personalized probabilities? A philosophical note on risk prediction.

Risk prediction is one of the central goals of medicine. However, ultimate prediction-perfectly predicting whether individuals will actually get a disease-is still out of reach for virtually all conditions. One crucial assumption of ultimate personalized prediction is that individual risks in the relevant sense exist. In the present paper we argue that perfect prediction at the individual level will fail-and we will do so by providing pragmatic, epistemic, conceptual, and ontological arguments.

The limits of Humeanism.

Humeans take reality to be devoid of 'necessary connections': things just happen. Laws of nature are to be understood in terms of what 'just happens', not vice versa. Here the Humean needs some conception of what it is that 'just happens' - a conception of the Humean mosaic. Lewis's Humeanism incorporates such a conception in the form of a Lewis-style metaphysics of objects, properties, and modality. Newer versions of Humeanism about laws of nature, such as the Better Best Systems approach (BBS), typically reject such a Lewisian metaphysics, but it remains unclear what they can offer in its place. By exploring different candidate conceptions, this paper sheds light on the limits of Humeanism about laws of nature: not all conceptions of the Humean mosaic form a suitable basis for a Humean theory of laws. In fact, only a metaphysics roughly in line with Lewis's will do. The paper ends with a tentative generalization of this result, thus pointing to the 'limit' of Humeanism in general: taking the Humean way of thinking to its limit results in a rejection of the whole idea of such a mosaic - and hence of Humean mosaic-based accounts of anything.