Eosinophil degranulation: an evolutionary vestige or a universally destructive effector function?

Many of the prevailing hypotheses regarding eosinophil effector functions trace their origins back to the 1879 observations of Paul Ehrlich who described the rich magenta eosin-staining granules within what became known as eosinophils [1]. Specifically, the intervening 1001 years bear witness to the remarkable adherence to a fundamental paradigm that has since arisen and is inescapably still taught in medical schools and reviewed now and again in the literature [2]: Eosinophils are granulocytes and therefore their dominant effector functions are mediated by granules. Indeed, the hyperbole surrounding this issue is astonishing as many texts and discussions often lead observers to believe that the release of the contents of these granules by degranulation is the only effector function of significance. Given this hyperbole, a logical place to begin a discussion of the importance of degranulation is to develop a definition of eosinophil effector functions inclusive of all potential activities mediated by this leucocyte. The definition we are proposing here is not a moment of ‘Einsteinian’ thought, but arises from observations reported in the literature and the many conversations we have had with innumerable colleagues: Our proposal is that eosinophil effector functions constitute any eosinophil-mediated activity that modulates the entropy of disease or is required for physiological homeostasis. Interestingly, modulations related to disease pathogenesis are most closely associated with the historical view of eosinophil degranulation that prevails today. That is, degranulating eosinophils contribute to the inflammatory responses and tissue damage resulting from helminth infections, solid tumour growth, fungal infections, and the immunohistopathologic events associated with allergic diseases such as asthma or atopic dermatitis. In each case, the assumption is that eosinophils execute effector functions primarily through the release of toxic cationic secondary granule proteins. We believe that the acceptance of this description as the singularly significant function of degranulation underestimates its importance as well as the value of other activities mediated by eosinophils. In particular, the recent recognition that eosinophils are likely to be regulatory cells contributing in significant ways to immune responses, tissue remodelling, and/or homeostasis suggests that the potentially toxic activities of the granule proteins may represent only a small fraction of their overall impact, and in that, a distortion of their normal function [3]. The goal of this review is to examine the importance of eosinophil degranulation from a ‘thinking outside of the box’ perspective in an attempt to shed new light on an old problem. In particular, we will pose and answer the questions ‘What is the evolutionary origin of eosinophils and degranulation and why is degranulation viewed as the ultimate eosinophil effector function? ’ More importantly, ‘Does the available data support an alternative to the prevailing hypothesis that degranulation is a destructive effector function? ’ We do not expect to adequately answer these questions and many of our answers may eventually be shown to be incorrect. However, as noted by the 19th century naturalist Charles Darwin: ‘False views, if supported by some evidence, do little harm, for everyone takes salutary pleasure in proving their falseness! ’