Protein crystallization promotes type 2 immunity and is reversible by antibody treatment

Abstract

Although spontaneous protein crystallization is a rare event in vivo, Charcot-Leyden crystals (CLCs) consisting of galectin-10 (Gal10) protein are frequently observed in eosinophilic diseases, such as asthma. We found that CLCs derived from patients showed crystal packing and Gal10 structure identical to those of Gal10 crystals grown in vitro. When administered to the airways, crystalline Gal10 stimulated innate and adaptive immunity and acted as a type 2 adjuvant. By contrast, a soluble Gal10 mutein was inert. Antibodies directed against key epitopes of the CLC crystallization interface dissolved preexisting CLCs in patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E (IgE) synthesis, and bronchial hyperreactivity (BHR) in a humanized mouse model of asthma. Thus, protein crystals may promote hallmark features of asthma and are targetable by crystal-dissolving antibodies.

Analytic Philosophy for Biomedical Research: The Imperative of Applying Yesterday’s Timeless Messages to Today’s Impasses

“…At the protein level, a big mystery is the presence of "intrinsically disordered" domains in the structure of proteins [21], with different functions attributed to their presence (see, e.g., [22]). Also at the protein level, there is the question of the enigmatic in vivo formation of protein crystals (e.g., Charcot-Leyden crystals formed of the Galectin-10 protein) 5 implicated in inflammatory and other unknown (and 'normal') biological processes [24,25]. At the cellular level, cell structures that might be sensitive to magnetic field changes remain controversial [26].…”

“…The accumulation of data, still less the erection of speculative theories, is not enough". 25 The imperative for a coherent and unified theoretical and philosophical biology Based on the historical precedents expounded thus far, and the current state of biomedical research outcomes, it appears vital to renew the application of philosophical reasoning to theoretical biology research. Philosophical biology would be biology through philosophy, with the aim of gaining insights into foundational questions in biology using a philosophical approach.…”

“…Biological Principles. p. 441 24 Ibid., p. 485 25 Ibid., p. 84 discussion post-Newton about intelligible theories about the world-a world which is not directly intelligible. Jeremy Gunawardena defines a model as "some form of symbolic representation of our assumptions about reality" [98], with "assumptions" here being a key term.…”

Protein phase separation and determinants of in cell crystallization

“…Further, in cellulo crystallization has also been associated with several diseases like cataract, hemoglobin C diseases, formation of Charcot‐Leyden crystals (CLCs), Reinke's crystals or mitochondrial myopathies, and more recently in cellulo crystallization was observed as a result of heterologous overexpression of genes in cell lines of bacteria, insect cells, yeast, CHO (Chinese hamster ovary) or HEK (human embryonic kidney) cells . Mostly, these protein crystals were located in different organelles (mitochondria, peroxisomes, lysosomes, or endoplasmic reticulum), as shown in Table but sometimes also within the cytosol or even in the nucleus, as shown in Figure and Table .…”

“…A recent study solved the Galectin 10 structure using CLCs from patients with rhinosinusitis and asthma. Further, CLCs bind and are dissolved by antibodies . This opens new avenues to explore disease related in vivo crystals as drug target .…”