Spontaneous protein crystallization as a driver of immunity

Spontaneous protein crystallization is a rare event in vivo, yet Charcot-Leyden crystals (CLC) consisting of the protein galectin-10 (Gal10) are frequently observed in eosinophilic diseases like asthma. It is unclear if they exacerbate disease. Release of Gal10 and extracellular crystallization was associated with EEtosis of eosinophils in human primary eosinophils. We found that recombinant crystalline Gal10 was completely biosimilar to in vivo obtained CLCs and induced innate airway inflammation, whereas a soluble Gal10 engineered to resist crystallization was inert in the airways. When co-administered with harmless antigens, only crystalline Gal10 stimulated adaptive immunity, Th2 sensitization, goblet cell metaplasia and airway eosinophilia. Transgenic mice engineered to overexpress human Gal10 in eosinophils (GALILEO mice) had enhanced features of asthma including mucus plugging and bronchial hyperreactivity. To probe for the drugability of this pathway, we generated a panel of antibodies. Antibodies directed against key epitopes of the crystallization interface dissolved pre-existing CLC in patient-derived mucus within hours, and reversed crystal driven inflammation, goblet cell metaplasia, IgE synthesis and bronchial hyperreactivity in a humanized asthma model. Thus, galectin10 and CLC promote key features of asthma and can be targeted by crystal dissolving antibodies.

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