Rationale : OSE

OSE are generated when the polyunsaturated fatty acids of membrane phospholipids become oxidized by enzymatic and non-enzymatic processes, giving rise to highly reactive lipid degradation products, which can covalently modify self-molecules, such as proteins, nucleic acids, and other lipids. This results in the generation of structural neo-epitopes that are recognized by specific antibodies. Because of the ubiquitous presence and conserved nature of lipids, OSE are universal markers of inflammation across different species.

 

OSE have been documented on the surface of oxidized lipoproteins18, dying cells19-21 and extracellular vesicles22 and were shown to accumulate in pathological tissues in atherosclerosis and non-alcoholic steatohepatitis (NASH) and other diseases16,23,24. In these settings, OSE mark sites of inflammation, but also have the potential to directly trigger sterile inflammation themselves25-29. Moreover, OSE-specific Abs have also been used to image vascular lesions30-33. Thus, OSE are both markers and mediators of inflammation, and targeting them limits inflammation. Associating IL-2 with OSE Abs should combine targeting to inflammation sites with limiting inflammation through both anti-OSE Abs effects and stimulation of Tregs.

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The generation of OSEs16. Tissue damage, cellular stress and cell death result in increased oxidative stress, which promotes lipid peroxidation. Lipid peroxidation can occur through non-enzymatic mechanisms, such as reactive oxygen species (ROS), and through enzymatic mechanisms, including myeloperoxidases, 12/15-lipoxygenases, cyclooxygenases and cytochrome P450. The oxidation of sn‐2 polyunsaturated fatty acids (PUFAs) of membrane phospholipids leads to fragmentation and the generation of highly reactive breakdown products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). In addition, different types of oxidized phospholipids (OxPLs) can be generated from different phospholipid backbones, including oxidized phosphatidylcholine, oxidized phosphatidylethanolamine

(OxPE), oxidized phosphatidylserine (OxPS) and oxidized cardiolipin (OxCL). The newly generated breakdown products and the oxidized and truncated residual core OxPLs can in turn react with free amino groups of protein side chains or lipids that are localized in their vicinity, forming stable covalent adducts and creating oxidation-specific epitopes (OSEs). Because phosphocholine (PC) as an OSE is only presented as an epitope in the context of OxPL, these epitopes are termed PC‐OxPLs for clarity. The PC moiety can also be a component of the capsular polysaccharide of bacteria, where it is not part of a phospholipid and is constitutively presented as an epitope. In addition, an adduct between an oxidative fragment of docosahexaenoic acid, (E)-4-hydroxy-7-oxohept-5-enoic acid and lysines of proteins (or aminophospholipids) can lead to the formation of 2-(ω-carboxyethyl) pyrrole (CEP). OSE‐modified proteins or lipids are sensed by innate immune responses and represent a unique class of damage-associated molecular patterns (DAMPs).