Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, Université Paris Cité, 75006 Paris, France.
Immunitrack Aps, Lersoe Park Alle 42, 2100 Copenhagen, Denmark.
Int J Mol Sci. 2023 Feb 8;24(4):3416. doi: 10.3390/ijms24043416.
The interaction of some human antibodies with heme results in posttranslational acquisition of binding to various self- and pathogen-derived antigens. The previous studies on this phenomenon were performed with oxidized heme (Fe). In the present study, we elucidated the effect of other pathologically relevant species of heme, i.e., species that were formed after contact of heme with oxidizing agents such as hydrogen peroxide, situations in which heme's iron could acquire higher oxidation states. Our data reveal that hyperoxidized species of heme have a superior capacity to heme (Fe) in triggering the autoreactivity of human IgG. Mechanistic studies demonstrated that oxidation status of iron was of critical importance for the heme's effect on antibodies. We also demonstrated that hyperoxidized heme species interacted at higher affinities with IgG and that this binding occurred through a different mechanism as compared to heme (Fe). Regardless of their profound functional impact on the antigen-binding properties of antibodies, hyperoxidized species of heme did not affect Fc-mediated functions of IgG, such as binding to the neonatal Fc receptor. The obtained data contribute to a better understanding of the pathophysiological mechanism of hemolytic diseases and of the origin of elevated antibody autoreactivity in patients with some hemolytic disorders.
一些人类抗体与血红素相互作用，导致翻译后获得与各种自身和病原体来源的抗原结合的能力。以前对这种现象的研究是使用氧化血红素（Fe）进行的。在本研究中，我们阐明了血红素的其他病理相关物质的影响，即血红素与过氧化氢等氧化剂接触后形成的物质，在这种情况下，血红素的铁可以获得更高的氧化态。我们的数据表明，超氧化的血红素物质比血红素（Fe）更能引发人 IgG 的自身反应性。机制研究表明，铁的氧化状态对血红素对抗体的作用至关重要。我们还证明，超氧化的血红素物质与 IgG 以更高的亲和力相互作用，并且这种结合与血红素（Fe）的结合机制不同。超氧化的血红素物质尽管对抗体的抗原结合特性具有深远的功能影响，但并不影响 IgG 的 Fc 介导的功能，例如与新生儿 Fc 受体的结合。所获得的数据有助于更好地理解溶血性疾病的病理生理机制以及某些溶血性疾病患者抗体自身反应性升高的起源。
