Various pathological processes are known to be associated with the production of IgG autoantibodies, which have high affinity for self-antigens and often cause tissue injury and the development of autoimmune diseases. However, the mechanism of their cytotoxic activity is not clearly understood yet. Here, we have shown that the action of these autoantibodies on cells expressing TNFR1 (the cell surface receptor for TNFα) can cause both caspase-dependent apoptosis and necroptosis of these cells, with suppression of apoptosis resulting in switching to RIP1-dependent necroptosis. Analysis of necroptotic mechanisms has shown that a critical point of necroptosis is phosphorylation of RIP1 and RIP3 kinases, which is followed by the involvement of lysosomes and mitochondria in this process. The induction of cytotoxicity is initiated by the interaction of autoantibodies with TNFR1, and autoantibodies can therefore be regarded as a new functional ligand for this receptor. The innate immunity protein Tag7 (PGLYRP1) described in our recent studies is also a ligand for TNFR1 and competes with autoantibodies for binding with it. Supposedly, the cytotoxic effect of autoantibodies is one of the factors responsible for autoimmune diseases that lead to tissue injury.

已知各种病理过程与IgG自身抗体的产生有关，它们对自身抗原具有高亲和力，并经常引起组织损伤和自身免疫性疾病的发展。但是，其细胞毒性活性的机制尚不清楚。在这里，我们已经表明，这些自身抗体对表达TNFR1（TNFα的细胞表面受体）的细胞的作用可以导致caspase依赖性凋亡和这些细胞的坏死性坏死，并抑制了凋亡，导致转为RIP1依赖性坏死性坏死。尸检机制的分析表明，尸检的关键点是RIP1和RIP3激酶的磷酸化，随后溶酶体和线粒体参与了这一过程。细胞毒性的诱导是通过自身抗体与TNFR1的相互作用而引发的，因此，自身抗体可以被视为该受体的新功能配体。我们最近的研究中描述的先天免疫蛋白Tag7（PGLYRP1）也是TNFR1的配体，并与自身抗体竞争与其结合。据推测，自身抗体的细胞毒性作用是导致导致组织损伤的自身免疫疾病的因素之一。