Abstract
Schizophrenia is known to be accompanied not only with an imbalance in the neurotransmitter systems but also with immune system dysregulation and chronic low-grade inflammation. Extracellular histones and nucleosomes as damage-associated molecular patterns (DAMPs) trigger systemic inflammatory and toxic reactions by activating Toll-like receptors. In this work, we obtained the first evidence that polyclonal IgGs of patients with schizophrenia effectively hydrolyze five histones (H1, H2a, H2b, H3, and H4). Several strict criteria were used to demonstrate that histone-hydrolyzing activity is a property of the analyzed IgGs. The IgGs histone-hydrolyzing activity level, depending on the type of histone (H1–H4), was statistically significantly 6.1–20.2 times higher than that of conditionally healthy donors. The investigated biochemical properties (pH and metal ion dependences, kinetic characteristics) of these natural catalytic IgGs differed markedly from canonical proteases. It was previously established that the generation of natural catalytic antibodies is an early and clear sign of impaired humoral immunity. One cannot, however, exclude that histone-hydrolyzing antibodies may play a positive role in schizophrenia pathogenesis because histone removal from circulation or the inflamed area minimizes the inflammatory responses. Thus, it can be assumed that histone-hydrolyzing antibodies are a link between humoral immunity and inflammatory responses in schizophrenia.
Highlights
Histones and their post-translational modifications play a key role in chromatin remodeling and gene transcription
According to ICD-10 classification, 11 patients were diagnosed with F20.00, 14 patients with F20.01, 11 patients with F20.02, eight patients were diagnosed with F20.09, and six patients were diagnosed with F20.6
All study participants had no signs of active inflammatory or autoimmune diseases, tumors, temporal lobe epilepsy, or encephalitis that contribute to the development of organic psychosis
Summary
Histones and their post-translational modifications play a key role in chromatin remodeling and gene transcription. In addition to intranuclear functions, histones act as damage-associated molecular patterns (DAMPs) [1,2] when they are released into the extracellular space, exhibiting significant toxic or inflammatory activity in vivo and in vitro [3,4]. The administration of exogenous histones to laboratory animals leads to systemic inflammatory reactions through the activation of Toll-like receptors and downstream inflammatory pathways. Anti-histone treatment (for instance, specific neutralizing antibodies, recombinant thrombomodulin, heparin, and activated protein C) protect animals from sepsis and lethal endotoxemia, ischemia/reperfusion injury, stroke, peritonitis, pancreatitis, thrombosis and hypercoagulation [5]. Extracellular histones can be considered as biomarkers and new promising therapeutic targets in several human diseases
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