Natural Catalytic IgGs Hydrolyzing Histones in Schizophrenia: Are They the Link between Humoral Immunity and Inflammation?

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.

Catalytic Antibodies in Bipolar Disorder: Serum IgGs Hydrolyze Myelin Basic Protein

“…We also showed earlier pronounced differences in the level of MBP-hydrolyzing activity of serum antibodies depending on the clinical features of schizophrenia, such as the type of course of the disease, the duration of the disease, and the presence of remission [38]. In addition, the cross-reactivity of antibodies with histone-hydrolyzing and MBP-hydrolyzing activity, as shown in a series of studies [39][40][41][42], indicates a connection between inflammation and damage of the myelin sheath.…”

Immune System Abnormalities in Schizophrenia: An Integrative View and Translational Perspectives

“…Catalytic antibodies are only a minor part of natural antibodies but significantly enhance the immune system’s functionality ( 55 ). Catalytic antibodies hydrolyzing DNA ( 56 ), RNA and miRNA ( 57 , 58 ), histones ( 59 ), and myelin basic protein (MBP) ( 60 , 61 ) have been described in schizophrenia. Notably, these antigens are DAMPs.…”

Secretory immunoglobulin A from human milk hydrolyzes 5 histones and myelin basic protein

“…The MBP-and histone-hydrolyzing abzymes have been detected in the blood sera of patients with multiple sclerosis (Polosukhina et al, 2004;Baranova et al, 2019b), SLE (Bezuglova et al, 2011), schizophrenia (Parshukova et al, 2019;Ermakov et al, 2020), and HIV infection (Baranova et al, 2016(Baranova et al, , 2017a(Baranova et al, ,b, 2018(Baranova et al, , 2019a(Baranova et al, , 2020(Baranova et al, , 2021. As mentioned above, fresh human milk contains many different abzymes with typical and unusual functions that are not present in the blood of patients with various autoimmune diseases.…”