TY - JOUR

T1 - Natural catalytic IgGs hydrolyzing histones in schizophrenia

T2 - Are they the link between humoral immunity and inflammation?

AU - Ermakov, Evgeny A.

AU - Parshukova, Daria A.

AU - Nevinsky, Georgy A.

AU - Buneva, Valentina N.

PY - 2020/9/30

Y1 - 2020/9/30

N2 - 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.

AB - 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.

KW - Abzymes

KW - Antibodies

KW - DAMPs

KW - Histones

KW - Humoral immunity

KW - IgG proteolytic activity

KW - Schizophrenia

KW - ANTIBODIES

KW - AUTOANTIBODIES

KW - humoral immunity

KW - SYSTEMIC-LUPUS-ERYTHEMATOSUS

KW - INCREASES

KW - EXTRACELLULAR HISTONES

KW - SERUM

KW - schizophrenia

KW - CYSTEINE CATHEPSINS

KW - AUTOPHAGY

KW - CELL-DEATH

KW - histones

KW - DNA

KW - antibodies

KW - abzymes

UR - http://www.scopus.com/inward/record.url?scp=85091988367&partnerID=8YFLogxK

U2 - 10.3390/ijms21197238

DO - 10.3390/ijms21197238

M3 - Article

C2 - 33008051

AN - SCOPUS:85091988367

VL - 21

SP - 1

EP - 25

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 19

M1 - 7238

ER -