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Evgeny Ermakov1, Valentina Buneva2, Georgy Nevinsky3
1ICBFM SB RAS, Novosibirsk, Russia; NSU, Novosibirsk, Russia, evgeny_ermakov@mail.ru
2ICBFM SB RAS, Novosibirsk, Russia; NSU, Novosibirsk, Russia, buneva@niboch.nsc.ru
3ICBFM SB RAS, Novosibirsk, Russia; NSU, Novosibirsk, Russia, nevinsky@niboch.nsc.com
Schizophrenia is known to be associated not only with imbalance in the neurotransmitter systems but also with immune system dysregulation. In this work, we found that pure polyclonal IgG preparations of patients with schizophrenia possess histone hydrolyzing proteolytic activity. The presence of proteolytic activity of IgGs is evidence of impaired humoral immune system in schizophrenia, which can be used as a biomarker for immunophenotyping of patients.
Thanks so much for your report. Let me clarify your conclusions. Are the histone-hydrolyzing antibodies a pathological factor that causes myelin damage? Or, conversely, protective, aimed at weakening immune inflammation in schizophrenia? In your opinion, what event is primary during the development of schizophrenia: the appearance of histones or the appearance of antibodies with proteolytic activity?
Dear Elena, thanks for your comment! I think that histone-hydrolyzing antibodies play a protective role in schizophrenia pathogenesis because histone removal from circulation minimizes the immune response. However, the appearance of catalytic antibodies among the total IgG pool is a sign of disturbances in the humoral immune system. It is possible that the formation of catalytic antibodies is a compensatory reaction to an increase in the level of histones in the bloodstream. Histones can intensely enter the blood during cell death caused by inflammation. Chronic low-grade inflammation is closely associated with the development of schizophrenia, which is confirmed by many works. Therefore, answering your question, in my opinion, the primary event in the development of schizophrenia is the appearance of histones in the bloodstream, as well as a pro-inflammatory state. Many factors contribute to the pro-inflammatory state of schizophrenia, including environmental factors, but they are still not well understood.
Moreover, according to the results of Parshukova D (Abstract ID: 333), patients with schizphrenia also form antibodies that hydrolyze the myelin basic protein (MBP). Interestingly, there is evidence of cross-reactivity of catalytic antibodies to MBP and histones [Baranova S.V., et al. Autoantibodies in HIV-infected patients: cross site-specific hydrolysis of H1 histone and myelin basic protein. BioFactors. 2019 Mar;45(2):211-222]. Therefore, it cannot be ruled out that compensatory antibodies against histones formed at the first stage initially play a protective role, but due to the cross-reactivity to MBP and disturbances in antibody generation, they cause long-term pathological effects.