Plasma levels of Th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia

Li, Haozhe; Zhang, Qinting; Li, Ningning; Wang, Fan; Xiang, Hui; Zhang, Zongfeng; Su, Yousong; Huang, Yueqi; Zhang, Shengyu; Zhao, Guangsheng; Zhou, Rubai; Mao, Ling; Lin, Zhiyun; Cai, Wei-Xiong; Fang, Yiru; Xie, Bin; Zhao, Min; Wu, Hong

doi:10.1016/j.psychres.2016.10.061

Cited by 62 publications

(62 citation statements)

References 70 publications

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“…In the peripheral blood of patients with schizophrenia, there are validated findings on an activation of the immune-inflammatory response system (IRS), including M1 macrophagic activation, with increased production of IL-6 and tumor necrosis factor alpha (TNF)-α, T helper (Th)-1 activation, with increased levels of interferon (IFN) and IL-2, and activation of a Th-17 response with increased levels of IL-17 [29][30][31]. Schizophrenia patients also show increased levels of immune products which have immunosuppressive effects, for example the sIL-2R and sIL-1RA, to name a few [32].…”

Section: Introductionmentioning

confidence: 99%

The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

Roomruangwong¹,

Noto²,

Kanchanatawan³

et al. 2018

Preprint

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In this paper we propose a novel theoretical framework, which was previously developed for major depression and bipolar disorder, namely the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first episode psychosis (FEP), acute relapses, chronic and treatment resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6 and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17) and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway as well as chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3 and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-a receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin and other acute phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic and deficit schizophrenia indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor which may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Components of the CIRS may offer promising therapeutic targets for schizophrenia.

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Section: Introductionmentioning

confidence: 99%

The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

Roomruangwong¹,

Noto²,

Kanchanatawan³

et al. 2018

Preprint

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“…Recently, Li et al reported immune factors (C3 and Th17-related cytokines) were related to schizophrenia and aggressive behavior ( 11 ), it suggested some immune factors would be potential biomarkers for aggressive behavior with schizophrenia. The immune repertoire sequencing is a new tool for deciphering mechanisms of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

“…Although the etiology of violent and aggressive behavior in schizophrenia is multifactorial, genetic inheritance may strongly contribute to it ( 4 , 6 , 7 ). Recent studies suggested that immuno-inflammatory processes are involved in the etiology of schizophrenia ( 8 – 10 ) and aggressive behavior in schizophrenia ( 11 ). For example, Toxoplasma gondii antibodies have been observed in some schizophrenic populations ( 12 , 13 ), as well as increases in maternal ( 14 – 16 ) and childhood infections ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Clonal Characteristics of T-Cell Receptor Repertoires in Violent and Non-violent Patients With Schizophrenia

Zhou

Cao

et al. 2018

Front. Psychiatry

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Background: Activated or impaired T-cell function in inflammatory and degenerative process can contribute to the risk and progression of schizophrenia. This study used immune repertoire sequencing to investigate the T-cell receptor beta variable chain (TRBV) presence in blood mononuclear cells in the violent or non-violent schizophrenic patients.Methods: Ten violent and 10 non-violent schizophrenic patients and 8 matched healthy controls were enrolled. The Brief Psychiatric Rating Scale (BPRS) was used to evaluate patients' psychiatric symptoms. The level of aggression was assessed using the Modified Overt Aggression Scale (MOAS). The complementarity-determining region 3 (CDR3) of TRBV was detected using multiplex-PCR and high-throughput sequencing.Results: The TCR repertoire diversity were no significant differences in the Shannon–Wiener or inverse Simpson diversity index between three groups. Principal component analysis (PCA) of TRBV composition and abundance showed that principal component 1 and principal component 2 can explain 28.88 and 13.24% of total variation, respectively. Schizophrenic patients (violent and non-violent) had significantly different V gene distribution compared to healthy controls. In particular, TRBV2 occurred at a significantly higher frequency in the violent schizophrenia group than in the non-violent schizophrenia and healthy control groups, and TRBV7-2 occurred at a significantly higher frequency in the non-violent schizophrenia group than in the violent schizophrenia and healthy control groups.Conclusions: The results suggest that violent and non-violent schizophrenic patients carry abnormal T-cell receptor repertoires, and these data provide a useful clue to explore the etiology of violent behavior in schizophrenia.

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“…As mentioned above, all of the complement pathways converge at the point of C3 and data related to C3 levels in blood from schizophrenia patients are also controversial. Some studies found no alteration (Spivak et al, 1993) or increased levels of C3 in patients compared to controls (Maes et al, 1997;Shcherbakova et al, 1999;Hakobyan et al, 2005;Boyajyan et al, 2010), while others found a decrease and suggest a negative correlation between the serum levels of C3 and the severity of the symptoms (Wong et al, 1996;Li et al, 2016; Figure 1). The reasons for these differences are unknown, but may include either population-specific genetics and environmental risk factors or the stage of illness (acute vs. chronic).…”

Section: Complement In Schizophreniamentioning

confidence: 99%

“…Additionally, C4b binds to the complement protein FIGURE 1 | Complement activation pathways and the activity or expression of their individual components (either protein or mRNA) in schizophrenia and autism spectrum disorder (ASD). ↑ red, increased protein activity or expression in blood from patients; ↓ red, decreased protein activity or expression in blood from patients; ↑ blue, increased RNA expression in brain tissues from patients; ↓ blue, decreased RNA expression in brain tissues from patients (Spivak et al, 1989(Spivak et al, , 1993Warren et al, 1994;Wong et al, 1996;Maes et al, 1997;Shcherbakova et al, 1999;Hakobyan et al, 2005;Mayilyan et al, 2006;Corbett et al, 2007;Boyajyan et al, 2010;Momeni et al, 2012;Nardone et al, 2014;Li et al, 2016;Sekar et al, 2016;Fagan et al, 2017;Shen et al, 2018). The Figure does not distinguish between strong and weak evidence.…”

Section: Complement System Activation: a Backgroundmentioning

confidence: 99%

Complement System in Brain Architecture and Neurodevelopmental Disorders

et al. 2020

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Current evidence indicates that certain immune molecules such as components of the complement system are directly involved in neurobiological processes related to brain development, including neurogenesis, neuronal migration, synaptic remodeling, and response to prenatal or early postnatal brain insults. Consequently, complement system dysfunction has been increasingly implicated in disorders of neurodevelopmental origin, such as schizophrenia, autism spectrum disorder (ASD) and Rett syndrome. However, the mechanistic evidence for a causal relationship between impaired complement regulation and these disorders varies depending on the disease involved. Also, it is still unclear to what extent altered complement expression plays a role in these disorders through inflammation-independent or-dependent mechanisms. Furthermore, pathogenic mutations in specific complement components have been implicated in the etiology of 3MC syndrome, a rare autosomal recessive developmental disorder. The aims of this review are to discuss the current knowledge on the roles of the complement system in sculpting brain architecture and function during normal development as well as after specific inflammatory insults, such as maternal immune activation (MIA) during pregnancy, and to evaluate the existing evidence associating aberrant complement with developmental brain disorders.

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Plasma levels of Th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia

Cited by 62 publications

References 70 publications

The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

Clonal Characteristics of T-Cell Receptor Repertoires in Violent and Non-violent Patients With Schizophrenia

Complement System in Brain Architecture and Neurodevelopmental Disorders

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