Relationship between immune and behavioral measures in schizophrenia

Kammen, Daniël P. van; McAllister, Cathy G.; Kelley, Mary E.

doi:10.1007/978-3-7091-6870-7_7

Cited by 33 publications

(19 citation statements)

References 16 publications

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“…For example, one study found plasma IL-6 to be elevated during acute phases of illness but found no difference when the patients were in remission (Frommberger et al 1997). Another study reported an association between negative behaviors and CSF levels of IL-10, but only in non-medicated patients (van Kammen et al 1997). Behavioral state, medication, age and duration of illness all contribute to the extent and most likely, the type of immune dysfunction experienced in individuals with SZ making it difficult to clearly elucidate the role of the immune system in this complicated neurodevelopmental disorder.…”

Section: 0 Discussionmentioning

confidence: 99%

Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation

Rose

Careaga

Water

et al. 2017

Brain, Behavior, and Immunity

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Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or Schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing of MIA. An additional three non-treated animals were used as controls. The offspring were followed until 4 years of age, with blood collected at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function. Induced responses from peripheral immune cells were measured using multiplex assays. At one year of age, MIA exposed offspring displayed elevated production of innate inflammatory cytokines including: interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor (TNF)α at baseline and following stimulation. At four years of age, the MIA exposed offspring continued to display elevated IL-1β, and there was also a pattern of an increased production of T-cell helper type (TH)-2 cytokines, IL-4 and IL-13. Throughout this time period, the offspring of MIA treated dams exhibited altered behavioral phenotypes including increased stereotyped behaviors. During the first two years, stereotyped behaviors were associated with innate cytokine production. Self-directed behaviors were associated with TH2 cytokine production at year 4. Data from this study suggests long-term behavioral and immune activation was present in offspring following MIA. This novel non-human primate model of MIA may provide a relevant clinically translational to help further elucidate the role between immune dysfunction and complex behavioral outputs following MIA.

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Section: 0 Discussionmentioning

confidence: 99%

Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation

Rose

Careaga

Water

et al. 2017

Brain, Behavior, and Immunity

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“…Additionally, an increase of IL-10 -a characteristic cytokine of the type-2 immune response -has been observed in schizophrenics (Cazzullo et al, 1998;Haack et al, 1999). Another study points out, that IL-10 levels in the CSF are related to the severity of the psychosis, especially to negative symptoms (van Kammen et al, 1997).…”

Section: Type-2 Immune Response Activation In Schizophreniamentioning

confidence: 96%

Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

2006

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This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by the N-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor, i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO - located in astrocytes and microglial cells - is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g., the use of anti-inflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.

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“…Darüber hinaus zeigten sich andere Zeichen einer Typ-2-Aktivierung, einschließlich der erhöhten Produktion von IgE [59]. Zudem wurde ein Anstieg von IL-10 beobachtet [9], IL-10-Spiegel im Liquor stehen dabei in Beziehung zur Schwere der schizophrenen Symptomatik [27].…”

Section: Aktivierung Der Typ-2-immunantwort Bei Schizophrenieunclassified

Immunology in schizophrenic disorders

Müller

Schwarz

2007

Nervenarzt

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This manuscript deals with whether immune-mediated mechanisms of inflammation contribute to the pathogenesis of schizophrenia. A model is presented which integrates psychoneuroimmunologic findings and actual results from pharmacological, neurochemical, and genetic studies in schizophrenia. A pivotal role in the neurobiology of schizophrenia is played by dopaminergic neurotransmission, which is modulated by influences of the glutamatergic system. The decreased function of the glutamate system described in schizophrenia seems primarily mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. Kynurenine acid is the only known endogenous NMDA receptor antagonist. In higher concentrations it blocks the NMDA receptor, but in lower concentrations it blocks the nicotinergic acetylcholin receptor, which has a prominent role in cognitive functions. Therefore, higher levels of kynurenine acid may explain psychotic symptoms and cognitive dysfunction. Several findings point out that prenatal infection, associated with an early sensitisation of the immune system, may result in an imbalance of the immune response (type 1 vs type 2) in schizophrenia. This immune constellation leads to inhibition of the enzyme indoleamin dioxigenase (IDO). It and tryptophane 2,3-dioxygenase (TDO) both catalyse the degradation from tryptophan to kynurenine. Due to the inhibition of IDO, tryptophan is metabolised to kynurenine primarily by TDO. In the CNS, TDO is located only in astrocytes, which are in particular activated in schizophrenia and in which kynurenine acid is the final product and can not be further metabolised. Therefore kynurenine acid accumulates in the CNS of schizophrenics and - due to its NMDA-antagonistic properties - leads to cognitive dysfunction and psychotic symptoms. This model describes the pathway of immune-mediated glutamatergic-dopaminergic dysregulation, which may lead to the clinical symptoms of schizophrenia. Therapeutic consequences (e.g. cyclo-oxygenase-2 inhibitors) are discussed.

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Relationship between immune and behavioral measures in schizophrenia

Cited by 33 publications

References 16 publications

Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation

Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation

Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

Immunology in schizophrenic disorders

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