Immune involvement in schizophrenia and autism: Etiology, pathology and animal models

doi:10.1016/j.bbr.2008.12.016

Behavioural Brain Research

Volume 204, Issue 2, 7 December 2009, Pages 313-321

https://doi.org/10.1016/j.bbr.2008.12.016 Get rights and content

Abstract

There is increasing evidence of immune involvement in both schizophrenia and autism. Of particular interest are striking abnormalities in the expression of immune-related molecules such as cytokines in the brain and cerebral spinal fluid (CSF). It is proposed that this represents a permanent state of brain immune dysregulation, which begins during early development. One possibility is that maternal infection, a known risk factor for schizophrenia and autism, sets this immune activation in motion. Several animal models are being used to investigate this hypothesis. There is also recent evidence that, among schizophrenic subjects, those associated with maternal infection display a distinctive pathology, which suggests that diverse causes for this disorder may explain some of its heterogeneity. The human and animal results related to immune involvement suggest novel therapeutic avenues based on immune interventions.

Section snippets

Immune dysregulation in schizophrenia and autism

Both long standing as well as recent, novel findings point to immune dysregulation in schizophrenia and autism. There have been many reports of abnormalities in peripheral immune cells, as well as associations between variants of genes for cytokines, their receptors and HLA in these disorders. In addition, numerous epidemiological studies have associated schizophrenia and autism with autoimmunity and allergies [1], [2], [3], [4], [5], [6]. The meaning of these associations is not yet clear, but

Maternal infection is an immune-related risk factor associated with schizophrenia and autism

A leading candidate for initiating immune changes early in development is maternal infection. Following the important work of Mednick, over 25 studies have analyzed schizophrenia incidence following influenza epidemics, and the majority have found an increased incidence among exposed offspring. Although these early studies were critical in highlighting this risk factor, their retrospective design had drawbacks. Brown and colleagues [14] used a prospective approach to examine the medical records

Animal models of maternal infection – influenza

Since maternal influenza infection is a well-established risk factor for schizophrenia, it was of interest to characterize its effects in an animal model. Respiratory infection with human influenza virus in pregnant mice at mid-gestation results in specific histological abnormalities in the hippocampus and cortex of the neonatal offspring [28], [29] (Table 1). These include layer- and region-specific changes in the expression of the presynaptic marker SNAP-25, as well as in nNOS and reelin.

Animal models of maternal infection – peridontal bacteria

Bacterial infections have recently been associated with schizophrenia [20], and obstetrical complications caused by such infections increase the risk for schizophrenia (e.g., [15]). Intrauterine infections are prevalent among women who give birth prematurely, and very low birth weight is correlated with perinatal mortality and neonatal morbidity, including serious neurological disorders. Among the microorganisms isolated from the preterm placenta are gram-negative bacteria that are known to be

Animal models of maternal immune activation – poly(I:C)

An alternative to infection is to induce a maternal anti-viral inflammatory response using the synthetic dsRNA, poly(I:C), in the absence of pathogen. Poly(I:C) acts through the toll-like receptor (TLR)3, and its injection in pregnant rats or mice is sufficient to cause all of the behavioral and histological abnormalities assayed for thus far in the offspring of maternal influenza infected mothers [31], [35], [42]. The poly(I:C) model of MIA has been widely adopted and many results have been

Animal models of maternal immune activation – LPS

To mimic bacterial infection, another method of MIA is used. Pregnant mice, rats, rabbits or ewes are injected (intrauterine, I.P. or I.V.) with lipopolysaccharide (LPS), which acts through TLR4. Some of the same behavioral abnormalities seen in the offspring of poly(I:C)-treated mothers have been observed in the offspring of LPS-treated mothers (Table 1) [24], [60], [61], [62]. For instance, a severe schedule of LPS administered I.P. causes a PPI deficit in the offspring [63]. Moreover, single

Maternal immune activation elevates cytokines in the fetal environment

In addition to the alterations in placental cytokines by periodontal infection, there is a significant literature on the cytokines induced in the fetal environment by LPS-induced MIA. It is clear that several cytokines are elevated in the placenta (IL-1β, IL-6, TNFα) and amniotic fluid (IL-6, TNFα) [24], [61]. The more difficult and interesting issue is whether cytokines are altered in fetal brain, and significant increases in IL-1β, IL-6, TNFα and IFNγ in fetal brain were found when LPS was

The pro/anti-inflammatory cytokine balance mediates MIA effects on the fetus

MIA induces cytokines, but what are their effects on the fetus? Two approaches have been taken towards answering this question: injecting or up-regulating cytokines during pregnancy in the absence of MIA, or blocking endogenous cytokines or preventing their induction during MIA. Investigation of the role of TNFα in LPS-induced fetal loss and growth restriction showed that injection of anti-TNF( antibodies or an inhibitor of TNFα synthesis (pentoxifylline) can reduce these effects of LPS.

Sites and mechanisms of cytokine action – therapeutic implications

The evidence of elevated cytokines in the fetal brain following MIA raises the obvious possibility that cytokines act directly on developing neurons and glia. It is known, for instance, that transgenic, early over-expression of IL-6 in astrocytes causes major neuropathology and decreases seizure threshold [120], and seizures are a common symptom in autism. IL-6 and related cytokines strongly influence many features of brain development and neural repair [80].

In addition to altering fetal brain

Other schizophrenia risk factors

Along with maternal infection, several other risk factors have been established, which appear at first glance to have little in common with each other or maternal infection. Among these are birth in winter–spring months, birth or development in an urban setting, prenatal nutritional deficiency, and maternal stress [99], [100], [101], [102]. These diverse environmental factors can, however, be linked to the immune hypotheses in various ways. For instance, birth in winter–spring months and

Perspectives

There are a rapidly increasing number of studies showing immune dysregulation in the young and adult autistic and schizophrenia brain. The evidence is based on microarray, ELISA, histological and PCR techniques, and involves CSF as well as postmortem material. Moreover, a variety of these findings have been replicated in independent laboratories. One gap in this story to date is that the evidence for activated astrocytes and microglia in the schizophrenic brain is much less striking than is the

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Research reportImmune involvement in schizophrenia and autism: Etiology, pathology and animal models

Abstract

Section snippets

Immune dysregulation in schizophrenia and autism

Maternal infection is an immune-related risk factor associated with schizophrenia and autism

Animal models of maternal infection – influenza

Animal models of maternal infection – peridontal bacteria

Animal models of maternal immune activation – poly(I:C)

Animal models of maternal immune activation – LPS

Maternal immune activation elevates cytokines in the fetal environment

The pro/anti-inflammatory cytokine balance mediates MIA effects on the fetus

Sites and mechanisms of cytokine action – therapeutic implications

Other schizophrenia risk factors

Perspectives

J Autoimmun

Biol Psychiatry

Pediatr Neurol

Schiz Res

Int J Dev Neurosci

Curr Opin Neurobiol

Biol Psychiatry

Trends Neurosci

J Psychiatr Res

J Psychiatr Res

Neurosci Biobehav Rev

Biol Psychiatry

Behav Brain Res

Neurosci

Brain Behav Immun

J Psychiatr Res

Brain Behav Immun

Neuropsychopharmacology

Schiz Res

Semin Fetal Neonatal Med

Clin Neurosci Res

Neurosci Res

J Neuroimmunol

Toxicol Lett

Am J Pathol

Brain Res Dev Brain Res

Neuroscience

Prog Neuropsychopharmacol Biol Psychiat

Regul Toxicol Pharmacol

J Reprod Immunol

Trends Immunol

Semin Fetal Neonatal Med

Brain Behav Immun

Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

Neurotox Res

Immunity, neuroglia and neuroinflammation in autism

Intl Rev Psychiat

Immunological aetiology of major psychiatric disorders. Evidence and therapeutic implications

Drugs

Rationale for a trial of immunosuppressive therapy in acute schizophrenia

Mol Psychiatry

Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review

Biol Psychiatry

Neuroglial activation and neuroinflammation in the brain of patients with autism

Ann Neurol

Inflammation-related genes up-regulated in schizophrenia brains

BMC Psychiat

Prenatal infectious and nutritional factors and risk of adult schizophrenia

Expert Rev Neurotherapeut

Serologic evidence of prenatal influenza in the etiology of schizophrenia

Arch Gen Psychiatry

Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring

Am J Psychiatry

Maternal effects on schizophrenia risk

Science

The neurobiology of infantile autism

Annu Rev Neurosci

Research report
Immune involvement in schizophrenia and autism: Etiology, pathology and animal models