Prenatal Immune Challenge – ‘Disease Primer’ Increasing the Offspring’s Vulnerability to Stress

Prenatal Immune Challenge ‘Disease Primer’ Offspring’s Vulnerability Stress
Prenatal immune challenge – ‘disease primer’ – offspring’s susceptibility to stress

A recent study published in Science is probably the first to provide evidence suggesting that prenatal immune challenge can function as a ‘disease primer’ that amplifies the offspring’s susceptibility to stress and its detrimental neuro-pathological effects in peri-pubertal life.

Prenatal maternal infection and postnatal exposure to psychological trauma are two environmental risk factors for developmental psychiatric disorders, including autism, schizophrenia, and bipolar disorder. Epidemiologic studies indicate that prenatal infection may play an important role in the etiopathogenesis of schizophrenia, which is primarily a neurodevelopmental disorder.

Around one per cent of the population suffers from schizophrenia. Prenatal infections such as toxoplasmosis or influenza, psychological, stress or family history have all come into question as risk factors. Nevertheless, until now researchers were unable to identify the interplay of the individual factors linked to this serious mental disease.

One possible reason proposed to explain the association between infection in utero and schizophrenia in the offspring, and particularly why several different infections could give rise to schizophrenia, is that they act through stimulation of the cytokine response.

In fact, an excess of proinflammatory maternal cytokines has been associated with several neurodevelopmental disorders.  To add further complexity, maternal stress during pregnancy and childhood trauma has also been implicated in the pathogenesis of schizophrenia.

The possibility of whether the actual combination of prenatal infection and postnatal stress contributes to schizophrenia is poorly understood, and this hypothesis may need direct verification.

However, the recent study published in the March issue of Science magazine suggests that stress in puberty has the potential to unmask latent psychopathology in neurodevelopmentally vulnerable subjects with prenatal infectious histories.

In this study, Sandra Giovanoli and colleagues from the Swiss Federal Institute of Technology, Zurich, Switzerland, and the University of Duisburg-Essen, Essen, Germany, used a model of prenatal immune activation in mice. They compared the consequences of prenatal immune activation with or without additional postnatal stress challenge in mice. A cytokine associated viral-like acute-phase response was induced by the viral mimetic [poly(I:C)], a synthetic analog of double-stranded RNA.

The investigators were able to find clear evidence that the combination of two environmental factors contributes significantly to the development of schizophrenia-relevant brain changes and at which stages in a person’s life they need to come into play for the disorder to break out.

The investigators show that a combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. Furthermore, the prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress.

The authors found that only the combined immune activation and stress led to a 2.5- to 3-fold increase in hippocampal and prefrontal brain regions’ expression of markers characteristic of activated microglia. Moreover, the hippocampal microglia response was accompanied by the presence of elevated levels of the pro-inflammatory cytokines interleukin (IL)-1-beta and tumor necrosis factor (TNF)-alpha.

In conclusion, these results show synergistic interactions between two environmental risk factors that have individually been associated with developmental psychopathology. Prenatal adversities (i.e. in the form of in utero immune challenge) can thus function as a ‘disease primer’ that increases the offspring’s vulnerability to the detrimental neuropathological effects of subsequent stress.

According to the authors, prenatal infection and stress in puberty may thus be important etiological risk factors for long-term mental illness especially upon combined exposure. The authors discuss further that the transient neuroimmunological changes emerging in peripubertal offspring that are exposed to combined immune activation and stress capture relevant aspects of neuroinflammatory processes. The precise inflammatory signature of these processes needs further elaboration and should be extended to other neuroimmunological aspects, including extension to other members of the cytokine network.

Schizophrenia and the infection-stress interaction

The first negative environmental influence that favours schizophrenia is a viral infection of the mother during the first half of the pregnancy. If a child with such a prenatal infectious history is also exposed to major stress during puberty, the probability that he or she will suffer from schizophrenia later increases markedly. Hence, the mental disorder needs the combination of these two negative environmental influences to develop. “Only one of the factors — namely an infection or stress — is not enough to develop schizophrenia,” underscores Urs Meyer, the senior author of the Science study.

The infection during pregnancy lays the foundation for stress to “take hold” in puberty. After all, the mother’s infection activates certain immune cells of the central nervous system in the brain of the fetus: microglial cells, which produce cytotoxins that alter the brain development of the unborn child.  More comments for this study are available on

Source: Science, 2013 Mar 1;339(6123):1095-9. doi: 10.1126/science.1228261
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