"Over 25 studies have analyzed schizophrenia following influenza epidemics, and the majority have found an increased incidence among exposed offsprings." A variety of other maternal infections, such as maternal rubella, toxoplasm, and genital/reproductive infections and other bacterial infections with schizophrenia. Similarly, research groups such as, "Ciaranello and Ciaranello are concluding that, 'the principal non-genetic cause of autism is prenatal viral infection.' For instance, prenatal exposure to rubella or cytomegalovirus[...]."
The common link between these bacterial and viral infections and offspring developing these disorders "is activation of the maternal immune response." Animal models have been conducted to model maternal bacterial infections, viral infections. One such study with P. gingivalis (involved in periodontal disease) found that P. gingivalis DNA could be found in placentas of affected fetuses and the placentas show elevation of pro-inflammatory and reduction of anti-inflammatory cytokines.
Other studies have mimicked bacterial infection, but modeled maternal immune activation via use of LPS. LPS in these models was administered via IV, intrauterine and IP to pregnant mice, rats, rabbits and ewes. Conclusions from these studies were that the offspring experienced increased anxiety, deficits in social interaction and learning, brain inflammation, and altered microglial immunostaining and PET imaging. Permanent activation of astrocytes and microglial was also detected in adult offsprings.
In both LPS-induced maternal immune activation and P. gingivalis infection, several cytokines were determined to be elevated in the placenta and amniotic fluid. With specific cytokines such at IL-6 remain elevated in the hippocampus of the offspring at 4 and 24 weeks of age. " This is reminiscent of the ongoing state of immune dysregulations in adult autistic and schizophrenic brains," and remember in the LPS model the offspring also had permanent activation of astrocytes and microglial. More impressive in the link of the immune response and specifically IL-6 expression and schizophrenia and autism is that "early over expression of IL-6 in astrocytes causes major neuropathology and decreases seizure threshold and seizures are a common symptom of autism. IL-6 and related cytokines strongly influence many features of brain development and neural repair."
Autistic and schizophrenic adults have permanent elevations of cytokines in the brain, due to this research and the knowledge that injection of cytokines into adults can induce psychiatric symptoms. This further strengthens the link between cytokine induction in the placenta and the development of these disorders. In this review, the authors also point out that there has been reports that some adults and children spontaneous develope autistic symptoms following CNS infection. Under the immune system and cytokine link, this observation begins to make sense since CNS infections are known to induce pro-inflammatory cytokine responses. This adds further evidence that these two disorders may be linked to maternal infection and cytokine generation which may act on the placenta.
I found this compilation of work interesting because it offers potential drug targets, but it also suggests that it may be possible to separate schizophrenia and autism cases, which may lead to a better understanding of what are the risk factors that are attributed to autism development.
Patterson, Paul H. "Immune involvement in schizophrenia and autism: Etiology, pathology and animal models." Behavioral Brain Research 204 (2009) 313-321.
This article was very interesting! It makes me wonder if decreasing the amount of cytokines would reverse or lessen the symptoms of schizophrenia and autism. In order to figure this out you would have to specifically target the expression of cytokines in the brain or cells in the brain that are producing the cytokines. Not sure if it can be done, but an animal study would be interesting.
ReplyDeleteHow does the early immune dysregulation during pregnancy become permanent in the individual? It makes sense that cytokines would increase in the placenta when there is an infection.. but how would that lead to permanent elevated cytokines and schizophrenia/autism? Very interesting topic!
ReplyDeleteInteresting! I agree with Amy7630....how does early immune dysregulation during pregnancy permanently influence the new baby? After what we talked about in class regarding immunizations during pregnancy, and infants testing positive at birth for those conditions that the mother was vaccinated against (via cord blood), but then testing negative a few weeks later when they develop their own IgM - I'd be curious as to how permanent immune memory in the cases of autism/schizophrenia works! (phew! that was a long sentence!)
ReplyDeleteHopefully this means that we're getting closer to identifying the causes of autism and schizophrenia!! Exciting!
Holly, sorry for the delay in response, in this review they do discuss that there was a preliminary study in 25 autistic children involving anti-inflammatory drugs and found that there was a significant decrease in irritability, lethary, stereotypy and hyperactivity and most efficacious in young children. For schizophrenia the data is not so straightforward and some antipsychotics are known to influence cytokine expression, so the data is debated.
ReplyDeleteAmy, one mechanism I did read stated that in the fetal brain cytokines may be acting directly of glia and neurons, which may be the reason for permanent immune dysregulation. Multiple groups have found that the same types of histological abdormalities, cytokine activation and cellular activation (astrocytes and microlial), in young and adult offsprings (mice), but similar data has also been found in adult schizophrenics.
Thanks for getting back to me Tanya. That mechanism does make sense! I hadn't thought of that.
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