By Annette M. Boyle
SAN ANTONIO — Can cytokines, the signaling proteins secreted by immune system cells, offer a way to prevent development of schizophrenia in susceptible individuals or keep psychosis from occurring in veterans with the disorder?
Dimitre Dimitrov, MD
Dimitre Dimitrov, MD, staff psychiatrist at the South Texas Veterans Health Care System and assistant professor at the University of Texas Science Center in San Antonio, thinks they just might.
Dimitrov and colleagues recently received a VA grant to try to identify a constellation of cytokines uniquely associated with schizophrenia.
“My goal is to identify specific cytokines active during an exacerbation of schizophrenia that correlate with psychosis. If we can identify the specific cytokines, we would have a signature of the disorder. Potentially, we would be able to prevent the occurrence of schizophrenia or its symptoms,” Dimitrov told US Medicine.
Dimitrov has been working toward this goal for years. Last fall, he and co-authors Nicole Braida, MD, chief of psychiatry services, South Texas Veterans Health Care System and Consuelo Walss-Bass, PhD, an associate professor in the department of psychiatry at the University of Texas Health Science Center, published an article in Psychiatric Times that presented evidence for immune system dysfunction in the development of schizophrenia.
The Role of Inflammation
While the theory that inflammation plays a role in schizophrenia is far from new, recent research has provided additional evidence of the relationship, wrote Dimitrov and his colleagues in “The Link Between Immune System Dysregulation and Schizophrenia.” Among the evidence for the link is the significantly greater proportion of mononuclear macrophages present in the spinal fluid of patients with schizophrenia than in spinal fluid of controls, indicating a dysfunction in the blood-brain barrier.
When activated, these macrophages produce inflammatory cytokines. “Chronically activated macrophages, microglia, and T cells synthesize inflammatory compounds that destabilize the brain and lead to schizophrenia,” explained the authors. Positron emission tomography shows that “microglial cells — the macrophages of the brain — are activated during psychosis,” they added. Activated microglia also stimulate astrocyte production of serum S100B, a marker of inflammation in the brain that is elevated in patients with schizophrenia.What Is the Role of Immune Dysfunction in Schizophrenia? VA Researchers Seek to Find Out
Common Etiological Factors for Schizophrenia and BPD
Fully understanding the role of cytokines extends beyond explaining the etiology of schizophrenia. High levels of pro-inflammatory cytokines also are associated with bipolar disorder (BPD). Dimitrov and colleagues observed that overlap in “distinct gene expression patterns have been found in the monocytes of patients with schizophrenia and bipolar disorder.” An analysis of the molecules that lead to inflammation might enable researchers to identify unique disease signatures and increase understanding of the development of both disorders.
The authors postulate that, “dysregulation of a particular set of cytokines may lead to schizophrenia, while another set may lead to depression or bipolar disorder.” Both could potentially be improved by targeted adjunctive anti-inflammatory therapy.
A study published in July in the Archives of General Psychiatry supports common etiological factors for schizophrenia and BPD, as well as autism spectrum disorders. Looking at population registers in Sweden and Israel, researchers found that the presence of schizophrenia or BPD in first-degree relatives was a consistent and significant risk factor for autism spectrum disorders — and the findings also were consistent with a similar study in Denmark.1
For Dimitrov, the likelihood of a common etiology for the disorders makes his quest even more compelling. “Can we find a different constellation of cytokines associated with schizophrenia than with BPD?” asked Dimitrov. “That is the challenge. Will there be just one signature for schizophrenia — or are there multiple diseases, several schizophrenias?”
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Lichtenstein P. Family History of Schizophrenia and Bipolar Disorder as Risk
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The Role of Pathogen Exposure
Macrophages often secrete cytokines in response to exposure to pathogens. Certain cytokines are elevated in patients with schizophrenia, indicating a role for infectious agents in development or triggering of the disorder. The authors note that pathogens might affect in utero development of the immune system, contributing to the etiology of schizophrenia. As evidence, children whose mothers contracted influenza while pregnant have a three-fold increase in risk of having schizophrenia. Maternal infection with rubella, varicella zoster, herpes and other viruses also has been associated with the development of schizophrenia.
Increases in cytokines caused by exposure to pathogens prenatally or in early childhood, particularly, may affect development of the brain and increase the risk of schizophrenia. Even later infection may contribute to development of the disorder. Mumps, meningitis, hepatitis C and toxoplasmosis in childhood or as an adult have all been implicated in schizophrenia.
In addition, some immune system genes that appear to have a role in schizophrenia also regulate the life cycle of several pathogens. “Understanding the interplay between gene function and pathogen exposure may help explain the role of gene-environment interactions in schizophrenia development,” noted the authors.
Recent studies have demonstrated an association between development of schizophrenia and specific variants of immune system genes. Pathogen exposure during early neurodevelopment may cause mutations that make individuals more susceptible to the disorder, while exposure later in life could determine the expression and severity of the symptoms.
Some pathogens might trigger symptoms by interfering with the function of neurotransmitters. “A number of viruses use the same receptors as are used for dopamine and can lead to psychosis,” Dimitrov said. Changes in the dopaminergic system have long been considered significant in the development of schizophrenia.
“The dopamine theory explains some symptoms of schizophrenia,” Dimitrov said. “The glutamatergic, abnormal immune function and neurodevelopmental theories explain some, too. I’m inclined to find something common to put it all together. The metabolism of tryptophan, which is affected by pro-inflammatory cytokines, could have an effect on a lot of receptors and explain many of the changes that occur. Maybe the theories are not mutually exclusive.”
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