Partners:
Jena, Germany
London, UK
Utrecht, Netherlands
Amsterdam, Netherlands
Barcelona, Spain
Bonn, Germany
Heidelberg, Germany
Szeged, Hungary
Zurich, Switzerland
Marie Curie Action:
035987
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Inflammatory Processes and Schizophrenic Disorders
From the psychiatric point of view, it is most intriguing that
active immune processes may be involved in the pathogenesis of
major psychiatric disorders, as suggested by evidence from recent
studies. Specifically, significant alterations of T-cell function,
along with activation of the inflammatory response system, appear
to be linked to treatment-resistant schizophrenia. Similar
processes have also been reported for affective disorders.
The abnormalities of CNS metabolism observed with functional
psychoses and depression might, therefore, arise because
genetically modulated inflammatory reactions damage the
microvascular system of the brain, with the nature of the
infectious agent being less important than the patients’
genetically influenced inflammatory response.
Chronically Elevated Poly-Reactive IgM Levels
The "natural" antibody IgM is in use, for example, as a standard
diagnostic test for rheumatoid arthritis, but possesses a low specificity.
Since the formation of chronically elevated poly-reactive IgM levels
develops years before clinical symptoms occur [Nielen et al. 2006], a
genetically predisposed aberrancy of the inflammatory response system
has been linked to various complex diseases. In the field of psychiatric
disorders, a population-based study of 7,704 patients with a diagnosis
of schizophrenia and 192,590 control subjects without psychiatric
history has revealed that a parental history of schizophrenia was
associated with a 5-fold risk for autoimmune diseases, whereas a
parental history of autoimmune diseases increased this risk only
slightly, by a factor of 1.45 [Eaton et al. 2006]. More specifically,
several antidepressants and antipsychotics show anti-inflammatory
effects [e.g., Müller and Schwarz 2006, 2007], while a quantitative
(R)-[11C]PK11195 positron emission tomography study demonstrated
microglia activation in recent-onset schizophrenia [van Berckel
et al. 2008].
Predicting Chronically Elevated IgM Levels from Genotype
To investigate the extent to which the patients’ genetically influenced inflammatory
response can be quantified and linked to vulnerability to psychiatric disorders, we have
carried out a normative study on a sample of 511 nuclear families ascertained trough
index cases with a clinical diagnosis of rheumatoid arthritis (RA). This population was
chosen, because (1) there is only a moderate overlap with psychiatric disorders, in the
range of 10-20% so that biases caused by the anti-inflammatory effects of antidepressants
and antipsychotics have little influence; (2) a genetic predisposition to RA is
well-established, so that a substantial number of subjects with elevated IgM levels can
be expected. The initial screening step revealed 80 clusters of at least 3 SNPs within
0.5 Mb regions which then served as SNP "pool" for the construction of Neural Network
classifiers. Averaged across the 10 solutions and applied to the 1,042 probes, the
optimization stopped when a plateau was reached at a rate of 77.3% [±0.636] correctly
classified subjects (cf. Table). A rate that was in good accordance with the value
expected from the mz twin results.
The final configuration included 15 genomic loci (61 SNPs) that later on served as reference
for the replication analysis (746 subjects genotyped for 545,080 SNPs of a 500k-chip).
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The IgM concordances in 53 monozygotic twin pairs (25 healthy pairs and 28 pairs with
schizophrenia) are in the range of 0.849±0.091 and show a left-skewed distribution, thus
indicating that more than 25% of twin pairs exhibit a reduced within-pair concordance which
cannot be explained by acute processes alone (18 dizygotic pairs: 0.113±0.072).
Our results suggest that mz co-twins concordant for schizophrenia may possess a less "robust"
variant of the inflammatory response system that can more easily be triggered by exogenous
factors compared to the more "robust" variants postulated for mz co-twins discordant for
schizophrenia.
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