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Inflammatory Processes and Schizophrenic Disorders

Active Immune Processes

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.

nna
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).

IgM concordances
Fig. 4: 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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Marie Curie Action:
035987

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