Immune dysregulation in schizophrenia: Do some cases of schizophrenia have an autoimmune basis?

Schizophrenia is a severe debilitating psychiatric disorder that affects approximately 1% of the global population. It is characterised by disruptions in language, thought, perception, social activity, affect and volition and is currently diagnosed by the presence of several distinct symptoms, deterioration in functioning and lack of a demonstrable biological cause. Numerous theories have been postulated as to the cause of schizophrenia and several risk factors have been suggested, but there is currently no known cause of schizophrenia. It is likely that the cause may not be the same in all patients. The most commonly accepted hypothesis for its cause currently is one of a polygenetic disease, where several genes confer susceptibility during development and subsequent exposure to environmental stress factors acting on this genetic background result in the development of schizophrenia. My research has focused on the hypothesis that schizophrenia may be the result of an autoimmune response in some people. Evidence from several different research groups suggests that there may be several immune abnormalities in some people with schizophrenia, including the presence of autoantibodies directed against the brain and neurotransmitter receptors. The presence of these autoantibodies directed against brain neurotransmitter receptors suggests that in some people the symptoms of schizophrenia could be the result of autoimmune attack on the brain. Initial experiments were conducted to confirm the presence of anti-brain autoantibodies in sera from people with schizophrenia, utilizing a modified immunohistochemical technique to screen samples. These showed elevated levels of filamentous staining by sera of people with schizophrenia compared to healthy controls. In view of the number of previous studies that have suggested that antibodies in schizophrenia target neurotransmitter receptors, the next step in this thesis was to determine levels of autoantibodies specific for an immunogenic region on the second extracellular loop of the muscarinic 1 acetylcholine receptor. These experiments showed a significant increase in the proportion of people with schizophrenia with elevated levels of antibodies compared to healthy controls. It has previously been suggested that neurotransmitter receptors may be different in people with schizophrenia. Since the initial studies in the thesis had been done using brain tissue from people with schizophrenia, we tested the ability of commercially available antibodies to label neurotransmitter receptors in two key brain areas from people with schizophrenia and controls to determine if the same epitopes were being recognized in tissue from people with schizophrenia and controls. We found a lower density of these neurotransmitter receptors in people with schizophrenia compared to controls. This confirms previous findings of reduced neurotransmitter receptor density studies carried out by others using radio-labelled ligands specific for the receptors, but also shows that the neurotransmitter receptors from people with schizophrenia and controls are recognized by the same antibodies. To determine what other antigens might be targeted by the autoantibodies that showed a filamentous staining pattern, we analysed the brain protein targets of antibodies in sera from people with schizophrenia using a proteomic approach. Proteins identified in this way were found to be primarily involved in neuronal structure rather than neurotransmission and included neurofilament medium and glial fibrillary acidic protein. To confirm these findings, an enzyme linked immunosorbent assay for neurofilament medium was developed, and sera from a large cohort of patients and controls were tested for reactivity against neurofilament medium. There was a highly significant increase in reactivity to neurofilament medium in a subgroup of people with schizophrenia compared to their family members and healthy controls. Several studies looking for genetic causes of schizophrenia have shown links to several genes including those related to immune function. Interestingly, one recent report showed an increased prevalence of a functional polymorphism in the CTLA-4 gene in people with schizophrenia compared to controls. CTLA-4 plays an important role in the regulation of T cells and functional polymorphisms have been reported in association with several antibody-mediated autoimmune diseases. Therefore,we examined 3 well characterised CTLA-4 polymorphisms in matched pairs of people with schizophrenia and healthy controls. In males, both the promoter region SNP (- 318C/T) and the 3’ UTR SNP demonstrated significant association with schizophrenia. In addition, all possible haplogenotypes showed significant association with disease in males, with two – both containing the 3’ UTR SNP – remaining significant following correction for the genotypic tests of all SNPs and haplogenotypes in males. The results of this study support the hypothesis that some cases of schizophrenia may have an autoimmune component. The work presented here forms the basis for future studies to establish the role that brain-specific autoantibodies play in people with schizophrenia