Several lines of evidence suggest that immunological factors contribute to schizophrenia. Since 1989, the role of complement system, a major effector of innate immunity and an adjuvant of adaptive immunity, has been explored in schizophrenia. Increased activity of C1, C3, C4 complement components in schizophrenia has been reported by two or more groups. Two studies on different subject cohorts showed increased MBL-MASP-2 activity in patients versus controls. More then one report indicated a significant high frequency of FB*F allotype and low prevalence of the FS phenotype of complement factor B in schizophrenia. From the data reported, it is likely that the disorder is accompanied by alterations of the complement classical and lectin pathways, which undergo dynamic changes, depending on the illness course and the state of neuro-immune crosstalk. Recent findings, implicating complement in neurogenesis, synapse remodeling and pruning during brain development, suggest a reexamination of the potential role of complement in neurodevelopmental processes contributing to schizophrenia susceptibility. It is plausible that the multicomponent complement system has more than one dimensional association with schizophrenia susceptibility, pathopsychology and illness course, understanding of which will bring a new perspective for possible immunomodulation and immunocorrection of the disease.
The role of the complement system in schizophrenia has not yet been widely explored. The multicomponent composition of complement makes it complex and expensive to examine the roles of individual components, and so more general assays that measure the overall activity of, for example, a whole pathway (total hemolytic activity), have been used. These are likely to be less informative than single component assays. Involvement of the immune system has been a relatively low priority for schizophrenia research, largely because evidence of classic inflammatory pathology has been consistently lacking, although several scientists since 1937 have pointed to the possible role of autoimmune and infectious processes in the etiology of schizophrenia.
Several studies have focused on the complement classical pathway activity in schizophrenia. Initial attention was focused on complement total hemolytic activity, to which classical pathway activity contributes about 85%. Spivak et al. reported a decrease in complement total hemolytic activity in schizophrenic patients vs. controls, while a year later a Japanese group reported no difference. More recent studies suggest that in schizophrenia there is a modest increase in complement total hemolytic activity (CH50), although neither study reached statistical significance.
The alternative pathway remains almost unexplored in schizophrenia. Our recent data showed that schizophrenic patients had the same functional activity of the alternative pathway as controls, although Yang et al. reported an increased plasma level of factor B in schizophrenia.
The lectin pathway, however, has been more extensively explored. In the lectin pathway, MBL or ficolin molecules can form complexes with one of three different proteases, named MASP-1, MASP-2 and MASP-3. When MBL or ficolins bind to a target, the proteases are activated. MASP-2 activates complement, and MASP-1 may have some (minor) involvement in complement activation, but the role of MASP-3 is unknown. In our study of different pathways of the complement system in a sample of chronic patients, a significant increase was detected in the functional activity of the lectin (MBL) pathway in schizophrenic patients, which is a reflection of the activity of MBL-MASP-2 complexes.This finding is in agreement with previous results, showing higher MBL-MASP-2 complex activity in patients in remission, there were no significant differences in MBL serum concentration and the activity of MBL-MASP-1 complexes in comparison with controls.
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