Investigating the immunological effect of schizophrenia-related antigens and anti-psychotic medication

The aims of this thesis were to investigate the immune response to linear peptide fragments derived from 15 distinct proteins encoded by schizophrenia-related genes. An antibody test was developed in-house to detect plasma IgG antibodies against selected target molecules in patients with schizophrenia and control subjects. Six peptide antigens derived from DPYD, MAD1L1, ZNF804A, DRD2, TRANK1 and MMP16 showed an increase in plasma IgG levels and three derived from TSNARE1, TCF4 and VRK2 showed a decrease. As the initial study was conducted with medicated patients with chronic schizophrenia and healthy controls from a European-derived Caucasian population, the initial findings were thus replicated in antipsychotic-naïve patients with first-episode schizophrenia from a Chinese population. The drug-naïve patients showed different results; notably, the significant decrease in plasma IgG levels against TSNARE1 was not observed, showing instead an increase. The inconsistency may result from different ethnicities, B-cell diversity, medication or other confounding factors. To examine the possible mechanism underlying abnormal immune response to these schizophrenia-related peptides, a B-cell model was developed with four immortalized B-cell lines derived from a Caucasian population, 2 cell lines derived from healthy donors and 2 from patients with schizophrenia. These four B-cell lines have proportionally different stages of maturation and differentiation, showing distinct responses to treatment either with target protein-derived antigens or antipsychotic drugs. For example, TRANK1-derived peptide antigen could induce an increase in the proportion of CD83 positive cells and apoptotic cells; antipsychotic treatment generated a dose-dependent reduction in both cell number and viability. Taken together, this PhD work identified novel autoantibodies that might play a role in underlying schizophrenia. A possible mechanism by which abnormal immune responses contribute to the development of schizophrenia was then discussed.