l-ficolin-MASP arm of the complement system in schizophrenia

Abstract

The abnormal neurodevelopment secondary to in utero adversities, such as hypoxia, malnutrition and maternal infections, underlies schizophrenia (SZ) etiology. As the genes of MBL-associated serine proteases (MASP) of the complement lectin pathway, MASP1 and MASP2, are expressed in the developing cortex and are functionally important for neuronal migration, we hypothesize that the malfunction ofl-ficolin-MASP arm may also be involved in schizophrenia pathophysiology as it was shown for MBL-MASP complexes. We investigated serum l-ficolin and plasma MASP-2 levels, the activity of l-ficolin-bound MASP-2, as well as an array of the complement-related variables in chronic schizophrenic patients in the acute phase of the disease and controls without physical or mental diagnoses. The median concentration of l-ficolin in Armenian controls was 3.66 μg/ml and similar to those reported for other Caucasian populations. SZ-cases had ∼40 % increase in serum l-ficolin (median 5.08 μg/ml; P < 0.0024). In the pooled sample, l-ficolin level was higher in males than in females (P < 0.0031), but this gender dichotomy was not affecting the variable association with schizophrenia (P < 0.016). Remarkably, MASP-2 plasma concentration showed gender-dependent significant variability in the group of patients but not in controls. When adjusted for gender and gender*diagnosis interaction, a significantly high MASP-2 level in female patients versus female controls was observed (median: 362 ng/ml versus 260 ng/ml, respectively; P < 0.0020). A significant increase in l-ficolin-bound MASP-2 activity was also observed in schizophrenia (on the median, cases vs controls: 7.60 vs 6.50 RU; P < 0.021). Correlation analyses of the levels of l-ficolin and MASP-2, l-ficolin-(MASP-2) activity and the demographic data did not show any significant association with the age of individuals, family history, age at onset and duration of the illness, and smoking. Noteworthy, the levels of l-ficolin and MASP-2 in circulation were significantly associated with the type of schizophrenia (paranoid SZ-cases had much higher l-ficolin (P < 0.0035) and lower MASP-2 levels than the other types combined (P < 0.049)). Correlations were also found between: (i) the classical pathway functional activity and l-ficolin level (rs = 0.19, P < 0.010); (ii) the alternative pathway functional activity and MASP-2 level (rs = 0.26, P < 0.00035); (iii) the activity of l-ficolin-bound MASP2 and the downstream C2 component haemolytic activity (rs = -0.19, P < 0.017); and (iv) l-ficolin and the upstream C-reactive protein (CRP) serum concentrations (r = 0.28, P < 0.018). Overall, the results showed l-ficolin-related lectin pathway alterations in schizophrenia pathophysiology. It is likely that in addition to the MBL-MASP component over-activity reported previously, the alterations of the lectin pathway in schizophrenia also involve variations of l-ficolin-(MASP-2) on protein concentration and activity levels.

Keywords: CRP; Complement system; Gender dichotomy; Lectin pathway activity; MASP-2; Schizophrenia; l-ficolin.