Recent studies provide evidence of the involvement of the complement system alterations in schizophrenia-associated immune system abnormalities including autoimmunity and inflammation [13–17]. In this work, we have extended the current knowledge on the state of the complement system in schizophrenia by studying CR1 expression on blood cells, the levels of CIC bound to CR1 ligands, the products of the complement activation, and the CR1 C5507G functional polymorphism in diseased and healthy subjects.
The results obtained for the first time demonstrate an increased expression of CR1 on erythrocytes and subpopulations of leukocytes (L, M, and N), accompanied by the elevated number of CR1 positive E and reduced number of CR1 positive L and M in patients with schizophrenia as compared to healthy subjects. Regarding CIC bound to complement-derived CR1 ligands, the increased levels of C1q-CIC in schizophrenia patients compared to healthy controls were detected, whereas no significant difference in the levels of C3d-CIC between patients and controls was observed.
Changes in CR1 expression on blood cells have been implicated in a variety of diseases (systemic lupus erythematosus, acute immunodeficiency syndrome, rheumatoid arthritis, malarial anaemia, insulin-dependent diabetes, myocardial infarction, etc) associated with immune system dysfunction, development of inflammatory and autoimmune reactions [26, 27, 29–33]. Depending on the diseased condition, these changes may be determined by either genetic or environmental factors. The present finding of the increased CR1 expression levels on blood cells of schizophrenia patients may be a consequence of the elevated levels of the total population of IC in circulation reported by us previously , as well as increased levels of C1q-CIC reported in the present work. As noted in the introduction, binding of erythrocyte CR1 to the complement component C1q attached to IC serves to mediate clearance of IC . In addition, increase of CR1 expression on leukocytes can be induced by tumor necrosis factor-α and interleukin-1 [35, 36], which are elevated in the blood of schizophrenic patients .
We also observed an enhanced number of CR1 positive E in schizophrenia patients, while fractions of CR1 positive L and M were significantly decreased compared to control subjects. Increased number of CR1 positive E in circulation might be related to the enhanced hematopoiesis in response to cytokines and other inflammatory agents , while reduced number of CR1 positive leukocyte subpopulations might be explained by increased rate of apoptosis induced by antipsychotic treatment [39–41].
Distributions of the allele and genotype frequencies of the CR1 C5507G SNP in schizophrenia patients do not differ from healthy subjects. Therefore, despite the important role of the complement system in the pathogenesis of schizophrenia [15–22], its type 1 receptor gene C5507G polymorphism does not contribute to the genetic susceptibility to this disease. Further, we compared the levels of CR1 expression on the blood cells of normal allele homozygotes and mutant allele carriers (CG+GG) in patients and controls. Both groups showed increased CR1 expression on E in CC homozygous subjects compared to mutant allele carriers (Figure 2), whereas levels of CR1 expression on L, M, and L did not differ between these genotypes (p > 0.05, table 3). Interestingly, Wilson et al. found the association of genomic polymorphism with a cis-acting regulatory element for the expression of CR1 on E .