Clara cell protein (CC16) and transferrin receptor (TfR) have been reported as possible biological markers for major depression and schizophrenia. However, the alternations of plasma TfR and CC16 levels and the influences of numerous clinical variables on them during bipolar mania are not sufficiently described. We investigated the immune function of 36 bipolar I, manic (DSM-IV) patients with Young Mania Rating Scale (YMRS) scores ⩾26 as well as during the subsequent remission (YMRS ⩽12) and age- and sex- matched healthy controls. The plasma TfR levels were increased during acute mania along with subsequent remission and were independent of medication status, individual variations, clinical and erythrocyte variables. Among inflammatory parameters and haematological variables, the plasma TfR levels merely had significant and negative relationship with the percentage of monocyte in circulating leukocyte counts despite of elevated plasma soluble interleukin-2 receptors levels during bipolar mania. The plasma levels of CC16 of bipolar patients did not significantly alter during acute mania, whereas smoking, body mass index, and co-existing psychotic features collectively contributed 42% of the plasma levels of CC16. We provide additional evidence to indicate the pathophysiological role of the immune systems in affective disorders. It is suggested that the elevation of plasma TfR levels might be a trait phenomenon in bipolar disorder.
There is increasing evidence that bipolar mania is characterized by the activation of the inflammatory response system (IRS) with increasing serum concentration of positive acute phase proteins (Hornig et al., 1998), increased plasma soluble interleukin-2 receptor (sIL-2R) levels (Maes et al., 1995a, Tsai et al., 1999 and Tsai et al., 2001), and elevated mitogen-induced lymphocyte proliferation (Tsai et al., 1999).
It has been suggested that the affective disorders and schizophrenia are accompanied by in vivo activation of cell-mediated immunity as indicated by higher plasma levels of sIL-2R and transferrin receptor (TfR) (Connor & Leonard, 1998, Maes et al., 1995a and Maes et al., 1995c). Expression of the TfR, a transmembrane glycoprotein, is regulated by two distinct mechanisms: the growth rate of cells and their requirements for iron (Woith et al., 1993). The TfRs are expressed at the cell surface of normal proliferating cells and are shed off into the plasma to act as a necessary signal promoting lymphocyte proliferation (de Jong et al., 1990 and Keyna et al., 1991). Moreover, the plasma TfR level is an excellent marker for erythropoiesis (Huebers et al., 1990) and may be a promising tool to detect iron deficiency during inflammatory states (Feelders et al., 1999). Physiological changes in serum TfR are related not only to small alternations in the iron supply to the erythroblasts, storage iron, erythrocyte haemoglobinization, and erythropoiesis, but also to changes in the immune status such as T-cell activation (Maes et al., 1997a). Increased plasma TfR level has been considered as a trait marker of major depression (Maes et al., 1995b). To our knowledge, only a 10-patient study demonstrated higher plasma TfR levels during bipolar mania (Maes et al., 1995a). However, confounding effects of numerous clinical or individual factors on plasma TfR levels in bipolar patients remain unclear.
Clara cell protein (CC16) is secreted by Clara cells in the lining fluid of bronchiolar and bronchial epithelium. The CC16 may have immunosuppressive and anti-inflammatory properties (Hermans and Bernard, 1996). Lowered serum CC16 may be a trait marker of schizophrenia and is likely related to the increased serum sIL-6R (Maes et al., 1996). Increasing serum CC16 concentrations in euthymic patients undergoing lithium treatments was reported (Rybakowski, 2000), but our early works found that there is no alternation of plasma sIL-6R levels during bipolar mania (Tsai et al., 1999 and Tsai et al., 2001). Unfortunately, no further report was available regarding serum CC16 levels in patients with bipolar disorder to illustrate the different immunomodulatory mechanism in various psychiatric conditions.
It is difficult to determine whether immune-inflammatory parameters play a role in the pathophysiology of psychiatric disorders before carefully taking into account confounding factors, such as influence of medication (Pollmacher et al., 2000 and Rapaport & Manji, 2001), body mass index (BMI), and a variety of clinical variables (Haack et al., 1999) . Thus, it is hypothesized that the plasma levels of CC16 or TfR may alter during acute mania and may be affected by medication, smoking, individual variation, or other psychopathological characteristics. Studies investigating the cytokines and soluble cytokine receptors should include simultaneous complete blood counts and employ more measures of clinical status to correlate with immune measures (Rapaport et al., 1999). Therefore, our goals were first to investigate the changes of plasma CC16 and TfR levels during acute mania in a large sample of bipolar disorder and to analyze the effects of medication and clinical characteristics on their levels. We also wanted to determine the relationship between plasma TfR levels and immune-inflammatory parameters (sIL-2R and sIL-6R) as well as haematological variables of bipolar manic patients.
