Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide
Introduction
Immune mechanisms have been discussed in the (co)etiology of schizophrenia and affective disorder during the past few decades. However, altered immunological parameters have been investigated mainly in peripheral blood and cerebrospinal fluid and less frequently in the brains of patients with schizophrenia or affective disorder. A review of the literature on this topic is given by Arolt and Rothermundt, 2005, Müller and Ackenheil, 1998, Schuld et al., 2004, Sperner-Unterweger, 2005.
Some postmortem studies have suggested microglial activation in the context of schizophrenia (Bayer et al., 1999, Radewicz et al., 2000, Wierzba-Bobrowicz et al., 2005), whereas others provided evidence against this notion (Arnold et al., 1998, Falke et al., 2000, Kurumaji et al., 1997, Steiner et al., 2006, Togo et al., 2000, Wierzba-Bobrowicz et al., 2004). Several microglial markers have been investigated in these studies, including MHC-II, CD40, CD68 and the peripheral-type benzodiazepine receptor. In particular, the induction of major histocompatibility complex class II (MHC-II, e.g. HLA-DR) in microglial cells is a well known, sensitive marker of neuroinflammatory and neurodegenerative processes in histological studies (Schmitt et al., 1998). The role of microglia in affective disorder has been investigated only qualitatively in a small number of cases (Bayer et al., 1999). HLA-DR immunostaining was observed in one of six patients with affective disorder, while five cases did not show any microglial immunolabelling. However, there is now a general consensus that microglia constitutively express HLA-DR, and that studies reporting microglia as HLA-DR negative used less sensitive immunostaining techniques (Mittelbronn et al., 2001).
We recently conducted our own postmortem study in which we did not observe significant microgliosis in schizophrenia (Steiner et al., 2006). However, single-case analysis revealed increased microglial densities in two schizophrenic patients who had committed suicide during acute psychosis. The other 14 patients in the schizophrenia group did not die during an acute disease phase. This led us to the hypothesis of microglial activation during acute psychosis. Alternatively, “suicide” could be a diagnosis-independent factor leading to microgliosis. The aim of our present study was to distinguish between these hypotheses.
Suicide has a high prevalence in the long-time course of schizophrenia and affective disorder. However, not much is known about the neurobiology that may underlie suicidality. The aim of this study was to find out if only patients with schizophrenia who committed suicide during acute psychosis exhibit microglial activation or if microgliosis can be demonstrated in suicide patients regardless of diagnosis. As far as we know, no previous studies have conducted a quantitative analysis of microglial density in affective disorder or addressed the question of neuroimmunological alterations in the context of suicide.
Section snippets
Human brain tissue
All brains were obtained from the Magdeburg Brain Collection. The collection of the human brain material was done in accordance with German laws and the rules approved by the local ethics committee. Postmortem brain tissue of 16 patients with a clinical diagnosis of schizophrenia (according to DSM-IV, mean age 53 years; seven males, nine females), 14 depressed patients with affective disorder (according to DSM-IV, mean age 49 years; six males, eight females) and 10 healthy control subjects
Results
HLA-DR immunostaining was detected in monocytes, perivascular macrophages, as well as ramified and ameboid microglia (Fig. 1a–c). Immunoreactivity was not restricted to macrophage-like ameboid cells, but appeared also in ramified microglia. Microglial cells were often assembled as clusters in the suicide group (Fig. 1e).
Multiple regression analyses revealed no significant influence of age, duration of disease, autolysis time and fixation time on the density of HLA-DR-positive microglial cells.
Discussion
Our recent postmortem study revealed increased microglial densities in two schizophrenic patients who had committed suicide (Steiner et al., 2006). Therefore, the hypothesis of microglial activation during acute psychosis was proposed. Alternatively, “suicide” could be a diagnosis-independent factor leading to microgliosis. To clarify this question, microglial HLA-DR-expression was analyzed by immunohistochemistry in 16 patients with schizophrenia, 14 depressed patients with affective disorder
Acknowledgements
The Saxony-Anhalt Ministry of Research (XN3594O/0405M, Signaltransduzierende Netzwerke N2-OGU) and Stanley Foundation supported the present study. Gabriela Meyer-Lotz and Renate Stauch provided excellent technical assistance.
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