Markers of inflammation in schizophrenia: association vs. causation

Inflammation is a complex response of the host to tissue injury, such as infection or physical insult 1. The main role of inflammation is to quickly eliminate pathogens by initiating an adaptive immune response through stimulation of antigen-specific T- and B-lymphocytes and their regulating immune-transmitters, the pro-inflammatory cytokines. Cytokines are divided into predominantly pro-inflammatory and predominantly anti-inflammatory types 2. Pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are secreted by monocytes and macrophages and activate other cellular components of the inflammatory response. Anti-inflammatory cytokines, such as interleukin-4 (IL-4), help to down-regulate the inflammatory immune response. The role of inflammation in schizophrenia has received intense attention and a cytokine-mediated mechanism represents the keystone of a number of hypotheses formulated in the past two decades 2–4. The macrophage T-lymphocyte hypothesis postulates that chronically activated macrophages produce cytokines, such as interleukin-1 (IL-1), interleukin-2 (IL-2), tumor necrosis factors, interferon-alpha and interferon-gamma 5. The “T helper hypothesis” advances the idea of a shift away from cytotoxic cell immune function toward humoral immune reactivity 6. The microglia hypothesis argues that pro-inflammatory cytokines and free radicals are released by activated central nervous system microglia, causing abnormal neurogenesis, neural degradation and white matter abnormalities, which are known to play a role in the pathogenesis of schizophrenia 7. A convergence between neuroinflammatory changes and dopamine and glutamate receptors has also been postulated, and clinical trials with biological therapies developed for the reduction of inflammation 8,9 and for autoimmune disorders 10,11 are seriously considered. The significance of cytokine abnormalities and other markers of immune dysfunction identified in patients with schizophrenia can be examined through the prism of Bradford Hill's guidelines 12, a widely accepted model for judging whether an association can contribute to cause a pathological phenomenon. Based on this framework, we evaluate here the strength of the association; its consistency in studies performed by different investigators on different samples; its temporality, by trying to determine whether the inflammation has preceded the onset of schizophrenia; its biological gradient, meaning that the severity of schizophrenia should correlate with the magnitude of the inflammatory process; its plausibility as a pathophysiological mechanism; the coherence between epidemiological and laboratory findings; and the specificity of inflammatory abnormalities.