Human and animal data suggest that neuroinflammatory and immunological abnormalities can contribute to the neurobiology of primary psychotic disorders [1, 2]. Human post-mortem brain, serological, cerebrospinal fluid (CSF), neuroimaging, genetic, and epidemiological studies have documented diverse inflammatory and immunological abnormalities in a subgroup of patients diagnosed with schizophrenia according to the currently established DSM/ICD criteria [1,2,3,4]. Among the main inflammatory abnormalities are microglial activation and proliferation in brain regions of functional relevance to psychosis (e.g., dorsolateral prefrontal, superior temporal, and anterior cingulate cortices), and upregulation of inflammatory mediators such as pro-inflammatory cytokines and matrix metalloproteinases [1,2,3,4]. Findings of post-mortem studies have not only linked microglial activation to the neurobiology of psychosis but also to suicidal state [3, 4]. Recent meta-analysis of post-mortem brains documented statistically significant increase in microglial density and pro-inflammatory gene expression, without significant alteration in the density of other glial cells or anti-inflammatory gene expression in schizophrenia compared with healthy subjects [5]. Studies documenting elevated serum levels of beta2-microglobulin in drug-naïve schizophrenia compared with healthy cohorts [6], with further elevation of its levels following treatment with antipsychotic medications, [7] suggest that immune dysregulation may play a role in a subgroup of these patients. Various CSF immunological and inflammatory changes are also well documented in a subset of individuals with drug-resistant schizophrenia [8, 9]. These changes include increased “CSF: serum albumin ratio” indicative of blood-CSF barrier hyperpermeability; increased intrathecal synthesis of IgG, IgM, and/or IgA; and presence of up to four IgG oligoclonal bands, mild pleocytosis, elevated neopterin levels, and elevated cytokines [8, 9]. These observations, together with documented elevated levels of S100B protein, a marker of glial activation and blood-brain barrier hyperpermeability, in the brain, CSF as well as blood support the hypothesis that hyperpermeability and/or disruption of blood-brain and blood-CSF barriers may contribute to the neurobiology of psychosis, in part via transendothelial inflammatory cell migration and increased cross-talk between brain innate immunity and peripheral adaptive immunity [1, 2, 8,9,10]. This is also supported by the post-mortem ultrastructural findings of inflammatory and degenerative changes affecting neurovascular unit in schizophrenia [1, 2].

In addition, several epidemiological studies reported a strong bidirectional relationship between autoimmune disorders and psychosis [2, 11]. One study showed a positive correlation between brain-reactive antibodies associated with autoimmune disorders and subsequent hazard of psychosis [11], although the abundance of brain-reactive IgG antibodies in the cortex of individuals with schizophrenia was shown in another study to be similar to that of healthy controls [12].

Moreover, the strong association between both early infections and increased risk of developing psychosis in the adult life [1, 11], as well as the significant increase in serum titers of anti-CMV and anti-HSV1 and anti-HSV2 IgG antibodies in schizophrenia patients [13], provide indirect argument in support of immune involvement [11]. Collectively, the above data point to the overlap between psychosis and pathological processes associated with immunological dysregulation as well as inflammation.