Emerging Concepts of Specific Components of the Immune System in Schizophrenia

Evidence suggests that immunological and inflammatory processes may play an important role in the pathophysiology of schizophrenia. In fact, the link between the immune system and psychosis has a long history. In 1927, Julius Wagner-Jauregg was awarded the Nobel Prize for his discovery of malarial inoculation as a treatment for syphilitic psychosis (1). In 1988, Sarnoff Mednick et al. (2) reported that the 1957 influenza correlated with an increased risk of adult schizophrenia in people born in the spring of 1958. In 1992, Ronald Smith (3) proposed that inappropriately activated macrophages result in the release of interleukin-2, and the effect on the interleukin-2 receptors was subsequently recognized as a potential biological cause of schizophrenia. In 2014, a genome-wide association study identified multiple genes linked to schizophrenia involving genetic loci found in the brain and involving adaptive immunity (CD19 and CD20B cells) (1, 4). Taken together, these studies suggest that schizophrenia is, at least in part, a psychiatric disorder that is bound to immune function.

Potential Clinical Implications

Better understanding of the connection between the immune system, histamine, and schizophrenia could result in the discovery of clinically relevant biomarkers. The main purposes of biomarkers are to help diagnose an illness, make prognostic evaluations, and even predict an individual response to therapy. In a study on the identification of biomarkers for the management of schizophrenia, Lai et al. (5) found that 70% of possible biomarkers for the disorder are included in the inflammatory response. Discovery of possible biomarkers and understanding of the immunological components of schizophrenia could allow for more research on new methods of pharmacology involving immunotherapy in addition to—or instead of—dopamine antagonists. Low response rates and the debilitating side effects of antipsychotics often lead to worsening treatment compliance (6). This emphasizes the need for objective marker-based tests that could help predict treatment options and enable early detection in individuals who may benefit from more specific therapeutic interventions (6).

Recently, biomarkers for cancer have become beneficial for early detection and for selective therapeutic options based on molecular markers (7). By contrast, treatment for schizophrenia is limited, and the clinical diagnosis remains reliant on symptoms (7). The ability to utilize any actual biologic marker to predict disease or treatment response has not been adequately developed or tested but may lie within the immune system, especially in basophils and histamine. Potential discoveries of blood-based biomarkers for schizophrenia could enable the development of diagnostic and prognostic tools and may help to solidify the link between the immune system and mental health (8).

Immunology and Schizophrenia

Interestingly, inflammatory and immunologic processes have been related to neurotransmitter abnormalities. Particular cells involved in this process are microglial cells, which release cytokines that bind to specific receptors on neurons, leading to changes in mood, cognition, and behavior. This cytokine elevation can cause changes to microglial cells, which can be associated with functional changes in the brain predisposing individuals to mental illness. Alterations in microglial cells have been found in persons with psychiatric disorders such as schizophrenia (9). Expanding on the concept of immunomodulation, Feigenson et al. (10) focused on the two-hit hypothesis. This theory suggests that an inflammatory event that occurs during the early stages of life—considered to be the "first hit"—may not interfere with normal development of the nervous system. However, if a second event later in life, such as a neurological stressor, should occur, it can disrupt brain function, ultimately leading to the full clinical syndrome of schizophrenia. Abnormal structural components of white blood cells in patients with schizophrenia were initially reported nearly 40 years ago (11). More recently, Miller et al. (12) documented increased CD4 and CD56 T lymphocytes among inpatients with acute relapsed schizophrenia compared with healthy control subjects. A year later, Semiz et al. (11) reported increased neutrophil and lymphocyte counts in patients with schizophrenia compared with psychiatrically healthy control subjects. Thus, immune system responses and irregularities may be contributing factors to the development and severity of psychiatric illness (10).

Histamine and Schizophrenia

Basophils can act as a storage site for histamine, and, when activated, release it as well. Additionally, basophils can produce large amounts of cytokines and interleukin-4 (13) that infiltrate tissue during allergic inflammation (14). Multiple studies have investigated the relationship between basophils and histamine. Some investigators have reported that a high basophil count is a good predictor of high blood histamine, with a strong positive correlation between basophil and histamine levels (15).

Early knowledge of histamine and its receptors was limited to the alimentary tract system and to the body's allergic reactions. Current knowledge suggests that they also play a pivotal role in the CNS as well as in behavior (16). Some of the functions of histaminergic neurons involve regulating sleep-wake cycles, learning, memory, and emotional behaviors (17). Histamine may demonstrate pleomorphic actions by acting as a neurotransmitter and as a component of inflammation. Yang et al. (18) suggested that dysregulation in histamine (not just dopamine) may play a causative role in schizophrenia. Moreover, histamine is already highly recognized in the pathogenesis and physiology of neurodegenerative diseases. Several brain disorders (such as Alzheimer's disease, schizophrenia, Parkinson's disease, and sleep disorders) have been associated with alterations in histamine (16). Interestingly, elevated histamine levels in the blood have been associated with schizophrenia (18). It has been observed that patients with schizophrenia are more tolerant to histamine levels, which may be attributed to an abnormality in histamine metabolism (19). Adam et al. (19) examined the urine samples of individuals with schizophrenia and found an increased tolerance of and lack of responsiveness to histamine in this patient population. Thus, it could be speculated that high histamine levels are a feature of schizophrenia that merits further investigation. Indeed, considering the role of histamine receptors in neurons, it seems that basophil and histamine-release control may be key components in the relationship between the immune system and schizophrenia.

Postmortem studies have shown that the density of histamine H1 receptors in the frontal cortex is lower in patients with schizophrenia compared with healthy control subjects (18), possibly due to down-regulation. Vohora and Bhowmik (20) suggested that H3 receptors take part in modulation of cognition, which is impaired in individuals with schizophrenia with psychotic symptoms (20). H3-receptor radio-ligand binding has been examined in certain brain regions (e.g., the prefrontal cortex and hippocampus) and reported to be increased in the prefrontal cortex in persons with schizophrenia (21). This region functions in learning and memory, suggesting that histamine may be a vital component for cognitive development and processing in schizophrenia.

Given these findings, it is not surprising that several studies have demonstrated that histamine receptors (such as H3), in particular ciproxifan and clobenpropit (17), are potential targets for antipsychotics in that H3-receptor antagonists and inverse agonists may improve treatment in patients with schizophrenia. The human histamine receptors hH1R and hH2R have also been formulated as potentially clinically relevant drug targets (22).

Key Points/Clinical Pearls