Evidence of innate immune dysfunction in first-episode psychosis patients with accompanying mood disorder

Abstract

Background: Inflammation and increases in inflammatory cytokines are common findings in psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). Meta-analyses of studies that measured circulating cytokines have provided evidence of innate inflammation across all three disorders, with some overlap of inflammatory cytokines such as IL-6 and TNF-α. However, differences across disorders were also identified, including increased IL-4 in BD that suggest different immune mechanisms may be involved depending on the type of disorder present.

Methods: We sought to identify if the presence or absence of an affective disorder in first-episode psychotic (FEP) patients was associated with variations in cytokine production after stimulation of peripheral blood mononuclear cells (PBMC). 98 participants were recruited and grouped into healthy controls (n = 45) and first-episode psychosis patients (n = 53). Psychosis patients were further grouped by presence (AFF; n = 22) or lack (NON; n = 31) of an affective disorder. We cultured isolated PBMC from all participants for 48 h at 37 °C under four separate conditions; (1) culture media alone for baseline, or the following three stimulatory conditions: (2) 25 ng/mL lipopolysaccharide (LPS), (3) 10 ng/mL phytohemagglutinin (PHA), and (4) 125 ng/ml α-CD3 plus 250 ng/ml α-CD28. Supernatants collected at 48 h were analyzed using multiplex Luminex assay to identify differences in cytokine and chemokine production. Results from these assays were then correlated to patient clinical assessments for positive and negative symptoms common to psychotic disorders.

Results: We found that PBMC from affective FEP patients produced higher concentrations of cytokines associated with both innate and adaptive immunity after stimulation than non-affective FEP patients and healthy controls. More specifically, the AFF PBMC produced increased tumor necrosis fctor (TNF)-α, interleukin (IL)-1β, IL-6, and others associated with innate inflammation. PBMC from AFF also produced increased IL-4, IL-17, interferon (IFN)γ, and other cytokines associated with adaptive immune activation, depending on stimulation. Additionally, inflammatory cytokines that differed at rest and after LPS stimulation correlated with Scale for the Assessment of Negative Symptoms (SANS) scores.

Conclusions: Our findings suggest that immune dysfunction in affective psychosis may differ from that of primary psychotic disorders, and inflammation may be associated with increased negative symptoms. These findings could be helpful in determining clinical diagnosis after first psychotic episode.

Keywords: Affective; Autism; Bipolar disorder; Cytokine; Immune; Inflammation; Major depressive disorder; Neurodevelopmental disorders; Psychosis; Schizophrenia.

Fig. 1

Basal cytokine and chemokine production in unstimulated PBMC culture supernatants following 48 h in media alone. Box and whiskers plots depict median, upper and lower interquartile ranges, *p < 0.05, **p < 0.01, ‡ indicates comparisons that were significant prior to multiple testing correction. HC n = 45, AFF n = 22, NON n = 31

Fig. 2

Cytokine and chemokine production from PBMC cell cultures following stimulation with LPS. Box and whiskers plots depict median, upper and lower interquartile ranges, *p < 0.05, ‡ indicates comparisons that were significant prior to multiple testing correction. HC n = 45, AFF n = 22, NON n = 31

Fig. 3

Cytokine and chemokine production following stimulation with PHA: box and whiskers plots depict median, upper and lower interquartile ranges, *p < 0.05, **p < 0.01, ‡ indicates comparisons that were significant prior to multiple testing correction. HC n = 45, AFF n = 22, NON n = 31

Fig. 4

Cytokine production after stimulation with α-CD3/α-CD28: box and whiskers plots depict median, upper and lower interquartile ranges, *p < 0.05. HC n = 45, ‡ indicates comparisons that were significant prior to multiple testing correction. HC n = 45, AFF n = 22, NON n = 31

Fig. 5

Increased and decreased cytokines across treatments and groups: heatmap plot shows group comparisons of increased (red) or decreased (blue) cytokines by stimulatory condition, with intensity of color indicating significance