Elevated serum chemokine CCL22 levels in first-episode psychosis: associations with symptoms, peripheral immune state and in vivo brain glial cell function

Abstract

Several lines of research support immune system dysregulation in psychotic disorders. However, it remains unclear whether the immunological marker alterations are stable and how they associate with brain glial cell function. This longitudinal study aimed at investigating whether peripheral immune functions are altered in the early phases of psychotic disorders, whether the changes are associated with core symptoms, remission, brain glial cell function, and whether they persist in a one-year follow-up. Two independent cohorts comprising in total of 129 first-episode psychosis (FEP) patients and 130 controls were assessed at baseline and at the one-year follow-up. Serum cyto-/ chemokines were measured using a 38-plex Luminex assay. The FEP patients showed a marked increase in chemokine CCL22 levels both at baseline (p < 0.0001; Cohen's d = 0.70) and at the 12-month follow-up (p = 0.0007) compared to controls. The group difference remained significant (p = 0.0019) after accounting for relevant covariates including BMI, smoking, and antipsychotic medication. Elevated serum CCL22 levels were significantly associated with hallucinations (ρ = 0.20) and disorganization (ρ = 0.23), and with worse verbal performance (ρ = −0.23). Brain glial cell activity was indexed with positron emission tomography and the translocator protein radiotracer [ 11 C]PBR28 in subgroups of 15 healthy controls and 14 FEP patients with serum CCL22/CCL17 measurements. The distribution volume (V T) of [ 11 C] PBR28 was lower in patients compared to controls (p = 0.026; Cohen's d = 0.94) without regionally specific effects, and was inversely associated with serum CCL22 and CCL17 levels (p = 0.036). Our results do not support the over-active microglia hypothesis of psychosis, but indicate altered CCR4 immune signaling in early psychosis with behavioral correlates possibly mediated through cross-talk between chemokine networks and dysfunctional or a decreased number of glial cells.

Metabolic syndrome following a first episode of psychosis: results of a 1-year longitudinal study conducted in metropolitan Lisbon, Portugal

“… 71 These immunological changes include high concentrations of pro-inflammatory cytokines and chemokines in the circulation and cerebrospinal fluid, as well as changes in immune cell function in the central nervous system. 72 , 73 Adipose tissue directly or indirectly secretes pro-inflammatory cytokines and proteins (IL-6, TNF-α, insulin-like growth factor-1, leptin, resistin, apelin, visfatin, CCL22, and nesfatin-1), 30 , 31 , 33 , 74 and patients with schizophrenia also show activation of microglia, which contributes to the high serum concentrations of pro-inflammatory cytokines. 73 , 75 Some of these substances are present and/or have receptors in parts of the central nervous system, but their exact roles in the pathophysiology of psychosis are still being studied.…”

Applicability, potential and limitations of TSPO PET imaging as a clinical immunopsychiatry biomarker

“…Out of 775 original hits, 32 research papers reporting on 31 original studies met our inclusion criteria, five of which were published within the last year (2020). In the field of immunopsychiatry, case-control TSPO PET studies have until now mostly been used in schizophrenia or related psychotic disorders (16 case-control studies [4,8,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]; previously reviewed elsewhere [26][27][28]), and to a lesser extent in mood disorders with seven case-control studies in major depressive disorder [29][30][31][32][33][34][35], two longitudinal studies of depressed patients [36,37] (MDD; previously reviewed elsewhere [10,38]) and one case-control study in euthymic bipolar disorder patients [39]. A further two studies have been performed in autism spectrum disorders [40,41], one study in Tourette's disorder [42], one study in obsessive-compulsive disorder (OCD) [43] and one study in posttraumatic stress disorder (PTSD) [44] (cfr Table 1).…”

Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients

“…OSM is a cytokine that enhances production of IL-6 and it was also increased in the FEP patients compared with controls. Other proteins that were elevated in FEP included TGFα and TNFSF14 with both having pro-in ammatory effects, as well as the chemokine CCL23 that in uences chemotaxis of blood cells including neutrophils [32]. The growth factor HGF was also increased in FEP plasma, and is known to regulate growth and motility of a variety of cells.…”