B Cell-activating factor (BAFF): A promising trans-nosographic biomarker of inflammation and autoimmunity in bipolar disorder and schizophrenia.

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.

A replication study of sHLA-E influence on schizophrenia and bipolar disorder.

OBJECTIVES: Schizophrenia (SZ) and bipolar disorders (BP) are chronic and severe neuropsychiatric diseases. These disorders are tightly related to immune deregulations. In the current study, we intended to replicate the previously reported involvement of the soluble HLA-E isoforms (sHLA-E) in the risk of developing the two conditions along with disease severity in a Tunisian population group. PATIENTS AND METHODS: One hundred and twenty-four patients with schizophrenia and 121 with bipolar disorder meeting the DSM-IV criteria along 111 healthy controls were included in this present case-control study. The soluble HLA-E isoforms circulating levels were measured using the ELISA method. The statistical analyses were performed using Kruskal-Wallis and Wilcoxon rank sum tests by R software and GraphPad prism 9. RESULTS: We found that the sHLA-E circulating levels were significantly higher in BP patients as compared to healthy controls (P<0.0001) and that such increases were mainly observed in patients during an acute phase of their disease (P<0.0001). In SZ patients, while we failed to observe an association with the levels of sHLA-E in the entire SZ sample, we found that high sHLA-E levels characterized stabilized patients in comparison with those during an acute episode (P=0.022). Finally, we did not observe any association between sHLA-E circulating levels and symptoms assessed by the classical clinical scales either in BP or SZ patients. CONCLUSION: Overall, the present findings replicate in a Tunisian population group the previously demonstrated implication of sHLA-E circulating levels in the risk of developing BP or SZ in a French patient cohort. Such replication allows to consider HLA-E as a potent and true inflammatory marker in the context of the two disorders.

Immune cell subsets in patients with bipolar disorder or schizophrenia with history of childhood maltreatment.

A history of Childhood Maltreatment (CM) has been repeatedly associated with an increased risk of developing bipolar disorders (BD) or schizophrenia (SZ). The impact of severe stress induced by CM has been proposed to be mediated by elevated inflammation reflected by dysregulated inflammatory processes. Little is known about the potential impact of CM on lymphocyte subpopulations or the role of pre-existing infections on CM physiological consequences. This study therefore explored the role of CM and past infection exposure impact on lymphocyte subpopulations to give an indication of their relevance as stressors in the pathoetiology of major mood and psychotic disorders. 118 adult patients with SZ, and 152 with BD were included in the analysis. CM history was assessed by the Childhood Trauma Questionnaire (CTQ), with current and past psychiatric symptomatology also evaluated. Circulating immune cell subsets were analyzed using flow cytometry-based analysis. Past exposure to common infectious stigma including toxoplasma, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were measured by solid phase-enzyme microplate and ELISA immunoassays. The relationship between CM, biological phenotypes (including immune cell subsets distribution and past infectious status) and clinical phenotypes were analyzed using univariate and multivariate analyses. BD patients with, versus without, CM had higher levels of CD3+CD8+ cytotoxic T cells and CMV antibodies along with decreased levels of CD45RA+CCR7+CD8+ naïve CD8+ T cells, and a more severe clinical profile. CMV antibody levels were inversely associated with the CD3 + CD8 + lymphocyte subset level. SZ patients with, versus without, CM, showed lower levels of CD14 + monocytes and no specific clinical characteristics. The accumulation of different types of maltreatment associated with increased body mass index and CMV autoantibodies as well as decreased levels of CD14 + monocytes. In both BD and SZ, further analysis according to the type and the number of CM subtypes showed association with specific changes in lymphocyte cell subsets, clinical profile, and infectious stigma. Adults with BD or SZ exposed to CM exhibit specific immune cell subset profiles, clinical features, and stigma of past infections. In BD, our data indicate an interplay between CM and CMV infections, which may possibly contribute to premature aging and cellular senescence, both of which have previously been shown to associate with mood disorders. Longitudinal studies of CM-exposed patients are required to clarify the interactions of CM and viral infections, including as to the pathophysiological processes driving patient symptomatology.

Combined effects of nitric oxide synthase 3 genetic variant and childhood emotional abuse on earlier onset of suicidal behaviours.

Marked heterogeneity in suicide attempters has been observed, with earlier onset being linked to stronger heritability, more childhood maltreatment. Nitric oxide signalling system might be implicated in this relationship through its role in the stress response/adaptation. This study examined how NOS genetic variants and childhood maltreatment were associated with age at first suicide attempt (SA). Adult patients with SA history (N = 414) filled in the Childhood Trauma Questionnaire, and six functionally relevant NOS2 and NOS3 polymorphisms were genotyped. Analyses included χ2, Mann-Whitney U tests, Kendall's regression, multivariate linear and Cox survival regressions, and a moderation analysis. The NOS3 promotor 27-bp variable number tandem repeat (VNTR) bb homozygous state and childhood emotional abuse were independently associated with earlier age at first SA, which was robust after controlling for confounders [regression coefficient - 3.975, 95% CI -6.980 - (-0.970), p = 0.010, and - 1.088, 95% CI -2.172 - (-0.004), p = 0.049]. No interaction was observed. In the Cox proportional hazards model for age at first SA, the hazard ratio for patients with childhood emotional abuse and NOS3 27-bp VNTR bb was 0.533 (95% CI 0.394-0.720, p < 0.001) compared to patients without. Intermediate scores were observed with either only the risk genotype or only childhood emotional abuse. A graded relationship was also observed for repeated SA, family history of SA, and severe SA history. These results are preliminary due to a low statistical power and call for replication and further characterization of the role of nitric oxide system in the susceptibility to early-onset SB.