Impairments in Peripheral Blood T Effector and T Regulatory Lymphocytes in Bipolar Disorder Are Associated with Staging of Illness and Anti-cytomegalovirus IgG Levels

Abstract

There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)-specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD.

The immune profile of Major Dysmood Disorder: proof of concept and mechanism using the precision nomothetic psychiatry approach

“…Thus, in MDD/BD, the number of prior depressive and manic episodes, as well as SBs, is associated with an increase in plasma IL-1β, sIL-1RA, IL-6, TNF-α, and neopterin, lowered antioxidant enzyme activities and damage to lipids and proteins [10–13], while other findings indicate that immune-inflammatory responses are more pronounced in later stages of illness [14,15]. In BD, we detected that the frequency of episodes is inversely related to the proportions of stimulated antigen specific activated CD3+CD4+ T cells, and the expression of early activation markers and the transferrin receptor on CD4+ and CD8+ cells, whereas later stages of illness are characterized by decreased frequencies of activated Treg cells [16]. The association between staging and immunological pathways was explained by the fact that pro-inflammatory signals may sensitize the immune system, as well as by abnormalities in CIRS and proliferative responses [12,16].…”

“…In this respect, using a new precision nomothetic psychiatry approach, Maes et al [17–20] established a) a new reoccurrence of illness index (ROI) of MDD/BD, namely a latent vector (LV) extracted from number of depressive and manic episodes and SB as well; b) a novel model of affective disorders based on antioxidant gene variants, adverse outcome pathways (immune-redox pathways), ROI, and the phenome, which was conceptualized as a LV extracted from depression, anxiety, clinical, SB, disability, and quality of life ratings; c) a new ROI-redox pathway phenotype, which was conceptualized as a LV extracted from ROI and redox biomarkers; and d) a new diagnostic class namely Major DysMood Disorder (MDMD), characterized by aberrations in immune-redox biomarkers, increased ROI, and phenome scores. Importantly, we found that MDMD cuts across unipolar depression and bipolar disorder and is more prominent than the latter diagnoses indicating that both are phenotypes of the same disorder [16,18,20]. Nevertheless, there are no data whether MDMD and increased phenome scores are accompanied by aberrations in IRS/CIRS and an increased immunoneurotoxicity and whether a ROI-immune pathway phenotype may be constructed by linking ROI and cytokines/growth factors.…”

“…In BD, we detected that the frequency of episodes is inversely related to the proportions of stimulated antigen specific activated CD3+CD4+ T cells, and the expression of early activation markers and the transferrin receptor on CD4+ and CD8+ cells, whereas later stages of illness are characterized by decreased frequencies of activated Treg cells [16]. The association between staging and immunological pathways was explained by the fact that pro-inflammatory signals may sensitize the immune system, as well as by abnormalities in CIRS and proliferative responses [12,16].…”

The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

“…While this cytokine may have protective effects (119, 120) and induces an acute phase response (121) it may also display more detrimental inflammatory effects (99). Most importantly, during inflammatory responses IL-22 is upregulated in the brain and may increase the production of TNF-α, IL-6, and prostaglandins and induce STAT3, MAP-kinase, and JAK-STAT pathways (118), which all play a role in schizophrenia (118, 122).…”

mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment

“…In a murine study, T-cell-specific ASM overexpression resulted in increased T-cell function [ 50 ], whereas ASM deficiency seemed to have the opposite effect [ 51 ]. The relations between T-cell subpopulations are dysregulated in bipolar disorder [ 52 ]. A meta-analysis showed the importance of lymphocyte percentage in MDD, as the ratio of neutrophils to lymphocytes differed between MDD patients and healthy controls and was suggested as a biomarker of inflammatory activation in mood disorders [ 53 ].…”