The Immune Profile of Major Dysmood Disorder: Proof of Concept and Mechanism Using the Precision Nomothetic Psychiatry Approach

Abstract

Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class, namely major dysmood disorder (MDMD), a new pathway phenotype, namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMD’s features and IRS, CIRS, macrophages (M1), T helper (Th)1, Th2, Th17, T regulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity, and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS/CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase-triggered STAT protein phosphorylation, TLR/NF-κB, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMD’s heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers.

The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium

“…There is now evidence that MDD is characterized by activation of the immune-inflammatory response system (IRS) with activation of M1 macrophage, T helper (Th)-1 and Th-17 phenotypes and increased production of growth factors, including platelet derived growth factor (PDGF) (Maes and Carvalho, 2018; Maes et al, 2022a). Some cytokines and chemokines that are overproduced in MDD, such as interleukin (IL)-15, IL-17, IL-1β, IL-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, CXCL8, CXCL10, and CCL5, have neurotoxic effects and may jeopardize neuronal functions, such as neurogenesis, neuroplasticity, receptor expression, axonogenesis, and dendritic sprouting (Maes et al, 2022a; Maes et al, 2009). Moreover, elevated levels of IL-6, IL-1β, and TNF-α induce an acute phase response in the liver, leading to increased production of C-reactive protein (CRP) (Sluzewska et al, 1996), which has additional toxic effects on endothelial cells, thereby increasing the permeability of the blood-brain barrier (BBB) and exacerbating the development of neurodegenerative and cerebrovascular processes (Belin et al, 2020; Ge et al, 2013; Hsuchou et al, 2012; Song et al, 2009; Windgassen et al, 2011).…”

Is the JAK-STAT Signaling Pathway Involved in the Pathogenesis of Depression?

“…They are highly expressed at the embryonic stages (especially JAK2, JAK1, STAT3, STAT6 and STAT1), and their expression gradually decreases during growth and adulthood [ 21 , 22 , 23 ]. Recently, a protein–protein interaction network analysis showed that the activation of JAK-STAT signaling is an important pathway underpinning the immune disorders in major depression [ 24 ].…”

General Transcription Factor IIF Polypeptide 2: A Novel Therapeutic Target for Depression Identified Using an Integrated Bioinformatic Analysis

“…From our results, GTF2F2 may affect the TGF-β pathway through NRF-1, and therefore, associate with MDD progression. Besides, JAK-STAT signaling pathway was reported in the MDD ( Gao et al, 2022 ; Maes et al, 2022 ), which may also act as a target of GTF2F2 affecting MDD.…”