Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia Is Present

Objective: Major depression (MDD) and a lifetime history of MDD are characterized by increased nitrosylation, while bipolar disorder type 1 (BP1), but not BP2, is accompanied by highly increased levels of oxidative stress and nitric oxide (NO) production. Nevertheless, it is unknown whether nitrosylation is involved in BP and whether there are differences in nitrosylation between BP1 and BP2.Methods: Serum IgM antibodies directed against nitroso (NO)-adducts were examined in MDD, BP1, BP2 and healthy controls, namely IgM responses to NO-cysteine, NO-tryptophan (NOW), NO-arginine and NO-albumin (SBA) in association with IgA/IgM responses to Gram-negative bacteria, IgG responses to oxidized low-density lipoprotein (oxLDL) and serum peroxides.Results: Serum IgM levels against NO adducts were significantly higher in BP1 and MDD as compared with healthy controls, whereas BP2 patients occupied an intermediate position. IgM responses to NO-albumin were significantly higher in BP1 and MDD than in BP2 patients. There were highly significant associations between the IgM responses to NO-adducts and IgG responses to oxLDL and IgA/IgM responses to Gram-negative bacteria.Conclusions: BP1 and MDD are characterized by an upregulation of the nitrosylome (the proteome of nitrosylated proteins), and increased IgM responses to nitrosylated conjugates. Increased nitrosylation may be driven by increased bacterial translocation and is associated with lipid peroxidation processes. Innate like (B1 and marginal zone) B cells and increased nitrosylation may play a key role in the major affective disorders through activation of immune-inflammatory and oxidative pathways, cardiovascular comorbidity and impairments in antioxidant defenses, neuro-glial interactions, synaptic plasticity, neuroprotection, neurogenesis, etc.

Download Full-text

Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia is Present

10.20944/preprints201907.0293.v1 ◽

2019 ◽

Author(s):

Denitsa Simeonova ◽

Drozdstoy Stoyanov ◽

Jean–Claude Leunis ◽

Andre F. Carvalho ◽

Marta Kubera ◽

...

Keyword(s):

Oxidative Stress ◽

Bipolar Disorder ◽

Major Depression ◽

Bacterial Translocation ◽

Rating Scale ◽

Gram Negative Bacteria ◽

Oxidative Stress Biomarkers ◽

Gram Negative ◽

Gut Dysbiosis

Major depression (MDD) is accompanied by higher serum IgM/IgA responses to LPS of Gram-negative bacteria, suggesting increased bacterial translocation and gut dysbiosis. Gut dysbiosis may occur in bipolar disorder (BD) and there are differences between MDD and BD type 1 (BP1) and -2 (BP2) in nitro-oxidative stress biomarkers associated with leaky gut. This study examines serum IgM/IgA responses directed to LPS of 6 Gram-negative bacteria in 29 BP1, 37 BP2, 44 MDD and 30 healthy individuals. MDD plus BD was best discriminated from controls by increased IgM/IgA responses to Pseudomonas aeruginosa. BP1 patients showed higher IgM responses to Morganella morganii as compared with MDD and BP2 patients. Patients with melancholia showed higher IgA responses to Citrobacter koseri as compared to controls and non-melancholic depression. The total score on the Hamilton Depression Rating Scale was significantly associated with IgA responses, especially C. koseri. IgG responses to oxidized low-density lipoprotein were significantly associated with signs of increased bacterial translocation. In conclusion, not only MDD but also BP1 and BP2 are accompanied by an immune response due to the increased load of plasma LPS of gut commensal bacteria while these aberrations in the gut-brain axis are most pronounced in BP1 and patients with melancholic features. Activated oxidative stress pathways and autoimmune responses to oxidative specific epitopes in mood disorders may be driven by a breakdown in gut paracellular, transcellular and/or vascular pathways. If replicated, drugs that protect the integrity of the gut barrier may offer novel therapeutic opportunities for BP1 and MDD.

Download Full-text

Upregulation of the nitrosylome in bipolar disorder type 1 (BP1) and major depression, but not BP2: Increased IgM antibodies to nitrosylated conjugates are associated with indicants of leaky gut

Nitric Oxide ◽

10.1016/j.niox.2019.07.003 ◽

2019 ◽

Vol 91 ◽

pp. 67-76 ◽

Cited By ~ 5

Author(s):

Michael Maes ◽

Denitsa Simeonova ◽

Drozdstoy Stoyanov ◽

Jean–Claude Leunis

Keyword(s):

Bipolar Disorder ◽

Major Depression ◽

Leaky Gut ◽

Igm Antibodies ◽

Disorder Type

Download Full-text

Increased Autoimmune Responses to Oxidative Specific Epitopes in Bipolar Disorder Type 1 and Major Depression: Towards A Data-Driven, Mechanistic Model of Mood Disorders

10.20944/preprints202009.0347.v1 ◽

2020 ◽

Author(s):

Drozdstoy Stoyanov ◽

Jean–Claude Leunis ◽

Marianna Murdjeva ◽

Michael Maes

Keyword(s):

Bipolar Disorder ◽

Major Depression ◽

Mood Disorder ◽

Mood Disorders ◽

Mechanistic Model ◽

Oxidized Ldl ◽

Data Driven ◽

Pls Analysis ◽

Disorder Type

Major depression is accompanied by increased IgM-mediated autoimmune responses to oxidative specific epitopes (OSEs). Nevertheless, these responses have not been examined in bipolar disorder type 1 (BP1) and BP2. IgM responses to malondialdehyde (MDA), phosphatidinylinositol, oleic acid, and azelaic acid were determined in 35 healthy controls, and 101 mood disorder patients, namely 47 major depressed (MDD), 29 BP1, and 25 BP2 patients. We also measured serum total peroxides, IgG to oxidized LDL (oxLDL), IgM to nitroso-adducts, and IgM/IgA directed to lipopolysaccharides (LPS). IgM responses to OSEs were significantly higher in MDD and BP1 as compared with controls and higher in MDD than in BP2. Partial Least Squares (PLS) analysis showed that 57.7% of the variance in the clinical phenome of mood disorders was explained by number of episodes, IgM directed to OSEs and nitroso-adducts, IgG to oxLDL, and peroxides. There were significant specific indirect effects of IgA/IgM to LPS on the clinical phenome, which were mediated by peroxides, IgM OSEs, and IgG oxLDL. Using PLS we have constructed a data-driven nomothetic network which ensembled causome (increased plasma LPS load), adverse outcome pathways (namely neuro-affective toxicity), and clinical phenome features of mood disorders in a data-driven model. Based on those feature sets, cluster analysis discovered a new diagnostic class characterized by increased plasma LPS load, peroxides, autoimmune responses to OSEs and nitroso-adducts, and increased phenome scores. Using the new nomothetic network approach, we constructed a mechanistically transdiagnostic diagnostic class indicating neuro-affective toxicity in 74.3% of the mood disorder patients.

Download Full-text

P-163 - P2RX7: Expression responds to sleep deprivation and associates with rapid cycling in bipolar disorder type 1

European Psychiatry ◽

10.1016/s0924-9338(12)74330-4 ◽

2012 ◽

Vol 27 ◽

pp. 1

Author(s):

L. Backlund ◽

C. Lavebratt ◽

L. Frisen ◽

P. Nikamo ◽

M.P. Vawter ◽

...

Keyword(s):

Bipolar Disorder ◽

Sleep Deprivation ◽

Rapid Cycling ◽

Disorder Type

Download Full-text

The role of type 1 interferons in Gram-negative bacteria-induced coagulation

Blood ◽

10.1182/blood.2019002282 ◽

2020 ◽

Cited By ~ 4

Author(s):

Xinyu Yang ◽

Xiaoye Cheng ◽

Yiting Tang ◽

Xianhui Qiu ◽

Zhongtai Wang ◽

...

Keyword(s):

Immune Responses ◽

Bacterial Infection ◽

Innate Immune ◽

Coagulation Cascade ◽

Outer Cell ◽

Gram Negative Bacteria ◽

Innate Immune Responses ◽

Gram Negative ◽

Type 1 Interferons

Bacterial infection not only stimulates innate immune responses but also activates the coagulation cascades. Over-activation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC through amplifying the release of high mobility box group box 1 (HMGB1) into the blood stream. Inhibition of the expression of type 1 IFNs, disruption of their receptor IFN-α/βR or downstream effector (e.g., HMGB1) uniformly decreased Gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the pro-coagulant activity of tissue factor (TF) by promoting the externalization of phosphatidylserine (PS) to the outer cell surface, where PS assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.

Download Full-text