T cell activation and lowered T regulatory cell numbers are key processes in severe major depressive disorder: Effects of recurrence of illness and adverse childhood experiences.

BACKGROUND: Major depressive disorder (MDD) is characterized by increased T helper (Th)1 polarization, T cell activation (e.g., CD71+ and CD40L+), and cannabinoid receptor type 2 bearing CD20+ B cells; and lower T regulatory (Treg) numbers. AIMS: To delineate the effects of adverse childhood experiences (ACEs) and recurrence of illness (ROI) on activated T and CB2-bearing B populations, and Tregs, including FoxP3 + CD152+, FoxP3 + GARP+, and FoxP3 + CB1+ cells. METHODS: We measured ROI, ACEs, the number of activated T cells, Tregs, and CD20 + CB2+ B cells, in 30 MDD patients and 20 healthy controls. RESULTS: A larger part of the variance in the depression phenome (40.8 %) was explained by increased CD20 + CB2+ and activated T cells, and lowered Tregs. ROI and lifetime suicidal behaviors were significantly and positively associated with CD20 + CB2+, CD3 + CD71+, CD3 + CD40L+, CD4 + CD71+, CD4 + CD40L+, and CD4HLADR+ numbers. ROI was significantly correlated with CD8 + CD40L+ numbers. The sum of ACEs was significantly associated with CD20 + CB2+, CD3 + CD40L+, CD4 + 40 L+ numbers, T cell activation (positively) and Treg (inversely) indices. One replicable latent vector could be extracted from activated T cells, lifetime and current suicidal behaviors, number of depressive episodes, and severity of depression, and 48.8 % of its variance was explained by ACEs. CONCLUSIONS: ACE-induced activation of T effector and cytotoxic cells and B cells with autoimmune potential, coupled with lowered Treg numbers are a key component of depression. The findings indicate that increasing ROI, the phenome of depression and suicidal behaviors, are caused by autoimmune processes, which are the consequence of ACEs and increasing sensitization of immune responses.

T cell activation and deficits in T regulatory cells are associated with major depressive disorder and severity of depression.

Major depressive disorder (MDD) is associated with T cell activation, but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP (glycoprotein A repetitions predominant)-bearing CD25+ FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1 cell, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+ FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+ CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+ CD71+, CD3+ CD40L+, CD4+ CD71+, CD4+ CD40L+, CD4+ HLADR+, and CD8+ HLADR+ T cells, increased CD3+ CD71+, CD4+ CD71+ and CD4+ HLADR+ expression, and lowered CD25+ FoxP3 expression and CD25+ FoxP+ CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30 and 40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+ CD40L+). In conclusion, increased T helper and cytotoxic cell activation along with decreased Treg homeostatic defenses are important parts of MDD that lead to enhanced immune responses and, as a result, neuroimmunotoxicity.

Role of T and B lymphocyte cannabinoid type 1 and 2 receptors in major depression and suicidal behaviours.

Early flow cytometry studies revealed T cell activation in major depressive disorder (MDD). MDD is characterised by activation of the immune-inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS), including deficits in T regulatory (Treg) cells. This study examines the number of cannabinoid type 1 (CB1) and type 2 (CB2) receptor-bearing T/B lymphocytes in MDD, and the effects of in vitro cannabidiol (CBD) administration on CB1/CB2-bearing immunocytes. Using flow cytometry, we determined the percentage of CD20+CB2+, CD3+CB2+, CD4+CB2+, CD8+CB2+ and FoxP3+CB1+ cells in 19 healthy controls and 29 MDD patients in 5 conditions: baseline, stimulation with anti-CD3/CD28 with or without 0.1 µg/mL, 1.0 µg/mL, or 10.0 µg/mL CBD. CB2+ was significantly higher in CD20+ than CD3+ and CD4+ and CD 8+ cells. Stimulation with anti-CD3/CD8 increases the number of CB2-bearing CD3+, CD4+ and CD8+ cells, as well as CB1-bearing FoxP3+ cells. There was an inverse association between the number of reduced CD4+ CB2+ and IRS profiles, including M1 macrophage, T helper-(Th)-1 and Th-17 phenotypes. MDD is characterised by lowered basal FoxP3+ CB1+% and higher CD20+ CB2+%. 33.2% of the variance in the depression phenome (including severity of depression, anxiety and current suicidal behaviours) is explained by CD20+ CB2+ % (positively) and CD3+ CB2+% (inversely). All five immune cell populations were significantly increased by 10 µg/mL of CBD administration. Reductions in FoxP3+ CB1+% and CD3+ /CD4+ CB2+% contribute to deficits in immune homoeostasis in MDD, while increased CD20+CB2+% may contribute to the pathophysiology of MDD by activating T-independent humoral immunity.

Lower Nerve Growth Factor Levels in Major Depression and Suicidal Behaviors: Effects of Adverse Childhood Experiences and Recurrence of Illness.

Major depressive disorder (MDD) and its severe subtype, major dysmood disorder (MDMD), are distinguished by activation of inflammatory and growth factor subnetworks, which are associated with recurrence of illness (ROI) and adverse childhood experiences (ACEs). Nerve growth factor (NGF) plays a crucial role in facilitating neuro-immune communications and may regulate the inflammatory response. METHODS: The present study examined the effects of ACEs and ROI on culture supernatant NGF, stem cell factor (SCF), stem cell GF (SCGF), hepatocyte GF (HGF), and macrophage colony-stimulating factor (M-CSF), in relation to a neurotoxicity (NT) cytokine profile. RESULTS: NGF levels are lower in MDD (p = 0.003), particularly MDMD (p < 0.001), as compared with normal controls. ROI and ACE were significantly and inversely associated with NGF (≤0.003) and the NGF/NT ratio (≤0.001), whereas there are no effects of ACEs and ROI on SCF, SCGF, HGF, or M-CSF. Lowered NGF (p = 0.003) and the NGF/NT ratio (p < 0.001) are highly significantly and inversely associated with the severity of the current depression phenome, conceptualized as a latent vector extracted from the current severity of depression, anxiety, and suicidal behaviors. We found that one validated and replicable latent vector could be extracted from NGF, ROI, and the depression phenome, which therefore constitutes a novel ROI-NGF-pathway-phenotype. ACEs explained 59.5% of the variance in the latter pathway phenotype (p < 0.001). CONCLUSIONS: The imbalance between decreased NGF and increased neurotoxic cytokines during the acute phase of severe depression may contribute to decreased neuroprotection, increased neuro-affective toxicity, and chronic mild inflammation.

Adverse Childhood Experiences Predict the Phenome of Affective Disorders and These Effects Are Mediated by Staging, Neuroimmunotoxic and Growth Factor Profiles.

Adverse childhood experiences (ACEs) enhance pro-inflammatory and pro-oxidant responses. In affective disorders, recent precision nomothetic psychiatry studies disclosed new pathway phenotypes, including an ROI-reoccurrence of illness (ROI)-oxidative stress latent construct. The aim of the present study is to delineate a) whether ACEs sensitize the M1 macrophage, the T helper cells (Th)1, Th2, and Th17, the IRS (immune-inflammatory-responses system), the CIRS (compensatory immunoregulatory system), and the neuroimmunotoxic and growth factor (GF) profiles and whether they are associated with ROI and the phenome of affective disorders and b) the molecular pathways underpinning the effects of the ACEs. We collected supernatants of stimulated (5 µg/mL of PHA and 25 µg/mL of LPS) and unstimulated diluted whole blood in 20 healthy controls and 30 depressed patients and measured a panel of 27 cytokines/GF using a Luminex method. ACEs (comprising mental and physical trauma, mental neglect, domestic violence, family history of mental disease, and parent loss) are accompanied by the increased stimulated, but not unstimulated, production of M1, Th1, Th2, Th17, IRS, neuroimmunotoxic, and GF profiles and are strongly correlated with ROI and the phenome. A latent vector extracted from the ROI features (recurrent episodes and suicidal behaviors) and the IRS/neuroimmunotoxic/GF profiles explains 66.8% of the variance in the phenome and completely mediates the effects of ACEs on the phenome. Enrichment analysis showed that the ACE-associated sensitization of immune/GF profiles involves JAK-STAT, nuclear factor-κB, tumor necrosis factor-α, G-protein coupled receptor, PI3K/Akt/RAS/MAPK, and hypoxia signaling. In summary, the ACE-induced sensitization of immune pathways and secondary immune hits predicts the phenome of affective disorders.

In Vitro Effects of Cannabidiol on Activated Immune-Inflammatory Pathways in Major Depressive Patients and Healthy Controls.

Major depressive disorder and major depressive episodes (MDD/MDE) are characterized by the activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). Cannabidiol (CBD) is a phytocannabinoid isolated from the cannabis plant, which is reported to have antidepressant-like and anti-inflammatory effects. The aim of the present study is to examine the effects of CBD on IRS, CIRS, M1, T helper (Th)-1, Th-2, Th-17, T regulatory (Treg) profiles, and growth factors in depression and healthy controls. Culture supernatant of stimulated (5 µg/mL of PHA and 25 µg/mL of LPS) whole blood of 30 depressed patients and 20 controls was assayed for cytokines using the LUMINEX assay. The effects of three CBD concentrations (0.1 µg/mL, 1 µg/mL, and 10 µg/mL) were examined. Depression was characterized by significantly increased PHA + LPS-stimulated Th-1, Th-2, Th-17, Treg, IRS, CIRS, and neurotoxicity profiles. CBD 0.1 µg/mL did not have any immune effects. CBD 1.0 µg/mL decreased CIRS activities but increased growth factor production, while CBD 10.0 µg/mL suppressed Th-1, Th-17, IRS, CIRS, and a neurotoxicity profile and enhanced T cell growth and growth factor production. CBD 1.0 to 10.0 µg/mL dose-dependently decreased sIL-1RA, IL-8, IL-9, IL-10, IL-13, CCL11, G-CSF, IFN-γ, CCL2, CCL4, and CCL5, and increased IL-1ß, IL-4, IL-15, IL-17, GM-CSF, TNF-α, FGF, and VEGF. In summary, in this experiment, there was no beneficial effect of CBD on the activated immune profile of depression and higher CBD concentrations can worsen inflammatory processes.

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

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 clinical significance of antinuclear antibodies and specific autoantibodies in juvenile and adult systemic lupus erythematosus patients.

BACKGROUND: Juvenile systemic lupus erythematosus (JSLE) and adult SLE (ASLE) patients present with different clinical manifestations, but it is unknown if there are differences in their antinuclear autoantibody (ANA) profiles or if staining patterns are associated with specific autoantibodies and clinical manifestations. OBJECTIVE: To determine whether distinct types and numbers of ANA-staining patterns are associated with specific autoantibodies and clinical manifestations in JSLE and ASLE patients. METHODS: A retrospective study was performed in Thai children (n = 146) and adults (n = 180) diagnosed with SLE using the Systemic Lupus International Collaborating Clinics classification criteria. RESULTS: JSLE patients with a homogeneous pattern of staining and anti-dsDNA or anti-nucleosome antibodies in serum, developed renal involvement, leukopenia and acute/subacute cutaneous LE. Coarse speckled pattern with anti-RNP or anti-Sm showed thrombocytopenia and renal involvement in JSLE patients, but leukopenia in both groups. JSLE patients with fine-coarse speckled pattern and anti-RNP, anti-Sm, anti-Ro-52 or anti-SSA developed leukopenia, thrombocytopenia and renal involvement, whilst hemolytic anemia and serositis were commonly found in those with anti-Ro-52. Median SLEDAI score was higher in JSLE than ASLE patients. CONCLUSIONS: Detailed ANA-staining patterns with specific autoantibodies show particular clinical manifestations and hence prompt further clinical investigations in both JSLE and ASLE patients. Therefore, this study demonstrates that distinct patterns of ANA staining and specific autoantibodies are clinically important in both children and adults with SLE.

Hospital epidemiology and antimicrobial susceptibility of isolated methicillin-resistant Staphylococcus aureus: a one-year retrospective study at a tertiary care center in Thailand.

BACKGROUND: Increased rates of Staphylococcus aureus resistance and its morbidity and mortality have raised concern about the strategy of antibiotic use. OBJECTIVES: This study aimed to determine the prevalence of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) isolates among Thai patients with S. aureus infection and to identify risk factors and appropriate antibiotics for these resistant strains. METHODS: Data of culture-proven S. aureus isolates from clinical specimens during 2017 in King Chulalongkorn Memorial Hospital, Thailand, were retrospectively collected and classified as methicillin-sensitive S. aureus or MRSA by cefoxitin screening and oxacillin minimum inhibitory concentration by the Vitek 2 system. Each isolate was also tested for susceptibility to teicoplanin, erythromycin, clindamycin, linezolid, trimethoprim/sulfamethoxazole, ciprofloxacin, moxifloxacin, tetracycline, doxycycline, and vancomycin by Vitek 2. Demographic information and comorbidities from medical records were reviewed to identify risk factors for S. aureus infection. RESULTS: MRSA isolates were identified in 147 (17%) of 890 patients with no different ratio in adults or children. A higher proportion of MRSA in hospital-acquired settings was observed (27% vs. 12%; p < 0.001). Comorbidities significantly associated with MRSA were chronic lung, cardiovascular, and neurological diseases. Atrial fibrillation, dementia, and benign prostatic hyperplasia were independently associated with MRSA isolation. Vancomycin was still susceptible to all kinds of infection. One VRSA isolate was from colonization. CONCLUSION: The prevalence of MRSA in our facility seemed to be comparatively low. Vancomycin is still an appropriate option for MRSA coverage since all S. aureus isolates in our center were sensitive to vancomycin. However, careful attention is warranted since one colonization isolate was VRSA.

Anti-neutrophil cytoplasmic antibodies and their clinical significance.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies that cause systemic vascular inflammation by binding to target antigens of neutrophils. These autoantibodies can be found in serum from patients with systemic small-vessel vasculitis and they are considered as a biomarker for ANCA-associated vasculitis (AAV). A conventional screening test to detect ANCA in the serum is indirect immunofluorescence study, and subsequently confirmed by enzyme-linked immunosorbent assay. A positive staining of ANCA can be classified into three main categories based on the staining patterns: cytoplasmic, perinuclear, and atypical. Patients with granulomatosis with polyangiitis (GPA) mostly have a positive cytoplasmic staining pattern (c-ANCA) whilst a perinuclear pattern (p-ANCA) is more common in microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) patients. Atypical pattern (a-ANCA) is rarely seen in patients with systemic small-vessel vasculitis but it can be found in other conditions. Here, techniques for ANCA detection, ANCA staining patterns and their clinical significances are reviewed.