Bronchoalveolar lavage fluid cytokines and chemokines changes after bronchial thermoplasty in severe asthma.

BACKGROUND: Bronchial thermoplasty (BT) is a non-pharmacological intervention in severe asthma with a well-known mechanism of reducing airway smooth muscle. However, its effect on airway inflammation remains uncertain. OBJECTIVE: To investigate the effect of BT on bronchoalveolar lavage fluid (BALF) cytokines and chemokines in severe asthma patients before BT, after the first BT, and 12 weeks after BT. METHODS: Ten severe asthma patients were recruited, and BALF was obtained from right lower lobe before BT, after the first BT, and 12 weeks after BT. BALF analytes were measured and values were compared among the time points. Lung function, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were also measured. RESULTS: Tumor necrosis factor (TNF)-α concentration was significantly decreased after the first BT and significantly increased at 12 weeks after BT. Interleukin-6 (IL-6) and TNF-related apoptosis inducing ligand (TRAIL) concentration were significantly increased at 12 weeks after BT. There were no significant changes in Regulated upon activation, normal T-cell expressed and secreted (RANTES) and transforming growth factor-beta1 (TGF-ß1) concentration over time after BT. At 12 weeks after BT, there were significantly greater improvements in the scores on AQLQ (3.93 ± 0.88 to 5.3 ± 0.99, p = 0.002) and ACT (13.6 ± 3.27 to 19 ± 4.44, p = 0.002). The lung function did not differ significantly between pre- and post-BT. CONCLUSIONS: BT has limited effect on TNF-α, IL-6, TRAIL, RANTES, and TGF- ß1 in BALF suggesting that its clinical benefit is not primarily related to this local airway inflammation. The effect on long-term airway inflammation probably needs further studies.

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.

TIGIT Monoallelic Nonsense Variant in Patient with Severe COVID-19 Infection, Thailand.

A heterozygous nonsense variant in the TIGIT gene was identified in a patient in Thailand who had severe COVID-19, resulting in lower TIGIT expression in T cells. The patient's T cells produced higher levels of cytokines upon stimulation. This mutation causes less-controlled immune responses, which might contribute to COVID-19 severity.

Host genetic factors of COVID-19 susceptibility and disease severity in a Thai population.

Host genetic factors have been shown to play a role in SARs-CoV-2 infection in diverse populations. However, the genetic landscape differs among various ethnicities; therefore, we explored the host genetic factors associated with COVID-19 disease susceptivity and disease severity in a Thai population. We recruited and genotyped 212 unrelated COVID-19 Thai patients and 36 controls using AxiomTM Human Genotyping SARs-COV-2 array, including 847,384 single nucleotide polymorphisms related to SARs-COV-2 pathogenesis, immune response, and related comorbidity No SNPs passed the genome-wide significance threshold of p value <1 × 10-8. However, with a threshold of p value <1 × 10-5, a locus on chromosome 5q32 was found to have a suggestive association with COVID-19 disease susceptibility (p value 6.9 × 10-6; Q-Q plot λ = 0.805, odds ratio 0.02). Notably, IL17B is a gene located in this linkage disequilibrium block and is previously shown to play a part in inflammation and pneumonia. Additionally, a suggestive locus on chromosome 12q22, harboring EEA1 and LOC643339, was associated with COVID-19 disease severity (p value 1.3 × 10-6 - 4.4 × 10-6, Q-Q plot λ = 0.997, odds ratio 0.28-0.31). EEA1 is involved in viral entry into cells, while LOC643339 is a long non-coding RNA. In summary, our study suggested loci on chromosomes 5q32 and 12q22 to be linked to COVID-19 disease susceptibility and disease severity, respectively. The small sample size of this study may lessen the likelihood that the association found is real, but it could still be true. Further study with a larger cohort is required to confirm these findings.

Notch signaling regulates function of human mucosal-associated invariant T (MAIT) cells.

BACKGROUND: Notch signaling plays an important role in the development of T lymphocytes and regulates their effector functions. The regulatory roles of Notch signaling on T cells have been intensely investigated, but whether it involves in effector functions of mucosal-associated invariant T (MAIT) cells has never been reported. OBJECTIVE: To elucidate the expression profiles of Notch receptors/ligands and to investigate their roles in human MAIT cell function. METHODS: Peripheral blood mononuclear cells (PBMCs) from health donors were stimulated with or without anti-CD3/ CD28-coupled beads, recombinant IL-12/IL-18 cytokines, riboflavin- or non-riboflavin-synthesizing bacterial cultured supernatant for 24 hours. The expression profiles of Notch receptors and ligands on MAIT cells were detected by flow cytometry. PBMCs were treated with a Notch signaling inhibitor, gamma secretase inhibitor (GSI), before stimulation to investigate the impact of interfering with Notch signaling on activation and function of MAIT cells. RESULTS: Resting MAIT cells predominantly expressed Notch2 receptor and the ligand, Jagged 2, on their surface. Upon stimulation, MAIT cells further upregulated Notch2 and also Notch1 with its cleaved form, indicating active Notch signaling. Cytokines and cytotoxic molecules which are secreted by activated MAIT cells, were suppressed by treatment with GSI. Moreover, both TCR-dependent MAIT cell activation by microbial-derived riboflavin intermediates and TCR-independent MAIT cell activation driven by IL-18 in synergy with IL-12, were blocked by GSI treatment. CONCLUSIONS: Notch signaling is operating in MAIT cells and is involved in their activation both in a TCR-independent and -dependent manners.

Notch 2 receptor expression and reduced cytotoxicity in MAIT cells of active pulmonary TB patients.

BACKGROUND: Knowledge of the prevalence of common sensitizing allergens may aid in overall management of allergic disease in a specified area. OBJECTIVE: The aim of this study was to identify and analyse the prevalence of common inhaled and food sensitizing allergens in Beijing. METHODS: This was a retrospective study, analysing demographic data and serum sIgE antibody test results from 59057 outpatients who presented to Beijing TongRen Hospital, from January 2013 to December 2019. RESULTS: 28879 patients (48.9%) showed positive sIgE test results; with significantly more males aged under 16 years sensitized to at least one allergen than females, and most patients (53.62%) were sensitized to multiple allergens. The first inhaled sensitizing allergens was Artemisia grass (11910 (41.24%)); and the first food allergens was crab (3547 (12.28%)). For Artemisia sensitized patients, sIgE levels were mostly at level 5. The number of patients with ragweed allergy is increasing year by year. The detection rates for sIgE to Artemisia, common ragweed, and Humulus grass allergens were significantly higher in August and September. R package ggplot2 analysis, demonstrated strong correlations between tree allergens and common ragweed and Humulus grass allergens (phi coefficients = 0.50 and 0.46, respectively; both P < 0.01). CONCLUSIONS: The prevalence of sensitization to different allergens in Beijing showed Artemisia grass was the most commonly inhaled sensitizing allergen, and the number of patients with ragweed grass allergy was increasing by year.

Down-regulation of let-7a and miR-21 in urine exosomes from lupus nephritis patients during disease flare.

BACKGROUND: The contents of exosomes determine their biological functions and represent a new class of epigenetic modulation of renal cells considering as novel class of biomarker. OBJECTIVE: Our study aims to investigate the expression of microRNAs (miRNA), including miR-10a/b, let-7a, and miR-21, in urinary exosomes isolated from patients with active lupus nephritis (LN) compared to inactive LN. METHODS: The exosomes were obtained from long-term follow up LN patients during active and 4 months after treatment (n = 3). The expression of candidate miRNAs was validated in group of LN patients with renal flare (n = 13) and remission stage (n = 18) using qPCR. All exosomes were characterized by NanoSight and western blotting. The correlation between miRNA expressions and kidney functions was studied. RESULTS: We found that let-7a and miR-21, but not miR-10a/b, were significantly down-regulated in LN patients with active disease compared with inactive disease. Long-term follow-up patients also showed down-regulation of let-7a and miR-21 during disease flare while the expressions were elevated after complete course of treatment. Although the miRNA expressions were not significantly correlated with classical kidney injury markers, negative correlations were found in both protein leakages and glomerular filtration rate. CONCLUSION: Our result suggested that urinary exosome-associated miRNA, let-7a and miR-21, could be used to guide the clinical stage of LN patients and possibly plays a role in epigenetic regulation of the kidney during the disease. Its expression might be able to use as liquid biopsy, however, validation in large sample size is required to show it significant in clinical implication.

Slow desensitization of imatinib-induced nonimmediate reactions and dynamic changes of drug-specific CD4+CD25+CD134+ lymphocytes.

BACKGROUND: Imatinib is a tyrosine kinase inhibitor indicated for the treatment of gastrointestinal stromal tumors (GISTs) and certain neoplastic diseases; however, nonimmediate adverse reactions are common. OBJECTIVE: To describe the process of imatinib slow desensitization in patients who experienced nonimmediate reactions to imatinib and the dynamic change in drug-specific CD4+CD25+CD134+ T-lymphocyte percentages. METHODS: Five patients diagnosed as having GISTs and with a recent history of imatinib-induced nonimmediate reactions (maculopapular exanthema with eosinophilia, exfoliative dermatitis, palmar-plantar erythrodysesthesia, and drug rash with eosinophilia and systemic symptoms) were desensitized using a slow desensitization protocol. The reintroduced imatinib dosage was stepped up every week starting from 10 mg/d and increasing to 25, 50, 75, 100, 150, 200, and 300 mg/d until the target dose of 400 mg/d was achieved. Prednisolone of up to 30 mg/d was allowed if allergic reactions recurred. The percentages of CD4+CD25+CD134+ T cells present after incubating peripheral blood mononuclear cells with imatinib, at baseline and after successful desensitization, were analyzed using flow cytometric analysis. RESULTS: By using a slow desensitization technique, all patients were able to receive 400 mg/d of imatinib, and prednisolone was gradually tapered off. The percentages of imatinib-induced CD4+CD25+CD134+ T cells decreased from a mean (SD) of 11.3% (6.5%) and 13.4% (7.3%) at baseline to 3.2% (0.7%) and 3.0% (1.1%) after successful desensitization, when stimulating peripheral blood mononuclear cells with 1 and 2 µM of imatinib, respectively. CONCLUSION: Slow desensitization is a helpful procedure in treating patients with imatinib-induced nonimmediate reactions other than simple maculopapular exanthema. The reduced percentages of imatinib-induced CD4+CD25+CD134+ T cells in these patients may be associated with immune tolerance.

Immunoprevalence and immunodominance of HLA-Cw*0801-restricted T cell response targeting the hepatitis B virus envelope transmembrane region.

HLA-C-restricted T cells have been shown to play an important role in HIV control, but their impact on protection or pathogenesis in other viral infections remains elusive. Here, we characterized the hierarchy of HLA class I-restricted hepatitis B virus (HBV) epitopes targeted by CD8 T cells in HBV-infected subjects. The frequency of CD8 T cells specific for a panel of 18 HBV epitopes (restricted by HLA-A∗0201/03/07 [hereinafter HLA-A0201/03/07], -A1101, -A2402/07, -B5801, -B4001, -B1301, and -Cw0801) was quantified in a total of 59 subjects who resolved HBV infection. We found that the HLA-Cw0801-restricted epitope comprised of Env residues 171 to 180 (Env171-180) is immunoprevalent in the Southeast Asian subjects (10/17 HLA-Cw0801-positive subjects) and immunodominant in the majority of HLA-Cw0801-positive subjects able to control HBV infection. HLA-Cw0801-restricted Env171-180-specific CD8 T cells recognized endogenously produced HBV surface antigen (HBsAg) and tolerated amino acid variations within the epitope detected in HBV genotypes B and C. In conclusion, we demonstrate that the HLA-Cw0801-restricted Env171-180 T cell response is an important component of the HBV-specific adaptive T cell immunity in Asians infected with HBV. Thus, HLA-C restricted T cells might play an important role in various viral infections.

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.

Preservation of Anti-SARS-CoV-2 Neutralizing Antibodies in Breast Milk: Impact of Maternal COVID-19 Vaccination and Infection.

Objectives: To investigate specific immunoglobulin A (sIgA), specific immunoglobulin G (sIgG), and neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in breast milk and compare immunity in mothers with hybrid immunity (infection and vaccination) versus those solely vaccinated (coronavirus disease [COVID]-naïve). Methods: A longitudinal study was conducted among lactating mothers who received at least two doses of the coronavirus disease 2019 (COVID-19) vaccine or tested positive for SARS-CoV-2. Details of vaccination and infection were collected through questionnaires and interviews. Fifteen milliliters of breast milk samples, self-collected at 1, 3, and 6 months postvaccination or infection, were sent to analysis for sIgA, sIgG, and NAbs using enzyme-linked immunosorbent assay. Results: In total, 119 lactating mothers (202 milk samples) were enrolled; 82 participants had hybrid immunity, and 32 were COVID-19-naïve. Two-thirds received a combination of different vaccines and booster shots. Breast milk retained sIgA, sIgG, and NAbs for up to 6 months post-COVID vaccination or infection. At 3 months, mothers with hybrid immunity had significantly higher sIgA and NAbs compared with COVID-naïve mothers (geometric mean [95% confidence interval (CI)] of sIgA 2.72 [1.94-3.8] vs. 1.44 [0.83-2.48]; NAbs 86.83 [84.9-88.8] vs. 81.28 [76.02-86.9]). No differences in sIgA, sIgG, and NAbs were observed between lactating mothers receiving two, three, or more than or equal to three doses, regardless of hybrid immunity or COVID-naïve status. Conclusion: sIgA, sIgG, and NAbs against SARS-CoV-2 in breast milk sustained for up to 6 months postimmunization and infection. Higher immunity was found in mothers with hybrid immunity. These transferred immunities confirm in vitro protection, supporting the safety of breastfeeding during and after COVID-19 vaccination or infection.

In major dysmood disorder, physiosomatic, chronic fatigue and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity.

Major depressive disorder (MDD) is accompanied by activated neuro-immune pathways, increased physiosomatic and chronic fatigue-fibromyalgia (FF) symptoms. The most severe MDD phenotype, namely major dysmood disorder (MDMD), is associated with adverse childhood experiences (ACEs) and negative life events (NLEs) which induce cytokines/chemokines/growth factors. To delineate the impact of ACE + NLEs on physiosomatic and FF symptoms in first episode (FE)-MDMD, and examine whether these effects are mediated by immune profiles. ACEs, NLEs, physiosomatic and FF symptoms, and 48 cytokines/chemokines/growth factors were measured in 64 FE-MDMD patients and 32 normal controls. Physiosomatic, FF and gastro-intestinal symptoms belong to the same factor as depression, anxiety, melancholia, and insomnia. The first factor extracted from these seven domains is labeled the physio-affective phenome of depression. A part (59.0%) of the variance in physiosomatic symptoms is explained by the independent effects of interleukin (IL)-16 and IL-8 (positively), CCL3 and IL-1 receptor antagonist (inversely correlated). A part (46.5%) of the variance in physiosomatic (59.0%) symptoms is explained by the independent effects of interleukin (IL)-16, TNF-related apoptosis-inducing ligand (TRAIL) (positively) and combined activities of negative immunoregulatory cytokines (inversely associated). Partial least squares analysis shows that ACE + NLEs exert a substantial influence on the physio-affective phenome which are partly mediated by an immune network composed of interleukin-16, CCL27, TRAIL, macrophage-colony stimulating factor, and stem cell growth factor. The physiosomatic and FF symptoms of FE-MDMD are partly caused by immune-associated neurotoxicity due to T helper (Th)-1 polarization and M1 macrophage activation and relative lowered compensatory immunoregulatory protection.

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.

Association of genetic variation on X chromosome with systemic lupus erythematosus in both Thai and Chinese populations.

OBJECTIVES: X chromosome has been considered as a risk factor for SLE, which is a prototype of autoimmune diseases with a significant sex difference (female:male ratio is around 9:1). Our study aimed at exploring the association of genetic variants in X chromosome and investigating the influence of trisomy X in the development of SLE. METHODS: X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined. RESULTS: Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002). CONCLUSION: Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.

Association of cytokine and cytokine receptor gene polymorphisms with the risk of chronic hepatitis B.

BACKGROUND: Hepatitis B (HBV) infection is a major cause of chronic liver diseases, and the polymorphisms of cytokine genes may affect the progression of HBV-related hepatitis. OBJECTIVE: The aim of this study was to examine the association of cytokine polymorphisms with the susceptibility to HBV-related chronicity. METHODS: Specifically, a LIFECODES Cytokine SNP Typing kit was used to investigate 22 cytokine single nucleotide polymorphisms (SNPs) from 14 cytokine and cytokine receptor genes with the aim of analyzing the role of Th1 and Th2 genotype combination. This population-based case-control association study included 131 chronic HBV patients and a control group of 142 healthy donors. RESULTS: When the combination of Th1 and Th2 genotypes was analyzed for the genetic risk factor for chronic hepatitis B, we did not observe any significant association. A non-significant association betweenTh1 and Th2 and this risk factor could have resulted from the limitation of our small sample size. When the results from each genotype were separately analyzed, the frequencies of the heterozygous CA (-592) and CT (-819) genotype of IL-10 gene-promoter polymorphisms were significantly higher in chronic HBV patients than that in healthy controls (OR=1.76, 9%CI =1.03-3.01, p =0.028; OR=1.79, 95%CI =1.04-3.06, p =0.024, respectively). Interestingly, the TCC (-1098/-590/-33) haplotype frequency of IL-4 showed a positive association with chronic hepatitis B as a protective haplotype (OR =0.53, 95%CI =0.32-0.85, p =0.005). CONCLUSION: These preliminary results suggest that polymorphisms in some cytokine genes, particularly the Th2 cytokine, influence persistence of HBV infection.

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.

The Persistence of Specific Immunoglobulin A Against SARS-CoV-2 in Human Milk After Maternal COVID-19 Vaccination.

Objectives: To investigate SARS-CoV-2 specific immunoglobulin A (sIgA) in breast milk of Thai mothers post COVID-19 vaccination and/or SARS-CoV-2 infection, and to compare the sIgA among lactating mothers with varying COVID-19 vaccination regimes. Materials and Methods: A longitudinal study was conducted in lactating mothers receiving ≥2 doses of COVID-19 vaccine or confirming SARS-CoV-2-positive test as a part of an infant feeding survey. Vaccination and infection details were collected through questionnaires and interviews. Self-collected breast milk samples (30 mL) at 1, 3, and 6 months postvaccination or infection were analyzed for sIgA through enzyme-linked immunosorbent assay (ELISA). Results: Eighty-eight lactating mothers (152 milk samples), average age of 30.7 ± 6.2 years, were recruited. Fifty-five percent of milk samples were from lactating mothers with both SARS-CoV-2 infection and vaccination (hybrid immunity); 40% were from those with vaccination alone (COVID naïve). Sixty percent of lactating mothers received mixed types of vaccines. Median sIgA ratio in breast milk was 2.67 (0.82-7.85). Breast milk sIgA at 1, 3, and 6 months were higher in mothers with hybrid immunity than in COVID naïve (geometric mean [95% confidence interval]: 3.30 [2.06-5.29] versus 1.04 [0.52-2.04], 3.39 [2.24-5.13] versus 1.26 [0.77-2.06], 4.29 [3.04-6.06] versus 1.33 [0.74-2.42], respectively). No significant differences were observed among various vaccination regimes. Conclusion: sIgA against SARS-CoV-2 was detected in breast milk for up to 6 months after immunization together with infection at a greater level than after immunization or infection alone. This immunity could be transferred and protective against SARS-CoV-2 infection. Discontinuation of breastfeeding among mothers who received COVID vaccination or experienced infection should be discouraged. Clinical Trial Registration number: TCTR20220215012.

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.

Immunogenicity of an mRNA-Based COVID-19 Vaccine among Adolescents with Obesity or Liver Transplants.

There are limited data regarding the immunogenicity of mRNA-based SARS-CoV-2 vaccine BNT162b2 among immunosuppressed or obese adolescents. We evaluated the humoral immune response in adolescents with obesity and adolescent liver transplant recipients (LTRs) after receiving two BNT162b2 doses. Sixty-eight participants (44 males; mean age 14.9 ± 1.7 years), comprising 12 LTRs, 24 obese, and 32 healthy adolescents, were enrolled. Immunogenicity was evaluated by anti-SARS-CoV-2 spike protein immunoassay and surrogate viral neutralization tests (sVNT) against the Delta and Omicron (BA.1) variants. At 27.1 ± 3.2 days after the second dose, the antibody levels were 1476.6 ± 1185.4, 2999.4 ± 1725.9, and 4960.5 ± 2644.1 IU/mL in the LTRs, obese adolescents, and controls, respectively (p < 0.001). Among obese individuals, liver stiffness <5.5 kPa was associated with higher antibody levels. The %inhibition of sVNT was significantly lower for the Omicron than that for the Delta variant. Injection site pain was the most common local adverse event. Nine participants (three obese and six controls) developed COVID-19 at 49 ± 11 days after the second vaccination; four were treated with favipiravir. All infections were mild, and the patients recovered without any consequences. Our study supports the need for the booster regimen in groups with an inferior immunogenic response, including LTRs and obese individuals.