HERV-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) are the two main mental disorders with unknown etiology that significantly impact individuals' quality of life. The potential pro-inflammatory role in their pathogenesis is postulated and Human Endogenous Retrovirus W (HERV-W) is an emerging candidate to modulate this pathogenic finding. HERVs, ancient retroviruses in the human genome, may play roles in inflammation and disease pathogenesis. Despite HERVs' involvement in autoimmune diseases, their influence on mental disorders remains underexplored. Therefore, the aim of this study was to assess the level of HERV-W-env expression and the systemic inflammatory profile through the concentration of IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ cytokines in BD and SZ patients. RESULTS: All participants showed HERV-W-env expression, but its expression was higher in mental disorder patients (p < 0.01) than in control. When separated, SZ individuals exhibited higher HERV-W expression than the control group (p < 0.01). Higher serum levels of TNF-α and IL-10 were found in BD (p = 0.0001 and p = 0.001, respectively) and SZ (p = 0.01) and p = 0.01, respectively) than in the control group, while SZ showed decreased levels IFN-γ and IL-2 as compared to controls (p = 0.05) and BD patients (p = 0.05), respectively. Higher TNF-α/IL-4 and TNF-α/IL-10 ratios, and lower IFN-γ/IL-10 were observed in BD and SZ patients than controls. Significant negative correlation between HERV-W-env expression and IL-10 (r=-0.47 p < 0.05), as well as positive correlations between HERV-W-env expression and TNF-α/IL-10 or IFN-γ/IL-10 ratios (r = 0.48 p < 0.05 and r = 0.46 p < 0.05, respectively) were found in BD patients. CONCLUSION: These findings suggest not only a potential link between HERV-W-env expression both in BD and SZ, but also a possible involvement of systemic inflammatory status in BD patients.

Prenatal exposure to RSV season influences first-year risk of RSV lower respiratory illness and RSV-specific immune responses assessed at birth.

Maternal-to-fetal transmission of respiratory syncytial virus (RSV) has been shown to occur but whether late prenatal exposure to RSV season influences offspring postnatal RSV-lower respiratory illness (LRI) risk in early life or RSV immune status at birth is unclear. In this study, the duration of third trimester RSV season exposure was determined for 1,094 newborns of the Tucson Children's Respiratory Study (TCRS) and found to show an inverse relation to risk for first RSV-LRI in the first year. Cord blood anti-RSV antibody is related to third trimester RSV season exposure but not to first year RSV-LRI risk. In a separate birth cohort (the Infant Immune Study), supernatants from cord blood mononuclear cells stimulated with the recall antigen, UV-inactivated RSV, were assayed for IFN-γ and IL-4. The frequency of detectable IFN-γ (but not IL-4) was increased for those with at least 2 mo of third trimester RSV season exposure, suggestive of a fetal immune response to RSV. IMPORTANCE Our study found that duration of third trimester exposure to RSV season related inversely to subsequent risk of postnatal RSV-LRI in the first year, thus implicating this exposure as an important factor in reducing risk of postnatal RSV-LRIs, a risk reduction that appears to be independent of maternally transferred anti-RSV antibody level. The increase in frequency of detectable IFN-γ and not IL-4 in response to UV-inactivated RSV in cord blood immune cells for infants with greater third trimester exposure to RSV season is suggestive of a Type-1 immune response to RSV occurring in utero.

Percentage of Th1 and Th17 cells and serum level of IL-17 and IFN-γ cytokines in COVID-19-associated mucormycosis.

The considerable number of the 2019 coronavirus disease (COVID-19) patients who developed mucormycosis infections in West and Central Asia urged a need to investigate the underlying causes of this fatal complication. It was hypothesized that an immunocompromised state secondary to the excessive administration of anti-inflammatory drugs was responsible for the outburst of mucormycosis in COVID-19 patients. Therefore, we aimed to study the implication of two major subsets of adaptive immunity T helper (Th)-1 and Th17 cells in disease development. Thirty patients with COVID-19-associated mucormycosis, 38 with COVID-19 without any sign or symptom of mucormycosis, and 26 healthy individuals were included. The percentage of Th1 and Th17 cells in peripheral blood, as well as the serum levels of interleukin (IL)-17 and interferon-gamma (IFN-γ), were evaluated using flow cytometry and ELISA techniques, respectively. Th17 cell percentage in patients with COVID-19-associated mucormycosis was significantly lower than in COVID-19 patients (P-value: <0.001) and healthy subjects (P-value: 0.01). In addition, the serum level of IL-17 in COVID-19 patients was significantly higher than that of healthy individuals (P-value: 0.01). However, neither the frequency of Th1 cells nor the serum level of IFN-γ was different between the study groups. Given the critical role of Th17 cells in the defense against mucosal fungal infections, these findings suggest that low numbers of Th17 and insufficient levels of IL-17 might be a predisposing factor for the development of mucormycosis during or after COVID-19 infection.

Considering the critical role of Th17 cells in defense against mucosal fungal infections, the low numbers of Th17 and insufficient amounts of IL-17 might be a predisposing factor to develop mucormycosis during or after COVID-19 infection.

Elevated serum IFN-γand IFN-γ/IL-6 ratio in Kikuchi-Fujimoto disease.

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is typically a benign, self-limiting inflammatory disease. The diagnosis of KFD can be challenging for nonspecific symptoms, laboratory or imaging findings. In this study, we aimed to describe the clinical manifestations of patients with KFD and to access the potential role of serum cytokines in the diagnosis of this disease. METHODS: Patients with KFD were retrospectively enrolled from January 2015 to November 2021 at Shenzhen Children's Hospital. Clinical data were collected from inpatient or outpatient medical records. Serum cytokines were detected by the Flowcytomix technique. Serum levels of cytokines were compared between patients with KFD and SJIA, or patients with KFD and KD. The data of patients without MAS were further analyzed. A receiver operating characteristic (ROC) curve analysis was further performed to access the potential role of serum cytokines in the diagnosis of KFD. RESULTS: Serum cytokines were detected in 25 (43.8%, 25/57) patients with a histological diagnosis of KFD. Compared to SJIA or KD patients, the KFD group had a significantly higher IFN-γ/IL-6 ratio and much lower levels of serum IL-6. The median level of serum IFN-γ in KFD was 41.65 pg/ml (range, 21.04-70.74 pg/ml), which was much higher than that in SJIA (median: 3.33 pg/ml, p = 0.16) or KD (median: 2.6 pg/ml, p = 0.01). After excluding patients with MAS, there was statistical significance in all comparisons of serum IFN-γ, IFN-γ/IL-6 ratio, and serum IL-6. The cutoff values of serum IFN-γ, IL-6, and IFN-γ/IL-6 ratio for differentiating KFD from SJIA were > 8.48 pg/ml, < 47.42 pg/ml, and > 0.45, respectively. The cutoff values of serum IFN-γ, IL-6, and IFN-γ/IL-6 ratio for differentiating KFD from KD were > 8.56 pg/ml, < 50.45 pg/ml, and > 0.45, respectively. The specificity of all those cutoff values for differentiating KFD from SJIA or KD was ≥ 94.7%. CONCLUSIONS: For patients with fever of unknown etiology and lymphadenopathy, after excluding HLH or MAS, serum IFN-γ > 8.56 pg/mL and IFN-γ/IL-6 ratio > 0.45 may highly suggest the diagnosis of KFD; serum IL-6 > 50.45 pg/mL indicates that the probability of KFD may be small, and sJIA, KD, and acute infection should be excluded first.

Transient and durable T cell reactivity after COVID-19.

This study analyzed whole blood samples (n = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2-derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until ∼70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-γ remained stable and highly correlated at 3 to 21 mo after infection. Similar cytokine dynamics were observed in unvaccinated, convalescent patients using whole-blood samples stimulated with peptides spanning the N-terminal portion of the spike 1 protein. These results unravel two phases of T cell reactivity following natural COVID-19: an early, synchronous response indicating transient presence of multipolar, antigen-specific T helper (TH) cells followed by an equally synchronous and durable TH1-like reactivity reflecting long-lasting T cell memory.

Microwave ablation of non-small cell lung cancer tumors changes plasma levels of cytokines IL-2 and IFN-γ.

Background: Combined therapy with immune checkpoint inhibitors (ICIs) and microwave ablation (MWA) is known to improve outcome in non-small cell lung cancer (NSCLC). However, the mechanism underlying the synergistic effect of these two treatments is unknown. Tumor immune microenvironment is known to affect the efficacy of ICI. Therefore, in the present study, we evaluated changes in the levels of peripheral cytokines at 48 h and 1-month post-ablation in patients with NSCLC. Materials and Methods: A total of 44 patients with primary NSCLC were retrospectively enrolled. All patients underwent MWA of the primary tumors. Plasma samples were collected pre- and post-ablation to examine the levels of various cytokines, including interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12, IL-17, tumor necrosis factor (TNF)-α, and interferon-gamma (IFN-γ). Results: Although the levels of the majority of cytokines remained within normal range, levels of IL-2 and IFN-γ were significantly decreased at 48 h post-ablation and increased at 1-month post-ablation. In the subgroup analyses, changes in IL-2 and IFN-γ levels were commonly identified. Moreover, the Eastern Cooperative Oncology Group status, sex, pathology type, tumor site, and tumor size were associated with cytokines' levels pre-ablation or post-ablation. Conclusion: MWA of NSCLC tumors influenced the plasma levels of cytokines IL-2 and IFN-γ.

Analysis of Serum Levels of IFN-γ, IL-4, and TNF-α in Patients with Cervicitis Complicated by HPV Infection and Their Clinical Significance.

In order to investigate the expression levels of serum IFN-γ, IL-4, and tumor necrosis TNF-α in patients with cervicitis complicated with human papillomavirus (HPV) infection and clinical significance, a retrospective study was conducted on 90 patients with chronic cervicitis complicated by HP V infection who visited our hospital from June 2020 to June 2021, and they are included in the research group. According to the degree of HPV infection, the patients are divided into low-risk HPV type group (n = 65 cases) and high-risk HPV type group (n = 25 cases); 50 patients with cervicitis (without HPV infection) who received treatment in our hospital are selected as control group 1. Fifty healthy women who underwent physical examination are selected as the control group 2. The general data of the two groups of patients during hospitalization are collected, and HPV-DNA, IFN-γ, IL-4, and TNF-α are detected in all patients. For patients with cervicitis complicated by HPV infection, the IFN-indexes in the body are significantly decreased, IL-4 and TNF-αare significantly increased, and with the degree of HPV infection, IFN-γ, IL-4, and TNF-α have high diagnostic performance with HPV infection, and there is a significant correlation between the three, which can be used in cervicitis complicated with HPV infection. It is widely used in the early diagnosis and screening of infected patients.

Association of single nucleotide polymorphisms of interferon-γ with pulmonary tuberculosis in population of Himachal Pradesh, India.

Interferon-gamma (IFN-γ) plays an integral role in the host immunity against tuberculosis (TB). The gene encoding IFN-γ is polymorphic and several studies have reported the association of its genetic polymorphisms with TB in different populations of the world. The present study investigated the association of rs2069705 (C/T), rs1861494 (C/T), rs1861493 (A/G) and rs2069718 (C/T) single nucleotide polymorphisms (SNPs) of IFN-γ with pulmonary TB in a population of Himachal Pradesh, India. For present study, 210 pulmonary TB patients and 205 healthy controls (HCs) were recruited. The selected SNPs of IFN-γ were genotyped by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and plasma IFN-γ levels were measured by ELISA. The 'T' allele of rs1861494 SNP was found to increase susceptibility to TB in the studied population (OR = 2.18, 95%CI = 1.57-3.03; p < 0.001). After stratifying the subjects on basis of sex, males with 'T' allele of rs2069718 SNP were found to be at higher risk to TB (OR = 1.55, 95%CI = 1.07-2.25; p = 0.02). We also found moderate linkage disequilibrium among the studied SNPs. The haplotypes C-T-A-T and T-T-G-T of rs2069705-rs1861494-rs1861493-rs2069718 were overrepresented in TB patients and found to increase susceptibility to TB (p = 0.012). The plasma IFN-γ levels in TB patients were around seven times higher in comparison to HCs (p < 0.0001). The HCs with genotype 'AA' of SNP rs1861493 were found with higher plasma IFN-γ levels than 'AG/GG' genotype (p = 0.023). In conclusion, the results suggest the association of rs1861494 (C/T) and rs2069718 (C/T) SNPs of IFN-γ with TB and genotype 'AA' of rs1861493 is associated with higher plasma IFN-γ levels in the population of Himachal Pradesh, India.

Innate Immune Responses of Vaccinees Determine Early Neutralizing Antibody Production After ChAdOx1nCoV-19 Vaccination.

Background: Innate immunity, armed with pattern recognition receptors including Toll-like receptors (TLR), is critical for immune cell activation and the connection to anti-microbial adaptive immunity. However, information regarding the impact of age on the innate immunity in response to SARS-CoV2 adenovirus vector vaccines and its association with specific immune responses remains scarce. Methods: Fifteen subjects between 25-35 years (the young group) and five subjects between 60-70 years (the older adult group) were enrolled before ChAdOx1 nCoV-19 (AZD1222) vaccination. We determined activation markers and cytokine production of monocyte, natural killer (NK) cells and B cells ex vivo stimulated with TLR agonist (poly (I:C) for TLR3; LPS for TLR4; imiquimod for TLR7; CpG for TLR9) before vaccination and 3-5 days after each jab with flow cytometry. Anti-SARS-CoV2 neutralization antibody titers (surrogate virus neutralization tests, sVNTs) were measured using serum collected 2 months after the first jab and one month after full vaccination. Results: The older adult vaccinees had weaker vaccine-induced sVNTs than young vaccinees after 1st jab (47.2±19.3% vs. 21.2±22.2%, p value<0.05), but this difference became insignificant after the 2nd jab. Imiquimod, LPS and CpG strongly induced CD86 expression in IgD+CD27- naïve and IgD-CD27+ memory B cells in the young group. In contrast, only the IgD+ CD27- naïve B cells responded to these TLR agonists in the older adult group. Imiquimode strongly induced the CD86 expression in CD14+ monocytes in the young group but not in the older adult group. After vaccination, the young group had significantly higher IFN-γ expression in CD3- CD56dim NK cells after the 1st jab, whilst the older adult group had significantly higher IFN-γ and granzyme B expression in CD56bright NK cells after the 2nd jab (all p value <0.05). The IFN-γ expression in CD56dim and CD56bright NK cells after the first vaccination and CD86 expression in CD14+ monocyte and IgD-CD27-double-negative B cells after LPS and imiquimod stimulation correlated with vaccine-induced antibody responses. Conclusions: The innate immune responses after the first vaccination correlated with the neutralizing antibody production. Older people may have defective innate immune responses by TLR stimulation and weak or delayed innate immune activation profile after vaccination compared with young people.

A phase I dose-escalation, safety/tolerability, and preliminary efficacy study of the intratumoral administration of GEN0101 in patients with advanced melanoma.

Despite recent advance in immunotherapy agents, safe new therapies that enhance the effects of immune checkpoint inhibitors are still required to develop. We previously demonstrated that hemagglutinating virus of Japan-envelope (HVJ-E) induced not only direct tumor cell death but also antitumor immunity through the activation of T and natural killer (NK) cells, thereafter, developed a manufacturing process of HVJ-E (GEN0101) for clinical use. We here performed a phase Ia clinical trial of intratumoral GEN0101 administration in six patients with stage IIIC or IV malignant melanoma. The primary aim was to evaluate the safety and tolerability of GEN0101, and the secondary aim was to examine the objective tumor response. Patients were separated into two groups (n = 3 each) and received a low dose of 30,000 and high dose of 60,000 mNAU of GEN0101. All patients completed a two-week follow-up evaluation without severe adverse events. The overall response rate was 33% (2 of 6), with 2 partial responses in the high-dose group and 2 with stable disease, and 2 with progressive disease in the low-dose group. Local complete or partial responses were observed in 11 of 18 (61%) target lesions. One patient demonstrated shrinkage of lung metastases after the treatment. The activity of NK cells and interferon-γ levels were increased in the circulation, indicating augmentation of antitumor immunity by GEN0101. This trial showed not only the safety and tolerability but also the significant antitumor effect of GEN0101, suggesting that GEN0101 might be a promising new drug for patients with advanced melanoma.

Immune correlates of Mycobacterium Tuberculosis patients in Zambia stratified by HIV serostatus and level of immunity-a cross-sectional analytical laboratory based study.

BACKGROUND: People living with HIV (PLHIV) co-infected with tuberculosis (TB) have a distinct clinical presentation and poorer treatment outcomes compared to HIV-seronegative TB patients. Excluding low CD4 count, innate immune factors associated with TB are not fully elucidated. We, therefore, characterised and compared the expression of IL-6, TNF-α, IFN-γ, and IL-10 in whole blood of treatment naïve TB patients stimulated with heat-killed Mycobacterium tuberculosis stratified by HIV status and the level of CD4 count. RESULTS: We recruited 39 HIV seropositive and 31 HIV seronegative TB patients. Median (IQR) age was 35(28-42) years and 31(25-36) years respectively, and a majority had pulmonary tuberculosis i.e. 38(95%) and 30(97%), respectively. The two groups were significantly different in the distribution of CD4 count, 563 [465-702.5 cells/mm3] vs 345 [157-483 cell/mm3] in HIV negative vs HIV positive respectively p = <0.001. Post stimulation, the expression of IL-6 in HIV negative TB patients was significantly higher than in the HIV positive 16,757366 [8,827-23,686 pg/ml] vs. 9,508 [5,514-15,008 pg/ml], respectively; p = 0.0360. TNF-α and IFN-γ were highly expressed in HIV negative TB patients compared to the HIV positive though not statistically significant. We only observed higher expression of IL-6 in HIV negative patients in comparison to the HIV positive when stratified by level of CD4 counts as < 500 and ≥ 500 cell/mm3 for both cohorts. 21,953 [8,990-24,206 pg/ml] vs 9,505 [5,400-15,313 pg/ml], p value = 0.0585 in patients with CD4 count < 500 cell/mm3 and 13,168 [7,087-22,584 pg/ml] vs 10,413 [7,397-14,806 pg/ml], p value = 0.3744 for patients with CD4 count of ≥ 500 cell/mm3 respectively. We found a positive pairwise correlation between TNF-α -alpha and IL-6 in both HIV positive and HIV negative patients, r = 0.61 (95% CI 0.36-0.72; p < 0.0001) and r = 0.48 (95% CI 0.15-0.68; p = 0.005) respectively. The IFNγ/IL-10 ratio was higher in HIV negative when compared to HIV positive individuals, 0.052 [0.0-0.28] vs 0.007 [0-0.32] respectively; p = 0.05759. IL-6 independently reduced the probability of TB/HIV, Adjusted odds ratio 0.99, p value 0.007. CONCLUSIONS: This study suggests that HIV seronegative TB patients have a higher pro-inflammatory response to MTB than HIV seropositive TB patients. Further, it also shows that the level of CD4 influences immunomodulation. The findings suggest that the difference in cytokine expression may be responsible for the distinct patterns of TB presentation between HIV positive and HIV negative patient.

Therapeutic Response Evaluation in Advanced Melanoma Patients Incorporating Plasma cfDNA, LDH, VEGF, PD-L1, and IFN-γ Measurements.

BACKGROUND/AIM: Current treatment strategies for advanced melanoma require serial assessment of disease status in affected patients. In this study, we sought to examine the relationship between radiographic tumour burden and blood borne biomarkers including plasma cfDNA, serum LDH, plasma VEGF, PD-L1 and IFN-γ in advanced melanoma patients receiving immunotherapy. We hypothesized that a combination of these explanatory variables in a suitable regression analysis model may predict changes in tumour burden during patient treatment. MATERIALS AND METHODS: We extracted and quantified circulating cfDNA, LDH, VEGF, PD-L1, and IFN-γ from thirty patients with stage IV melanoma at baseline and at six months. All participating patients were evaluated with paired blood sample collection and CT scan assessments during treatment. RESULTS: Changes in radiographic tumour burden correlated with changes in levels of cfDNA (p≤0.001), LDH (p≤0.001), VEGF (p≤0.001), and PD-L1 (p<0.05) during treatment. Multiple regression analysis consisting of the follow-up to baseline assessment ratios of cfDNA, LDH, VEGF and PD-L1 explained changes in tumour burden (F (4, 23)=32.05, p<0.001); with an R2 of 0.8479 (Y=ß0+ß1*B+ß2*C+ß3*D+ß4*E). CONCLUSION: A quantitative measure of cfDNA, LDH, VEGF and PD-L1 may complement current methods of assessing tumour burden in advanced melanoma patients.

Kinetics and persistence of cellular and humoral immune responses to SARS-CoV-2 vaccine in healthcare workers with or without prior COVID-19.

SARS-CoV-2 vaccines are highly efficient against severe forms of the disease, hospitalization and death. Nevertheless, insufficient protection against several circulating viral variants might suggest waning immunity and the need for an additional vaccine dose. We conducted a longitudinal study on the kinetics and persistence of immune responses in healthcare workers vaccinated with two doses of BNT162b2 mRNA vaccine with or without prior SARS-CoV-2 infection. No new infections were diagnosed during follow-up. At 6 months, post-vaccination or post-infection, despite a downward trend in the level of anti-S IgG antibodies, the neutralizing activity does not decrease significantly, remaining higher than 75% (85.14% for subjects with natural infection, 88.82% for vaccinated after prior infection and 78.37% for vaccinated only). In a live-virus neutralization assay, the highest neutralization titres were present at baseline and at 6 months follow-up in persons vaccinated after prior infection. Anti-S IgA levels showed a significant descending trend in vaccinated subjects (p < 0.05) after 14 weeks. Cellular immune responses are present even in vaccinated participants with declining antibody levels (index ratio 1.1-3) or low neutralizing activity (30%-40%) at 6 months, although with lower T-cell stimulation index (p = 0.046) and IFN-γ secretion (p = 0.0007) compared to those with preserved humoral responses.

Immunogenicity and Reactogenicity of Vaccine Boosters after Ad26.COV2.S Priming.

BACKGROUND: The Ad26.COV2.S vaccine, which was approved as a single-shot immunization regimen, has been shown to be effective against severe coronavirus disease 2019. However, this vaccine induces lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S)-specific antibody levels than those induced by messenger RNA (mRNA)-based vaccines. The immunogenicity and reactogenicity of a homologous or heterologous booster in persons who have received an Ad26.COV2.S priming dose are unclear. METHODS: In this single-blind, multicenter, randomized, controlled trial involving health care workers who had received a priming dose of Ad26.COV2.S vaccine, we assessed immunogenicity and reactogenicity 28 days after a homologous or heterologous booster vaccination. The participants were assigned to receive no booster, an Ad26.COV2.S booster, an mRNA-1273 booster, or a BNT162b2 booster. The primary end point was the level of S-specific binding antibodies, and the secondary end points were the levels of neutralizing antibodies, S-specific T-cell responses, and reactogenicity. A post hoc analysis was performed to compare mRNA-1273 boosting with BNT162b2 boosting. RESULTS: Homologous or heterologous booster vaccination resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination. The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster. The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration. CONCLUSIONS: The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting. (Funded by the Netherlands Organization for Health Research and Development ZonMw; SWITCH ClinicalTrials.gov number, NCT04927936.).

A close-up view of dynamic biomarkers in the setting of COVID-19: Striking focus on cardiovascular system.

Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID-19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life-threatening SARS-CoV-2 virus, it would be more helpful for screening, clinical management and on-time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID-19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID-19.

Circulating JNK pathway-associated phosphatase: A novel biomarker correlates with Th17 cells, acute exacerbation risk, and severity in chronic obstructive pulmonary disease patients.

BACKGROUND: JNK pathway-associated phosphatase (JKAP) involves in the regulation of inflammation, immunity, and lung injury. The current study aimed to investigate correlation of JKAP with Th1, Th17 cells, acute exacerbation risk, and disease severity in chronic obstructive pulmonary disease (COPD) patients. METHODS: Totally, 45 stable COPD (SCOPD) patients, 45 acute exacerbation COPD (AECOPD) patients, and 45 controls were enrolled. Serum was collected for JKAP, interferon-gamma (IFN-γ) (Th1 cytokine), and interleukin 17 (IL-17) (Th17 cytokine) detection. Besides, peripheral blood mononuclear cell from COPD patients was collected for evaluating Th1 and Th17 cells. RESULTS: JKAP was highest in controls followed by SCOPD patients and lowest in AECOPD patients (median: 105.673 vs. 75.374 vs. 41.807 pg/ml, p < 0.001). Meanwhile, receiver operating characteristic (ROC) curves revealed that JKAP differentiated the AECOPD patients from the controls (area under curve (AUC): 0.910 (95% confidence interval (CI): 0.849-0.970)) and AECOPD patients from SCOPD patients (AUC: 0.726 (95% CI: 0.622-0.830)). Moreover, JKAP positively correlated with FEV1 (%predicted) in AECOPD patients (r = 0.347 p = 0.019). Additionally, JKAP was negatively correlated with the GOLD stage in AECOPD patients (r = -0.344, p = 0.021) and SCOPD patients (r = -0.357, p = 0.016). Whereas, JKAP was not associated with other clinical features (all p > 0.05). Besides, JKAP was negatively linked with Th17 cells (r = -0.378, p = 0.010), IFN-γ (r = -0.358, p = 0.016), IL-17 (r = -0.414, p = 0.005) in AECOPD patients and Th17 cells (r = -0.342, p = 0.022), IL-17 (r = -0.299, p = 0.046) in SCOPD patients. CONCLUSION: Downregulated JKAP correlates with Th17 cells, higher acute exacerbation risk, and severity in COPD patients, indicating its underlying potency as a biomarker for COPD.

Inflammatory and immune marker trajectories from pregnancy to one-year post-birth.

BACKGROUND: Pregnancy is an immunomodulatory state, with reported systematic changes in inflammatory and immune activity by pregnancy stage. Published data are inconsistent as to how inflammatory and immune markers change and recover across pregnancy and the postpartum period, or the sociodemographic, health and pregnancy-related factors that could affect biomarker trajectories. The purpose of this study is to describe inflammatory and immune marker trajectories from pregnancy to a year post-birth, and to test associations with sociodemographic, health and pregnancy-related variables. METHODS: A sample of 179 pregnant women were assessed three times during pregnancy (between 8 and 36 weeks gestation) and three times during the postpartum period (between 1 and 12 months). Maternal sociodemographic characteristics, health, and pregnancy factors were obtained at study entry. Blood samples from each assessment were assayed for interleukin(IL)-6, tumor necrosis factor(TNF)α, IL-8, IL-10, and interferon(IFN)γ. Multilevel modelling was used to characterize biomarker trajectories and associations with sociodemographic and health variables. RESULTS: Distinct trajectories over time emerged for each biomarker. Male pregnancies were associated with higher TNFα, IL-10, and IFNγ; higher pre-pregnancy BMI was associated with higher IL-6 and IFNγ. Nulliparity was associated with greater increases in IL-6 and TNFα. CONCLUSIONS: Patterns observed for inflammatory and immune markers from pregnancy to a year postpartum support the hypothesis that the maternal immune system changes systematically across pregnancy and through an extended postpartum period. Parity, pre-pregnancy BMI and child sex are associated with inflammatory marker patterns over time. These results contribute to our understanding of how immune system activity changes from pregnancy to the post-birth period, and the factors that could affect those changes.

Effects of antidepressant drug therapy with or without physical exercise on inflammatory biomarkers in major depressive disorder: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To conduct a systematic review and meta-analysis of the effects of antidepressant drug therapy (with or without physical exercise) on peripheral inflammatory markers in patients with major depressive disorder (MDD). METHODS: MEDLINE, PyscINFO, Embase, and Google Scholar databases were searched until May 2020. Randomized trials that measured at least one inflammatory biomarker and included adult outpatients with MDD under antidepressant drug therapy (any drug) with or without physical exercise (any modality) were eligible. Results were summarized using the standardized mean difference (SMD) with 95% confidence intervals (95% CI) under a random-effects model. The Cochrane risk of bias tool (2010) was used to evaluate the risk of bias in the included trials. RESULTS: Sixty-three trials were identified, encompassing data from 3482 patients, and 20 investigated biomarkers. Trials had biases across multiple domains, rising concerns primarily to selection bias/performance bias/detection bias/attrition bias. SMDs between pre- and post-results indicated a significant reduction in the levels of IL-2 (SMD, - 0.25; 95% CI, - 0.41 to - 0.09, P = 0.002), IL-6 (SMD, - 0.19; 95% CI, - 0.35 to - 0.025, P = 0.024), IL-10 (SMD, - 0.32; 95% CI, - 0.57 to - 0.07, P = 0.011), and serum cortisol (SMD, - 0.35; 95% CI, - 0.58 to - 0.12, P = 0.002). Evidence supporting the influence of physical exercise combined with antidepressant drugs on peripheral inflammatory markers in MDD is sparse and heterogeneous. CONCLUSION: There is some evidence that antidepressant drug therapy is associated with an overall positive reduction in inflammatory markers, but the evidence is heterogeneous. Further research linking how inflammatory biomarkers modulate physiology related to antidepressant response is required. TRIAL REGISTRATION: CRD42020220735.

Th1 cytokine gene polymorphism and the corresponding plasma cytokine levels: A comparative study in HIV-1 positive and exposed uninfected infants.

The pro-inflammatory (Th1) cytokines namely interleukin (IL)-2, IL-6, IL-12, interferon (IFN)-γ, tumor necrosis factor-α (TNF-α) are vital in the clearance of HIV infection. This prospective cohort study aimed to evaluate the polymorphisms of Th1 cytokine genes and their corresponding plasma cytokine levels in HIV-1 positive and exposed uninfected (EU) infants born to HIV-1 positive mothers. CD4 count, viral load of HIV-1 positive mothers was done using commercially available reagents. Cytokine genotyping analysis and levels were done in 20 HIV-1 positive and 54 EU infants. The polymorphisms of Th1 cytokines were done using the PCR-SSP method. Plasma cytokine levels were estimated using Bio-Plex-Pro cytokine assay (BIO-RAD; USA). Results revealed treatment status of the mothers and viral load were the two confounding factors having a significant effect on HIV status of the infant. TNF-α GG genotype is significantly higher in EU infants as compared with HIV-1 positive infants. GG genotype was associated with high TNF- α levels in HIV-1 positive infants but the difference was not statistically significant. HIV-1 positive infants with -IFN-γ (+874) TT genotype was significantly associated with high IFN-γ levels. To the best of our knowledge, this is the first study reporting the role of Th1 cytokine gene polymorphisms and their corresponding plasma cytokine levels in HIV-1 positive and EU infants from India.

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. OBJECTIVE: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). METHODS: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). RESULTS: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57-/KLRGhi/CD161+/CD38- natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. CONCLUSION: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.