Higher Levels Of IL-4 Research Articles

Circulating Cytokines in Metastatic Breast Cancer Patients Select Different Prognostic Groups and Patients Who Might Benefit from Treatment beyond Progression.

Cancer induces immune suppression to overcome its recognition and eradication by the immune system. Cytokines are messengers able to modulate immune response or suppression. There is great interest in the evaluation of their changes during treatment in order to identify their relationship with clinical outcome. We evaluated 18 cytokines in breast cancer patients treated with eribulin before starting treatment (T0) and after four courses of therapy (T1). Longitudinal modifications were considered and cytokine clusters through PCA and HCPC correlated to patients’ outcomes were identified. Forty-one metastatic breast cancer patients and fifteen healthy volunteers were included. After clustering, we identified at T0 six patient clusters with different risk of relapse and death. At T1, only four clusters were identified, and three of them accounted for thirty-eight of forty-one patients, suggesting a possible role of treatment in reducing heterogeneity. The cluster with the best survival at T1 was characterized by low levels of IL-4, IL-6, IL-8, IL-10, CCL-2, CCL-4, and TGF-β. The cluster showing the worst survival encompassed high levels of IL-4, IL-6, IL-8, IL-10, CCL-2, and IFN-γ. A subgroup of patients with short progression-free survival (PFS) and long overall survival (OS) was comprised in the cluster characterized by low levels of CCL-2, IL-6, IL-8, IL-10, and IL-12 at T0. Our data support the prognostic significance of longitudinal serum cytokine analysis. This approach may help identify patients for whom early treatment stop avoids needless toxicity or might justify treatment beyond early progression. Further investigations are required to validate this hypothesis.

Stable and exacerbation period serum cytokine and periostin levels of the five distinct phenotypes of severe asthma.

The differences in molecular mechanisms during a stable period and the changes in the inflammatory responses during exacerbations between distinct severe asthma phenotypes remain unclear. In this study, we aimed to characterize stable and exacerbation period serum cytokine and periostin levels of 5 different predefined severe asthma phenotypes with real-life data. Changes in the viral infection-induced exacerbations were also analyzed. Serum levels of 8 cytokines and periostin were measured from the sera obtained from the adult patients with five different severe asthma phenotypes based on the presence/absence of aeroallergen sensitivity, peripheral eosinophilia and chronic rhinosinusitis with nasal polyposis (CRSwNP) during stable and exacerbation periods, and from the matched controls. Serum IL-13, IL-25, TSLP, and periostin levels were similar between the patient and the control groups during stable and exacerbation periods. Serum IL-25 and TSLP levels, and peripheral eosinophil count and periostin level showed a strong correlation. Stable period periostin levels were significantly higher in eosinophilic patients, and eosinophilic patients without long-term systemic steroid therapy had higher IL-13 levels. Compared to stable period, exacerbation period serum periostin levels found significantly lower [5853 (2309-8427) pg/mL vs. 4479 (2766-6495) pg/mL; p = 0.05] and periostin levels were much lower in viral infection-induced exacerbations [2913 (893-4770) pg/mL vs. 7094 (4782-9596) pg/mL; p = 0.022]. Our study showed that serum periostin levels were decreased in viral infection-induced exacerbations and increased in the presence of eosinophilia independent from atopy and it can help to differentiate eosinophilia even if the patient is under long-term systemic steroid therapy. Also, serum IL-13 levels may reflect peripheral eosinophilia in patients without long-term systemic steroid use.

Role of Inflammatory Cytokines in the Conversion of Mild Cognitive Impairment to Dementia: A Prospective Study.

The effect that cytokines can exert on the progression from mild cognitive impairment (MCI) to ongoing dementia is a matter of debate and the results obtained so far are controversial. The aim of the study is to analyze the influence of markers of subclinical inflammation on the progression of MCI to dementia. A prospective study involving a cohort of patients ≥ 65 years of age diagnosed with MCI and followed for 3 years was conducted. 105 patients were enrolled, and serum concentrations of several subclinical inflammatory markers were determined. After 3.09 (2 - 3.79) years of follow-up, 47 (44.76%) patients progressed to dementia. Alpha 1-antichymotrypsin (ACT) was found to be significantly higher in patients who progressed to dementia (486.45 ± 169.18 vs. 400.91 ± 163.03; p = 0.012), and observed to significantly increase the risk of developing dementia in patients with mild cognitive impairment (1.004, 1.001-1.007; p = 0.007). IL-10 levels were significantly higher in those who remained stable (6.69 ± 18.1 vs. 32.54 ± 89.6; p = 0.04). Regarding the type of dementia to which our patients progressed, we found that patients who developed mixed dementia had higher IL-4 levels than those who converted to AD (31.54 ± 63.6 vs. 4.43 ± 12.9; p = 0.03). No significant differences were observed between the groups with regard to the ESR and LPa, CRP, IL-1 and TNF-α levels. ACT levels have a significant predictive value in the conversion of MCI to dementia. IL-10 levels could be a protective factor. It is necessary to conduct studies with serial determinations of these and other inflammatory markers in order to determine their effect on the progression of MCI to dementia.

Peripheral Blood Cytokines Levels in Senegalese Women with Cervical Cancer during Chemotherapy

Cervical cancer is the leading cause of cancer deaths of women in developing world. Several studies demonstrated evidences of inflammatory cytokines implication in cancer progression including in initiation, promotion and invasion by affecting the immune surveillance. Our aim was to measure blood circulating pro- and anti-inflammatory cytokines levels, their profiles according to treatment issue and relation with prognostic factors in cervical cancer during chemotherapy. Blood samples were collected from a cohort of 35 cervical cancer women and 42 women healthy controls (HC) with no history of malignancy. For each CP, three samples were taken at three-week intervals. The first one (S1) was taken before initiation of the chemotherapy protocol. S2 and S3 were samples collected respectively at day 21 and day 42. Cytokines levels were evaluated by ELISA. Mean age of patients was 54.1 year (35 - 77 yo). In groups, no relation was observed between age and cytokines levels. Before chemotherapy, high levels of IL-6, IL-4 and IFN-γ were observed in CP compared to HC (p 0.001) and at the same period, IL-10 and TNF-α levels were significantly low in CP (p 0.05) and negatively correlated (r = —0.79; p = 0.017). In this CP group, IL-4 levels were positively correlated between S1 and S2 (r = 0.72; p = 0.002) and between S1 and S3 (r = 0.74; p = 0.019). Similar correlations were observed for TNF-α levels: S1/S2 (r = 0.54; p = 0.027), S2/S3 (r = 0.82; p = 0.009) and S1/S3 (r = 0.66; p = 0.036) with a significant increase of TNF-α in blood during treatment. Depending on chemotherapy’s efficacy, CP patients were separated into 1) non responders (NR), 2) partial responders (PR) and 3) good responders (GR). Compared to PR and GR groups, NR patients showed: a) higher serum levels of IL-6, IL-10 and IFN-γ during the follow-up and b) lower serum levels of IL-4 and TNF-α. In addition, serum levels of IL-4 were significantly higher in GR patients however TNF-α was the predominant cytokines in PR group. Our results highlight the variation of circulating cytokines such as IL-6, IL-10 and IFN-γ during cervical cancer chemotherapy. In addition, this study suggested that IL-4 and TNF-α might represent potential biomarkers candidate in cervical cancer. Applications in cancer management need further investigations particularly about the relevant prognostic indicator following chemotherapy and validation studies must provide more assurance for translation into clinical practice.

Postoperative cytokine levels and their predictive value in critical patients after major abdominal surgery: a retrospective cohort study.

It remains uncertain as to what impact cytokine expression level has on patient outcomes. The association of serum levels of interleukin-1β (IL-1β), IL-2, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), and procalcitonin with critically ill patient outcomes after major abdominal surgery still need to be explored. From January 1, 2018 to June 30, 2019, a retrospective cohort study was conducted on patients admitted to the surgical intensive care unit (SICU). Levels of IL-1β, IL-2, IL-6, IL-8, IL-10, TNF-α, and procalcitonin were assessed in 1,228 patients undergoing major abdominal surgery with blood samples drawn within 24 h after surgery. Of the 1,228 patients admitted to the SICU for the first time, 1,152 survived and 76 patients died, with a mortality rate of 6.2% (76/1,228). The results of univariate and multivariate analyses revealed that non-survivors had higher levels of IL-1β (OR =2.438, P<0.001) and IL-2 (OR =1.561, P=0.006). Of 62 (5.0%) readmitted to the SICU, the data of 59 were collected, and showed 46 patients survived and 13 died, giving a mortality rate of 22.0% (13/59), which was 3.5 times higher than the mortality rate during the first SICU admission. Serum IL-6 level associated with SICU readmission (OR =1.37, P=0.029). Furthermore, non-survivors had a longer SICU stay and higher rates of mechanical ventilation and continuous renal replacement therapy (CRRT). High levels of IL-1β and IL-2 were associated with mortality, and a high level of IL-6 was a risk factor for SICU readmission in critically ill patients who underwent major abdominal surgery. The mortality rate was higher during the second SICU stay.

Clinical spectrum of endemic leptospirosis in relation to cytokine response.

To describe the clinical spectrum and the cytokine response of leptospirosis patients in an endemic setting of Sri Lanka. Patients presenting to the university teaching hospital, Anuradhapura, Sri Lanka with a leptospirosis-compatible illness were recruited over a period of 12 months starting from June 2012. Daily clinical and biochemical parameters of the patients were prospectively assessed with a follow-up of 14 days after discharge. A magnetic bead-based multiplex cytokine kit was used to detect 17 cytokines. Of the 142 clinically suspected leptospirosis patients recruited, 47 were confirmed and, 29 cases were labeled as "probable." Thrombocytopenia and leukocytosis were observed at least once during the hospital stay among 76(54%) and 39(28%) patients, respectively. Acute kidney injury was observed in 31 patients (22%) and it was significantly higher among confirmed and probable cases. Hu TNF-α and IL-1β were detected only in patients without complications. Hu MIP-1b levels were significantly higher among patients with complications. During the convalescence period, all tested serum cytokine levels were lower compared to the acute sample, except for IL-8. The cytokine response during the acute phase clustered in four different groups. High serum creatinine was associated GM-CSF, high IL-5 and IL-6 level were correlates with lung involvement and saturation drop. The patients with high billirubin (direct)>7 mmol/l had high IL-13 levels. Results of this study confirms that the knowledge on cytokine response in leptospirosis could be more complex than other similar tropical disease, and biosignatures that provide diagnostic and prognostic information for human leptospirosis remain to be discovered.

Structural and functional state of blood lymphocytes in patients with infectious mononucleosis with different course

The article presents the results of our own studies. The aim was to determine the structural and functional status of blood lymphocytes in patients with acute and prolonged course of infectious mononucleosis (IM) in children. Materials and methods. 102 children were under clinical and laboratory-instrumental supervision, the children were divided into groups: group 1 – 65 children with IM with an acute course of the disease; group 2 – 37 children with a prolonged course of the disease. All children underwent standard clinical laboratory and instrumental laboratory examinations. The diagnosis of IM was confirmed by PCR (detection of EBV DNA in the blood) and ELISA (anti-EBV IgM and IgG). Research results. In the study of the structural state of the cytoplasmic membrane of the lymphocytes in the blood of patients with MI in the onset of the disease, it was found that the average values of penetration rate of the electron paramagnetic resonance of spin probes (PR EPR s. p.) in children of both groups were significantly higher than normal (P &lt; 0.001). There are also differences between groups of patients. In this case, the value of PR EPR s. p. in patients with a prolonged course by 15.8 % exceeded those in patients with acute IM (P &lt; 0.001). According to the rate of microviscosity of the intracellular content (MV IC), its values were reduced compared with the control – by 22.1 % (P &lt; 0.001) in patients with acute course of the disease and by 25.1 % – with a prolonged course of IM). In addition, in patients with a prolonged course of the disease, the values were 9 % lower than in the group with acute infectious mononucleosis. When considering immunological parameters, it was found that the indicators of the T-immune system for patients with a prolonged course of the disease in comparison with the alternative group was characterized by a decrease in the content of CD3 &lt;50 % (respectively in 51.3 % and 26.2 % of patients; P &lt; 0.05); CD4 &lt;31 % (62.1 % and 32.4 %, respectively; P &lt; 0.05) and CD8 &lt;15 % (37.8 % and 10.8 %, respectively; P &lt; 0.01). With regard to the cytokine profile, the level of IL-1 &lt;20.0 pg/ml was determined 3.5 times more often in patients with a prolonged course of the disease compared to the acute course (64.8 % and 18.5 % of patients, respectively); TNFα &lt;20.0 pg/ml 1.9 times more often (48.6 % and 24.6 %, respectively) and a very high (&gt;30.1 pg/ml) level of IL4 in 40.5 % and 20 %). From the B-system of immunity in patients with a prolonged course of IM in comparison with the acute course increased content of CD22 was more often determined, as well as low levels of IgA, IgM &lt;1.1 g/l and IgG &lt;10.0 g/l. Conclusions. According to the results of observations, the pathogenetic role of the violation of the structural organization of blood lymphocytes in the formation of IM is established. It was found that these disorders in the form of increased permeability of their cytoplasmic membrane and reduced viscoelastic properties of their intracellular environment are more pronounced with a prolonged course of the disease, which is a factor in the prolongation of the disease. It is determined that the indicators of cellular and humoral parts of the immune system affect the course of IM. During formation of an acute course of IM in children already in the acute period of a disease activation of both cellular and humoral links of immunity, which is shown in the form of increase in relative content of CD3+, CD4+, CD8+ and CD22+ and levels of immunoglobulins M, A, is noted. For the prolonged course of the disease depression of T-cell immunity in the form of a decrease in the relative content of CD3+, CD4+ and CD8+ lymphocytes and an increase in CD22+, as well as inhibition of antibody genesis are characteristic. It was found that the variant of IM depends on the type of reaction of T-helper clones, namely – in the initial period of manifestation of IM with its acute course there is activation of T1 and T2 helper response, which manifests itself in a significant increase in IL-1, TNFα and moderate IL-4. Prolonged course of the disease is formed against the background of weak activation of pro-inflammatory interleukins (IL-1, TNFα) and significant – anti-inflammatory IL-4.

Immunoproteomic and Immunopeptidomic Analyses of Histoplasma capsulatum Reveal Promiscuous and Conserved Epitopes Among Fungi With Vaccine Potential.

As there are more than 6 million human deaths due to mycoses each year, there is an urgent need to develop fungal vaccines. Moreover, given the similarities among pathogenic fungi, it may be possible to create a multi-fungi vaccine. In this study, we combined immunoproteomic and immunopeptidomic methods, for which we have adapted a technique based on co-immunoprecipitation (Co-IP) that made it possible to map Histoplasma capsulatum epitopes for the first time in a natural context using murine dendritic cells (DCs) and macrophages (Mφ). Although polysaccharide epitopes exist, this research focused on mapping protein epitopes as these are more immunogenic. We used different algorithms to screen proteins and peptides identified by two-dimensional electrophoresis (2-D) and Co-IP. Seventeen proteins were revealed by 2-D gels, and 45 and 24 peptides from distinct proteins were presented by DCs and Mφ, respectively. We then determined which epitopes were restricted to MHC-I and II from humans and mice and showed high promiscuity, but lacked identity with human proteins. The 4 most promising peptides were synthesized, and the peptides with and without incorporation into glucan particles induced CD4+ and CD8+ T cell proliferation and produced a Th1 and Th17 response marked by the secretion of high levels of IFN-γ, IL-17 and IL-2. These epitopes were from heat shock protein 60, enolase, and the ATP-dependent molecular chaperone HSC82, and they each have a high degree of identity with proteins expressed by other medically important pathogenic fungi. Thus, the epitopes described in this study have the potential for use in the development of vaccines that could result in cross-protection among fungal species.

The Expression of CD28 and Its Synergism on the Immune Response of Flounder (Paralichthys olivaceus) to Thymus-Dependent Antigen.

CD28 is well known as a critical T-cell costimulatory receptor involved in T cell activation by binding to its ligands. In this study, CD28 was cloned, and its expression profiles were characterized in flounder (Paralichthys olivaceus); variations of CD28+ cells after being stimulated with different types of antigens and the function of the CD28 costimulatory pathway on T-cell activation were investigated in vitro. fCD28 consists of four exons and three introns, and the full-length cDNA of fCD28 was 675-bp encoded 224 amino acids. The conserved motif (121TFPPPF126) binding to the CD80/86 ligand exists in the Ig-superfamily homology domain. The high expression of fCD28 is in gills, PBLs, head kidney, and spleen. CD28+ cells were co-localized with CD4+ T lymphocytes but not on IgM+ B lymphocyte cells. Moreover, the expression of CD28 was significantly varied in flounder after being stimulated by keyhole limpet hemocyanin (KLH) at both the transcriptional and cellular levels, while no significant differences were observed between lipopolysaccharide (LPS) stimulation and the control group. Notably, treatment of PBLs cultured in vitro with CD28 molecule-specific antibody (anti-CD28 Abs) and PHA produced more cell colonies and stimulated the proliferation of cultured leukocytes compared to PHA stimulation alone and the control group, and a higher level of IL-2 was detected in the culture medium. Meanwhile, anti-CD28 Abs increased the percent of CD28+ cells (10.41 ± 1.35%), CD4+ T lymphocytes (18.32 ± 2.15%), and CD28+/CD4+ double-positive cells (6.24 ± 1.52%). This effect also resulted in significant variations in the genes of cell membrane-bound molecules, cytokines, and related signaling pathways in cultured leukocytes, with significant changes in the genes of interleukin-2 (IL-2) and nuclear factor of activated T cells (NFAT) in the early stages of culture, and the expression of other molecules increased over time. These results proved the localization of the CD28 molecule on T lymphocytes in flounder, and anti-CD28 may act as the B7 ligand involved in T cell activation after antigen stimulation. These data provide a basis for a more in-depth study of the mechanism of the CD28 costimulatory pathway in T cell activation.

Estimation of Interleukin‐10 and Interleukin‐22 Levels in the Advances of Breast Cancer

Background: Breast cancer is the secant-kind of carcinoma in women with higher incidence in Iraq.There are many prognostic and predicitive factors used for management of the breast cancer. Serumlevels of the cytokines may be utilized as a marker of immunity status and prognosis in CA breast.Aims of the Study: Measuring the IL-10 and IL-22 in breast cancer patients and association IL-10and IL-22 with stage and grade for breast cancer. Materials and Methods: The case-control studywas conducted on 60 women with CA. Breast and 60 controls group, patients with CA. Breast werereferred to Middle Euphrates cancer center in Najaf during the period November 2019-October 2020.Measurement of Interleukin-10 and Interleukin-22 by using ELISA. Results: The showed a levels ofIL-10 and IL-22 in breast cancer group higher than levels of IL-10 and IL-22 in control, and showeda high levels of IL-22 in advances stage and grade III. The showed non-significant in IL-10 levelsbetween four stages and three grade. Conclusions: A significant elevation levels of IL-10 and IL-22 inbreast cancer groups comparison with control, elevation significant IL-22 levels in stages and gradesof breast cancer.

Abstract 104: Deletion Of Myd88 In T-Cells Worsens Pathology In A Mouse Model Of Non-Ischemic Heart Failure Through Enhanced T-Cell Survival And Effector Function:

Background: Heart failure (HF) is a leading cause of death worldwide, associated with cardiac and systemic inflammation. However, no anti-inflammatory therapies have shown success thus far. Damage associated molecular patterns (DAMPs) released in the heart can activate myeloid cells to promote antigen presentation to T-cells, which infiltrate the heart and participate in adverse cardiac remodeling. DAMP signaling converges onto the adaptor protein “Myeloid differentiation primary response 88” (MyD88). DAMP receptors and MyD88 are also expressed in T-cells, but their role in T-cell activation is unclear, and is unknown in the context of HF. We hypothesized that T-cell recognition of DAMPs through MyD88 causes “bystander activation” of T-cells and contributes to cardiac pathology in HF. Methods and Results: We reconstituted Tcra -/- mice, normally protected from HF, with WT or Myd88 -/- Type 1 helper T-cells (Th1) in the onset of transaortic constriction (TAC), a well-established model of HF. Surprisingly, we found that mice given Myd88 -/- Th1 cells exhibited significantly higher levels of cardiac T-cell infiltration, more severe fibrosis, and lower fractional shortening than mice given WT Th1 cells. We found that WT and Myd88 -/- Th1 cells had similar levels of IFNγ and Tbx21 by intracellular staining and RT-qPCR, indicating that MyD88 does not alter Th1 differentiation. However, Myd88 -/- Th1 cells secreted higher levels of IL-2 and TNFα, suggesting enhanced proliferative and pro-inflammatory effector function. We performed viability studies using live cell microscopy and measuring propidium iodide incorporation in real time, as well as by flow cytometry, and found that Myd88 -/- Th1 cells have a survival advantage compared to WT Th1 cells. Moreover, we found that Myd88 -/- Th1 cells exhibited higher levels of adhesion to ICAM-1 and VCAM-1, protein ligands involved in T-cell recruitment, compared to WT Th1 cells when perfused under conditions of shear flow. Conclusion: Together, these data demonstrate that T-cell MyD88 limits T-cell mediated pathology in HF by modulating Th1 effector function, survival, and adhesion ability. We identify novel role for T-cell MyD88 in cardiac inflammation that may be modulated in HF.

Pseudo-Anaphylactic Reactions to Pfizer BNT162b2 Vaccine: Report of 3 Cases of Anaphylaxis Post Pfizer BNT162b2 Vaccination

Anaphylactic reactions were observed after Singapore’s national coronavirus disease 2019 (COVID-19) vaccination programme started in December 2020. We report the clinical and laboratory features of three patients in our institution who developed anaphylactic reactions after receiving the Pifzer BNT162b2 vaccine. IgM and IgG antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine, were detected in all subjects. Similarly, mild to high elevated levels of anti-polyethylene glycol (PEG) IgG (1035–19709 U/mL, vs. vaccine-naive < 265 U/mL, vaccine-tolerant < 785 U/mL) and IgM (1682–5310 U/mL, vs. vaccine-naive < 1011 U/mL, vaccine-tolerant < 1007 U/mL) were detected in two out of three patients via commercial ELISA. High levels of serum anaphylatoxin C3a (79.0 ± 6.3 μg/mL, mean ± SD, vs. normal < 10 μg/mL) were observed in all three patients during the acute phase of the reaction, while tryptase levels, a marker of mast cell activation, were not elevated. Finally, one patient with the highest levels of anti-PEG IgG, IgM, and anti-Pfizer BNT162b2 IgG and IgM exhibited an enhanced Th2 cytokine serum profile during an acute reaction, with high levels of IL-4 (45.7 pg/mL, vs. vaccine-naive/tolerant < 2.30 pg/mL), IL-33 (86.4 pg/mL, vs. vaccine-naive/tolerant < 5.51 pg/mL) and IL-10 (22.9 pg/mL, vs. vaccine-naive/tolerant < 12.49 pg/mL) diminishing over time following corticosteroid treatment. Taken together, we propose these cases of anaphylaxis described are driven by a complement activation-related pseudoallergy (CAPRA), rather than classical IgE-mediated mechanisms.

Roles of Clara cell 10-kD protein and type 2 innate lymphoid cells in allergic rhinitis

ABSTRACT This study examined the potential roles of CC10 (Clara cell 10-kD protein) and ILC2s (type 2 innate lymphoid cells) in allergic rhinitis (AR). After ovalbumin was used to construct the AR model, microarray analysis was performed to reveal the key differentially expressed genes. The phenotypic changes of nasal mucosa were examined by H&E staining. Western blot analysis, qRT-PCR, ELISA and immunohistochemistry were performed to identify the levels of cytokines. The lineage markers (CD127 and CD117) of ILC2s were detected using immunofluorescence. The microarray analysis and qRT-PCR results showed that CC10 overexpression inhibited the expression of A20, BAFF, and IL-4 R in vivo. Also, CC10 overexpression was found to ameliorate the damage of nasal mucosa in AR mice. Investigations revealed that the ILC2s were activated in AR mice and AR patients with high levels of IgE, IgG1, IL-4, IL-5, IL-13, IL-25, and IL-33. Moreover, CD127+ was found to activate ILC2s. However, CC10 overexpression suppressed the activation of ILC2s. In conclusion, this research suggested that CC10 could suppress the activation of ILC2s to attenuate the damage of nasal mucosa and that CD127+ may be a biomarker of the activation of ILC2s in AR mice and AR patients.

Network pharmacology analysis and experimental validation to explore the mechanism of Hanchuan Zupa Granule in asthma

Ethnopharmacological relevanceHanchuan Zupa Granule (HCZP) is a classic prescription of Uyghur medicine, that is used for cough and abnormal mucinous asthma caused by a cold and “Nai-Zi-Lai”. Aim of the studyThis study aimed to explore the possible molecular mechanism of HCZP in the treatment of asthma, using a network pharmacology method and in vivo experiments. Materials and methodsFirst, we conducted qualitative analysis of the chemical composition of HCZP as a basis for network pharmacology analysis. Using network pharmacology tools, the possible signaling pathways of HCZP in the treatment of asthma were obtained. An OVA-sensitized asthma model was established, and HCZP was continuously administered for one week. BALF was collected for cell counting, and serum and lung tissues were collected to analyze the expression of IgE, IL-4, IL-5, IL-13 and IFN-γ. Hematoxylin & eosin (H&E) staining was performed to assess the pathological changes in the lung tissues. Related protein expression in the lung tissues was analyzed by Western blotting for molecular mechanism exploration. ResultsFifty-six chemical compounds were identified by UPLC Q-TOF MS. According to the network pharmacology results, 18 active compounds were identified among the 56 compounds, and 68 target genes of HCZP in the treatment of asthma were obtained. A total of 19 pathways were responsible for asthma (P < 0.05) according to KEGG pathway analysis. In vivo results showed that OVA sensitivity induced increased respiratory system resistance and inflammatory responses, which included inflammatory cell infiltration and high levels of IgE, IL-4, IL-5 and IL-13 in serum and lung tissues. Furthermore, OVA upregulated p-PI3K, p-JNK and p-p38 expression in lung tissues. Moreover, HCZP treatment significantly downregulated respiratory system resistance, and the expression of IL-4, IL-5, IL-13 and IgE, as well as significantly improved inflammatory cell infiltration in lung tissues. Moreover, the protein expression of p-PI3K, p-JNK and p-p38 in lung tissues decreased after HCZP treatment. ConclusionHCZP significantly inhibited the OVA-induced inflammatory response via the PI3K-Akt and Fc epsilon RI signaling pathways.

Macrophages: The Good, the Bad, and the Gluttony.

Macrophages are dynamic cells that play critical roles in the induction and resolution of sterile inflammation. In this review, we will compile and interpret recent findings on the plasticity of macrophages and how these cells contribute to the development of non-infectious inflammatory diseases, with a particular focus on allergic and autoimmune disorders. The critical roles of macrophages in the resolution of inflammation will then be examined, emphasizing the ability of macrophages to clear apoptotic immune cells. Rheumatoid arthritis (RA) is a chronic autoimmune-driven spectrum of diseases where persistent inflammation results in synovial hyperplasia and excessive immune cell accumulation, leading to remodeling and reduced function in affected joints. Macrophages are central to the pathophysiology of RA, driving episodic cycles of chronic inflammation and tissue destruction. RA patients have increased numbers of active M1 polarized pro-inflammatory macrophages and few or inactive M2 type cells. This imbalance in macrophage homeostasis is a main contributor to pro-inflammatory mediators in RA, resulting in continual activation of immune and stromal populations and accelerated tissue remodeling. Modulation of macrophage phenotype and function remains a key therapeutic goal for the treatment of this disease. Intriguingly, therapeutic intervention with glucocorticoids or other DMARDs promotes the re-polarization of M1 macrophages to an anti-inflammatory M2 phenotype; this reprogramming is dependent on metabolic changes to promote phenotypic switching. Allergic asthma is associated with Th2-polarised airway inflammation, structural remodeling of the large airways, and airway hyperresponsiveness. Macrophage polarization has a profound impact on asthma pathogenesis, as the response to allergen exposure is regulated by an intricate interplay between local immune factors including cytokines, chemokines and danger signals from neighboring cells. In the Th2-polarized environment characteristic of allergic asthma, high levels of IL-4 produced by locally infiltrating innate lymphoid cells and helper T cells promote the acquisition of an alternatively activated M2a phenotype in macrophages, with myriad effects on the local immune response and airway structure. Targeting regulators of macrophage plasticity is currently being pursued in the treatment of allergic asthma and other allergic diseases. Macrophages promote the re-balancing of pro-inflammatory responses towards pro-resolution responses and are thus central to the success of an inflammatory response. It has long been established that apoptosis supports monocyte and macrophage recruitment to sites of inflammation, facilitating subsequent corpse clearance. This drives resolution responses and mediates a phenotypic switch in the polarity of macrophages. However, the role of apoptotic cell-derived extracellular vesicles (ACdEV) in the recruitment and control of macrophage phenotype has received remarkably little attention. ACdEV are powerful mediators of intercellular communication, carrying a wealth of lipid and protein mediators that may modulate macrophage phenotype, including a cargo of active immune-modulating enzymes. The impact of such interactions may result in repair or disease in different contexts. In this review, we will discuss the origin, characterization, and activity of macrophages in sterile inflammatory diseases and the underlying mechanisms of macrophage polarization via ACdEV and apoptotic cell clearance, in order to provide new insights into therapeutic strategies that could exploit the capabilities of these agile and responsive cells.

Elevations in Liver Transaminases in COVID-19: (How) Are They Related?

Liver involvement in COVID-19 is not yet well-understood, but elevations in liver transaminases have been described to occur in 14–53% of the cases and are more frequently seen in severe disease. This cross-sectional study explored the relationship between the elevations in liver transaminases and inflammatory parameters in 209 adults with COVID-19. Demographic and clinical data, serum levels of inflammatory cytokines and liver aminotransferases were analyzed. Three groups were formed according to the liver transaminase abnormalities: (I) Normal transaminases, (II) Borderline transaminases elevation, and (III) Mild to severe transaminases elevation. Altered liver transaminases were directly related to disease severity, showing association with the NEWS2 score at admission and greater need for ICU or death. Moreover, higher levels of IL-2 and CRP were associated with borderline transaminases elevations, whereas higher levels of IL-10 and Neutrophil to Lymphocyte ratio were associated with mild to severe transaminases elevation. These results reinforce the importance of liver transaminases in patients with COVID-19 as a complementary marker for disease severity and also point to them as a parameter reflecting the continuous dynamics between viral infection and the immune response.

Role of Different Hormones (Testosterone, Estrogen, Melatonin, Glucocorticoid, Thyroxin) in Immune Modulation of Thymocyte and Splenocyte Functions of Indian Goat C. hircus: An in vitro Study

The immune system is coordinated by a number of cytokines which are regarded as chemical messengers of immunity. Some of them are pro-inflammatory (e.g. IL-2), some are anti-inflammatory (e.g. IL-6), some can be regarded as a switch between pro and anti-inflammatory processes (e.g. TNF-α). Further, immune regulation in body is a proper balance between mitosis and apoptosis occurring simultaneously in the body. In the present chapter we explored the spleen and thymus functions by assessing %SR and % apoptotic rate of splenocytes and thymocytes being significantly high levels of cell proliferation (in terms of %SR) and apoptosis rate during monsoon and winter seasons. We noted IL-2 (a pro-inflammatory cytokine), IL-6 (an anti-inflammatory cykine), TNF-α (a switch between pro and anti-inflammatory cytokine) and IFN-γ (a marker of viral infection) in circulation of goats. We noted significantly high levels of IL-2 and TNF-α levels during monsoon and winter but IFN-γ and IL-6 levels were only high during monsoon. Hence, to ameliorate the elevated inflammatory stress level particularly during monsoon goats have evolved a number of adaptive strategies. But, simultaneously during monsoon the gonadal steroid levels are also high which are reported as immune suppressor. Thus, the basic query may arise how goats are proved to be a better survivor under the season of stress (particularly during monsoon) when the level of potent immune enhancer neurohormone melatonin level is also low.

Plasma cytokines during acute human fascioliasis.

Fascioliasis is a foodborne trematode endemic worldwide. Children under 15years have the highest prevalence of infection. We hypothesized that acute fascioliasis would be associated with more pronounced cytokine changes than in chronic disease or no helminth infections. To test this hypothesis, 33 children who lived in the Peruvian highlands were classified into 3 groups: acute fascioliasis, chronic fascioliasis, and no helminth infection. Type Th1, Th2, and Th17 cytokines were measured in plasma by cytometric bead array. Children with acute infection had higher levels of IL-5 and IL-17 compared with controls (p < 0.001 and p < 0.007, respectively). The increased IL-5 plasma concentration in children with acute infection was associated with the eosinophilia found in that group.

A Proinflammatory Cytokine Network Profile in Th1/Type 1 Effector B Cells Delineates a Common Group of Patients in Four Systemic Autoimmune Diseases.

The effector T cell and B cell cytokine networks have been implicated in the pathogenesis of systemic autoimmune diseases, but the association of these cytokine networks with the heterogeneity of clinical manifestations and immune profiles has not been carefully examined. This study was undertaken to examine whether cytokine profiles can delineate distinct groups of patients in 4 systemic autoimmune diseases (systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, and systemic sclerosis). A total of 179 patients and 48 healthy volunteers were enrolled in the multicenter cross-sectional PRECISE Systemic Autoimmune Diseases (PRECISESADS) study. Multi-low-dimensional omics data (cytokines, autoantibodies, circulating immune cells) were examined. Coculture experiments were performed to test the impact of the cytokine microenvironment on T cell/B cell cross-talk. A proinflammatory cytokine profile defined by high levels of CXCL10, interleukin-6 (IL-6), IL-2, and tumor necrosis factor characterized a distinct group of patients in the 4 systemic autoimmune diseases. In each disease, this proinflammatory cluster was associated with a specific circulating immune cell signature, more severe disease, and higher levels of autoantibodies, suggesting an uncontrolled proinflammatory Th1 immune response. We observed in vitro that B cells reinforce Th1 differentiation and naive T cell proliferation, leading to the induction of type 1 effector B cells and IgG production. This process was associated with an increase in CXCL10, IL-6, IL-2, and interferon-γ production. This composite analysis brings new insights into human B cell functional heterogeneity based on T cell/B cell cross-talk, and proposes a better stratification of patients with systemic autoimmune diseases, suggesting that combined biomarkers would be of great value for the design of personalized treatments.

Proinflammatory TH17 cytokine activation, disease severity and outcomes in peripartum cardiomyopathy

BackgroundImmune dysregulation is implicated in the development and clinical outcomes of peripartum cardiomyopathy (PPCM). Methods and results98 women with PPCM were enrolled and followed for 1 year postpartum (PP). LVEF was assessed at entry, 6-, and 12-months PP by echocardiography. Serum levels of soluble interleukin (IL)-2 receptor (sIL2R), IL-2, IL-4, IL-17, IL-22, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by ELISA at entry. Cytokine levels were compared between women with PPCM by NYHA class. Outcomes including myocardial recovery and event-free survival were compared by cytokine tertiles. For cytokines found to impact survival outcomes, parameters indicative of disease severity including baseline LVEF, medications, and use of inotropic and mechanical support were analyzed. Levels of proinflammatory cytokines including IL-17, IL-22, and sIL2R, were elevated in higher NYHA classes at baseline. Subjects with higher IL-22 levels were more likely to require inotropic or mechanical support. Higher levels of TNF-α and IL-22 were associated with poorer event-free survival. Higher TNF-α levels were associated with lower mean LVEF at entry and 12 months. In contrast, higher levels of immune-regulatory cytokines such as IL-4 and IL-2 were associated with higher LVEF during follow up. ConclusionProinflammatory cytokines IL-22 and TNF-α were associated with adverse event-free survival. IL-17 and IL-22 were associated with more severe disease. In contrast, higher levels of IL-2 and IL-4 corresponded with higher subsequent LVEF. Increased production of TH17 type cytokines in PPCM correlated with worse disease and outcomes, while an increased immune-regulatory response seems to be protective.