Immunological dysfunction has been suggested to play a major role in the pathogenesis of idiopathic granulomatous mastitis (IGM). We recently showed that ozone therapy was effective in patients with ...steroid‐resistant IGM. This study assessed alterations in intracellular cytokine expression patterns in different T‐lymphocyte subsets after ozone therapy in refractory IGM. Peripheral blood T lymphocyte subsets (CD8+, CD4+, CD4+CD25+CD127−) were analyzed via flow‐cytometry for intracellular cytokine expressions IFN‐γ, TNF‐α, IL‐10, and TGF‐β before and after completion of 4‐month systemic ozone therapy. Ozone therapy significantly increased the CD4+IFN‐γ+ (p = 0.032), CD4+TNF‐α+ (p = 0.028), and the CD8+TNF‐α+ (p = 0.012) T cells. In contrast, significant decreases in CD4+ IL‐10+ (p = 0.047) and CD8+IL‐10+ T cells (p = 0.022) and CD4+CD25+CD127−//low Treg cells secreting TGF‐β (p = 0.005) were found after ozone therapy. When patients were analyzed according to the response to ozone therapy, patients with a complete remission were more likely to have increased CD3−CD16+CD56+ natural killer cells (p = 0.0027) and decreased CD19+ B lymphocytes (p = 0.046) following ozone therapy. Our results suggest that ozone therapy stimulated a T‐helper‐1 response associated with IFN‐γ production and downregulation of TGF‐β expression in CD4+CD25+CD127− Treg cells. These alterations in the immune system following ozone therapy can improve wound healing and restore immune dysfunction in patients with refractory IGM.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating ...regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.
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•Notch4 expression on Treg cells is associated with COVID-19 disease severity•Notch4 inhibition suppresses lung inflammation in proxy viral mouse models•Notch4 limits amphiregulin-dependent lung Treg cell tissue repair functions
Harb, Benamar, et al. find that interleukin-6 increases Notch4 expression on lung regulatory T cells, which, in turn, restrains production of the tissue repair cytokine amphiregulin and promotes severe lung inflammation. Their findings have implications for treatment of COVID-19 and other respiratory viral infections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970's. They are members of innate immunity and were initially ...defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don't express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16
CD56
subset is best-known by their cytotoxic functions, CD16
CD56
NK cell subset produces a bunch of cytokines comparable to CD4
T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet's disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and "bridge" them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.
High expression of immune checkpoint receptors (ICRs) in the tumor microenvironment regulates the anti-tumor response. In this study, the differential expressions of ICRs on tumor-infiltrating ...lymphocytes (TILs) in patients with early-stage breast cancer were investigated. The study included 32 patients who underwent surgery with a diagnosis of early-stage breast cancer between September 2018 and March 2020. TIL isolation was performed using a MACS tumor separation device and tumor separation kit. PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT expression of cytotoxic T and natural killer (NK) cells on TILs and peripheral blood lymphocytes (PBLs) were determined by flow cytometry. Patients with a high Ki-67 index, high TIL density, and HER-2 positivity were more likely to have increased CD16.sup.+CD56.sup.dim NK cells on TILs. Patients with T2 tumors were more likely to have increased expression of PD-1, LAG-3, and TIGIT on tumor-infiltrating CD8.sup.+ cytotoxic T cells than those with T1 tumors. PD-1, CTLA-4, TIGIT, LAG-3, and TIM-3 expression of CD8.sup.+ T and CD16.sup.-CD56.sup.bright NK cells in TILs showed significant positive correlations with each other. PD1.sup.+CD8.sup.+, TIGIT.sup.+CD16.sup.+, and CTLA-4.sup.+CD56.sup.+ cells in PBLs and TILs were found to be negatively correlated, whereas only TIM-3.sup.+ expression of CD8.sup.+ T and CD16.sup.+CD56.sup.dim cells in PBLs and TILs showed positive correlations. Our results suggest that CD16.sup.+CD56.sup.dim NK cells on TILs may play a major role in the immune response against HER2-positive or highly proliferating breast tumors in patients with early-stage breast cancer. Furthermore, various ICRs were found to be highly co-expressed with each other on TILs, including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT. These receptors may synergistically suppress the response to the tumor, which may trigger immune escape mechanisms in the early stage of carcinogenesis. However, ICR expressions other than TIM3 on PBLs were not found to accompany their counterparts on TILs. Keywords: Early-stage breast cancer, TIL, NK, PD-1, CTLA-4, TIGIT, LAG-3, TIM-3
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To investigate plasma concentrations of S100B (a calcium-binding protein derived primarily from the glia) and inflammatory cytokines in children with autism and the relationship between S100B and ...cytokine concentrations.
Plasma levels of S100B, tumor necrosis factor alpha (TNF-α), interferon gamma, interleukin (IL)-1β, IL-4, IL-6, IL-10, and IL-17A were measured in 40 unmedicated children with autism and 35 normally developing healthy children. The severity of autism was assessed using the Childhood Autism Rating Scale (CARS).
Concentrations of both S100B and TNF-α were higher in children with autism before and after adjusting for a priori-selected confounders (age, sex, and body mass index). S100B concentrations were higher in children with severe autism compared to children with mild-moderate autism. However, this association remained as a trend after adjusting for confounders. S100B concentrations correlated positively with TNF-α concentrations.
Our findings showing an increase in peripheral concentrations of S100B and TNF-α provide limited support to the hypothesis about the roles of altered immune function and S100B in autism spectrum disorder (ASD). Studies of larger numbers of well-characterized individuals with ASD are needed to clarify the potential role of the immune system in the pathophysiology of this disorder.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Various synthetic and biological meshes have been developed to reduce recurrence and complications in ventral incisional hernia repairs. Adipose tissue is a rich reserve for mesenchymal stromal ...cells. In the present study we aimed to examine the effects of adipose-derived mesenchymal stromal cells (AD-MSCs) on abdominal incisional hernia repairs in rats.
The study involved 32 male Wistar-Albino rats, weighing 200-250 g, which were divided into three groups. In Group 1 (control group) only an incisional hernia model was created. In Group 2, the incisional hernia model was created and 1 ml stromal vascular fraction (SVF), obtained from inguinal lipectomy material and containing mesenchymal stromal cells, was injected into the edges of the defect in the same session. In Group 3, only the incisional hernia model was created in the first stage and after 14 days, 1 ml of SVF was injected into the edges of the defect. Skin incisions of rats in Group 1 and 2 were opened on postoperative day 28 while in group 3 were opened on day 42. Peritoneal formation in abdominal wall defect was evaluated macroscopically and histopathologically.
Peritoneal formation was significantly superior in Groups 2 and 3 than in Group 1 (p: 0.031). In histopathological evaluation, the structural distortion and polymorphonuclear leukocyte (PMNL) levels were significantly higher in Group 1 than in Group 3 (p: 0.048 and p: 0.046, respectively). Granulation, capillary density, fibrosis and collagen organization were higher in Group 2 and 3, however this difference was not statistically significant (p > 0.05).
Adipose-derived stromal vascular fraction cells obtained from inguinal lipectomy material in rats positively affect the repair of abdominal incisional hernias by increasing peritoneal formation, and reducing structural distortion and PMNL infiltration.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Objective. Behçet's disease (BD) is a systemic inflammatory disease with unknown etiology. Studies have shown that some T helper (Th) 1-associated cytokines have role in the inflammation of ...BD. The CD4+ Th cells can be differentiated into Th1, Th2, Th17 and Th22 secrete different cytokines to regulate immune system. In this study, cytokine secretion of Th subsets in BD was investigated.
Methods. The study group consisted of 26 BD patients with mucocutaneous involvement and 12 healthy subjects. Lymphocyte subpopulations, IL-5, IL-10, IL-17, IL-22 and IFN-γ secretion of CD4+ T and Foxp3+ Treg cells were determined by flow cytometry.
Results. Compared with healthy subjects, Th1 (IL-17A−IL-22−IFN-γ+), Th22 (IL-17A−IL-22+IFN-γ) and IL-17A+IFN-γ+-secreting cells were significantly increased, and the percentage of Treg cells were dramatically reduced in BD patients. The frequency of recurrent oral ulcers was associated with increased Th22 cells.
Conclusions. Our study describes an association between Th22 cell subset and IL-17A+ IFNγ+-secreting cells with mucocutaneous BD. These findings revealed that reduced levels of Tregs and increased levels of Th1 and Th22 cells as well as Th17/Th1 cells might be associated with the pathogenesis of BD.
•The pathogenesis of Behcet's disease has not been fully elucidated yet.•ILCs and NK cells have important effector and regulatory functions in innate immunity.•The increase of both IL-17 expressing ...NK cells and NKp44−ILC3 cells were observed in BD patients.•IL-17 secreting ILC3 and NK cells might play a role in the pathogenesis of BD.
Innate lymphoid cells (ILCs) are lymphoid cells that have important effector and regulatory functions in innate immunity and tissue remodeling. Uncontrolled activation and proliferation of ILCs can contribute to inflammatory autoimmune diseases. Behcet's disease (BD) is a complex systemic inflammatory disorder of unknown etiology. It has been shown that natural killer (NK) cells may play an immunoregulatory role in BD, however the role of ILCs is unknown. In this study, the levels and functions of ILCs and NK cell subsets in BD patients were investigated. Cell surface and cytotoxic granules (perforin and granzyme) expression of NK cells and ILCs were evaluated and labeled according to whole blood lysing protocol in peripheral blood samples obtained from the patients and healthy subjects. Cytokine levels of NK cells were investigated in stimulated peripheral blood mononuclear cells. All data were analyzed by flow cytometry. Total ILC and ILC3+ cells were increased in active BD patients compared to inactive BD patients and healthy subjects. There was no significant difference between the patients and healthy subjects regarding NK cell surface and intracellular molecule expression. Although, an increase in IFN-γ and IL-17, and a decrease in IL-4 levels were observed in CD56dim NK cell subset of BD patients. Recent studies showed increased neutrophilic infiltration and IL-17 secreting Th17 cells in BD patients. It is known that ILC3+cells are similar to Th17 subset regarding their cytokine profile and transcription factor expression patterns. Results of current study may suggest that inflammatory microenvironment in BD patients might direct ILC cells to differentiate into ILC3+ subset, and IL-17 released by NK cells might have a role in neutrophilic infiltration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Obesity‐associated asthma (OA) is a difficult to treat asthma phenotype due to its severity and poor response to inhaled steroids. Early‐onset allergic (EoOA) and late‐onset non‐allergic ...(LoOA) OA are suggested subtypes of this phenotype. Natural Killer (NK) cells are key elements of innate immunity involved in cytotoxicity and immune regulation, with uncertain role in OA pathogenesis.
Methods
Early‐onset allergic and LoOA patients together with obese non‐asthmatic (ONA) controls have been enrolled in the study. Peripheral blood samples have been collected for analysis. Percentages of total NK cells, CD3−CD56dim and CD3−CD56bright NK cell subsets, cytotoxic activity, intracellular interferon‐γ, interleukin (IL)‐10, IL‐13, IL‐17 secretion and activatory receptors (NKG2D, NKp46i and NKp44) have been investigated by flow cytometry. The effect of IL‐12 and IL‐23 stimulation on NK cells and intracellular cytokines in different groups have also been analysed and compared with unstimulated conditions.
Results
Results of ONA (n = 5, age 42 ± 8), EoOA (n = 5, age 42 ± 10) and LoOA (n = 8, age 46 ± 8) patients have analysed. Body Mass Index has been found to be negatively correlated with CD69 (p = .022, r = −0.534). NKG2D receptor has been significantly low in CD56dim cells of asthma population (p = .046). NKp44 receptor expression has increased after IL‐12 stimulation in EoOA and control group (p = .02). Intracellular IL‐10 content has increased in LoOA and control subjects (p = .018, p = .03) but not in the EoOA group. Intracellular IL‐17 level has found be higher in allergic OA group. LoOA patients showed a decreased NK cytotoxicity compared with the early‐onset asthma group (p = .05).
Conclusion
Our study suggests an impaired NK receptor expression, activation and reduced cytotoxicity in OA patients together with variances between different subtypes of this phenotype. This data would be beneficial for tailoring a more personalized treatment strategy combatting steroid resistance and frequent exacerbations in this group of patients.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Erroneous immune responses in COVID-19 could have detrimental effects, which makes investigation of immune network underlying COVID-19 pathogenesis a requisite. This study aimed to investigate ...COVID-19 related alterations within the frame of innate and adaptive immunity. Thirty-four patients clinically diagnosed with mild, moderate and severe COVID-19 disease were enrolled in this study. Decreased ILC1 and increased ILC2 subsets were detected in mild and moderate patients compared to healthy controls. NK cell subsets and cytotoxic capacity of NK cells were decreased in severe patients. Moreover, CD3
+
T cells were reduced in severe patients and a negative correlation was found between CD3
+
T cells and D-dimer levels. Likewise, moderate and severe patients showed diminished CD3
+
CD8
+
T cells. Unlike T and NK cells, plasmablast and plasma cells were elevated in patients and IgG and IgA levels were particularly increased in severe patients. Severe patients also showed elevated serum levels of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-8, reduced intracellular IFN-γ and increased intracellular IL-10 levels. Our findings emphasize that SARS-CoV-2 infection significantly alters immune responses and innate and acquired immunity are differentially modulated in line with the clinical severity of the disease. Elevation of IL-10 levels in NK cells and reduction of CD3
+
and CD8
+
T cells in severe patients might be considered as a protective response against the harmful effect of cytokine storm seen in COVID-19.
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