Accelerated apoptosis of neutrophils in familial Mediterranean fever

The causative mutations for familial Mediterranean fever (FMF) are located in the MEFV gene, which encodes pyrin. Pyrin modulates the susceptibility to apoptosis via its PYD domain but how the mutated versions of pyrin affect apoptotic processes is poorly understood. Spontaneous and induced rates of systemic neutrophil apoptosis as well as the levels of proteins involved in apoptosis were investigated ex vivo in patients with FMF using flow cytometry and RT-qPCR. The freshly collected neutrophils from the patients in FMF remission displayed a significantly larger number of cells spontaneously entering apoptosis compared to control (6.27% ± 2.14% vs. 1.69% ± 0.18%). This elevated ratio was retained after 24h incubation of neutrophils in the growth medium (32.4% ± 7.41% vs. 7.65% ± 1.32%). Correspondingly, the mRNA level for caspase-3 was also significantly increased under these conditions. In response to the inducing agents the neutrophils from FMF patients also displayed significantly elevated apoptotic rates compared to control. The elevated rates, however, can be largely explained by the higher basal ratio of apoptotic cells in the former group. Monitoring of several proteins involved in apoptosis has not revealed any conventional mechanisms contributing to the enhanced apoptotic rate of neutrophils in FMF. Although the exact molecular mechanisms of accelerated neutrophil apoptosis in FMF remain unknown, it may provide a protection against excessive inflammation and tissue damage due to a massive infiltration of neutrophils in the acute period of the disease

Elevated systemic antibodies towards commensal gut microbiota in autoinflammatory condition

Article No. e3172Non peer reviewedPublisher PD

Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects

A growing body of studies highlights involvement of neutrophils in cancer development and progression. Our aim was to assess the phenotypic and functional properties of circulating neutrophils from patients with chronic lymphocytic leukemia (CLL). The percentage of CD54+ and CD64+ neutrophils as well as CD54 expression on these cells were higher in CLL patients than in age-matched healthy controls. Neutrophils from CLL produced more reactive oxygen species (ROS) compared to controls in both resting and activated conditions. Lipopolysaccharide-induced production of IL-1 beta and TNF-a as well as reduced TLR2 expression in neutrophils from CLL than in neutrophils from controls suggesting their tolerant state. Finally, phenotypic alterations of neutrophils, particularly elevation of CD64 and CD54 markers, correlated with disease activity and treatment, and low percentage of neutrophils. Taken together, the alterations in percentage and functional characteristics of neutrophils reflect the clinical course of CLL. Our data provide first evidence that neutrophils in CLL are permanently primed and have functional defects.Web of Science849849018488

High CXCR3 on leukemic cells distinguishes IgHV(mut) from IgHV(unmut) in chronic lymphocytic leukemia: Evidence from CD5(high) and CD5(low) clones

Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5(high) and CD5(low) neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5(high)and CD5(low) subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients (n=60) subgrouped according to the IgHV mutational status (IgHV(mut),n=24;IgHV(unmut),n=36). CD5(high) subpopulation showed a high percentage of CXCR3 (P<0.001), CCR10 (P=0.001), and CD62L (P=0.031) and high levels of CXCR5 (P=0.005), CCR7 (P=0.013) compared to CD5(low) cells expressing high CXCR4 (P<0.001). Comparing IgHV(mut) and IgHV(unmut)patients, high levels of CXCR3 on CD5(high) and CD5(low) subpopulations were detected in theIgHV(mut) patients, with better discrimination in CD5(low) subpopulation. Levels of CXCR3 on CD5(low) subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5(high) and CD5(low) neoplastic cells inIgHV(mut) with a better prognosis compared to IgHV(unmut) patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations.Web of Science2020art. no. 708426

Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukaemia using patient similarity networks

The tissue microenvironment in chronic lymphocytic leukaemia (CLL) plays a key role in the pathogenesis of CLL, but the complex blood microenvironment in CLL has not yet been fully characterised. Therefore, immunophenotyping of circulating immune cells in 244 CLL patients and 52 healthy controls was performed using flow cytometry and analysed by multivariate Patient Similarity Networks (PSNs). Our study revealed high inter-individual heterogeneity in the distribution and activation of bystander immune cells in CLL, depending on the bulk of the CLL cells. High CLL counts were associated with low activation on circulating monocytes and T cells and vice versa. The highest activation of immune cells, particularly of intermediate and non-classical monocytes, was evident in patients treated with novel agents. PSNs revealed a low activation of immune cells in CLL progression, irrespective of IgHV status, Binet stage and TP53 disruption. Patients with high intermediate monocytes (>5.4%) with low activation were 2.5 times more likely (95% confidence interval 1.421-4.403, P=0.002) to had shorter time-to-treatment than those with low monocyte counts. Our study demonstrated the association between the activation of circulating immune cells and the bulk of CLL cells. The highest activation of bystander immune cells was detected in patients with slow disease course and in those treated with novel agents. The subset of intermediate monocytes showed predictive value for time-to-treatment in CLL.Web of Science111art. no. 32

Impaired Inflammatory Response to LPS in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a severe health problem worldwide, reaching epidemic levels. High susceptibility to infections of T2DM patients indicates dysregulated immune responses to pathogens. However, innate immune responses, including monocyte functions, in T2DM are poorly investigated. Therefore, in this study we aimed to assess lipopolysaccharide- (LPS-) induced immune responses of circulating monocytes from T2DM patients. The results showed that monocytes from T2DM were hyporesponsive to LPS challenge as reflected by significantly suppressed secretion of TNFα (p<0.01) and expression of CD11b (p<0.001) and TLR4 (p<0.001) compared to those in monocytes from healthy subjects. Furthermore, LPS-induced IL-10 levels were similar in diabetic and healthy supernatants, while expression levels of CD163 were found to be downregulated on monocytes from T2DM (p<0.001) suggesting impaired ability of monocytes to switch their phenotype to anti-inflammatory. Taken together, our results suggest compromised function of monocytes in T2DM, which may explain, at least partly, high incidence of infection in these patients

Microbial and Environmental Factors in Autoimmune and Inflammatory Diseases

In recent years there has been a substantial increase in the number of diseases with the inflammatory component such as such as allergy, asthma, rheumatoid arthritis, inflammatory bowl disease (IBD, which includes ulcerative colitis and Crohn's disease), chronic sinusitis, and many other conditions. The majority of these diseases are multifactorial, with the contribution of genetic and environmental factors. Among the latter, the role of certain microorganisms and viruses in triggering or sustaining the inflammatory process is most controversial. In rheumatoid arthritis, for example, the following bacteria and viruses have been implicated in triggering the disease: Mycoplasma spp., Proteus mirabilis, Escherichia coli, Staphylococcus spp., Bordetella spp., Acinetobacter spp., the parvoviruses, Epstein-Barr virus, and retroviruses. The list of putative microbial triggers of rheumatoid arthritis is still growing, and it becomes essentially impossible to make a causation link between certain infectious agents and the disease. In the light of these disappointing results there are calls for even larger studies with the use of more advanced and large-scale technologies. The primary function of the immune system is the maintenance of body homeostasis and protection against any threats to it via several lines of elaborate and complex immune defense. Given even higher complexity that involves the microbiota and the corresponding host-microbe interaction, the conditions for this equilibrium become even more challenging. In the absence of a defined pathogen, for example, the spectrum of microorganisms involved in triggering inappropriate immune responses may include polymicrobial communities or the cumulative effect of several microbial/viral factors. Under the normal circumstances there is a fine-tuned balance between commensal microbiota and the host’s immune responses. However, when this balance is compromised, for example in IBD, a massive immune response is launched against commensal microbiota resulting in chronic inflammation. Besides the microbial/viral factors, the balance of the immune system can be compromised by other causes. Given, for example, the close and inclusive interaction of the immune, nervous and endocrine systems, the list of these provoking factors can expand even more. For instance, it has been demonstrated that even mild sleep deprivation may increase the production of interleukin-6 and C-reactive protein. Understanding the complex role of microbial and environmental factors in inflammatory and autoimmune diseases, therefore, is the main subject of this topic

Combustion Synthesis of Materials for Application in Supercapacitors: A Review

A supercapacitor is an energy storage device that has the advantage of rapidly storing and releasing energy compared to traditional batteries. One powerful method for creating a wide range of materials is combustion synthesis, which relies on self-sustained chemical reactions. Specifically, solution combustion synthesis involves mixing reagents at the molecular level in an aqueous solution. This method allows for the fabrication of various nanostructured materials, such as binary and complex oxides, sulfides, and carbon-based nanocomposites, which are commonly used for creating electrodes in supercapacitors. The solution combustion synthesis offers flexibility in tuning the properties of the materials by adjusting the composition of the reactive solution, the type of fuel, and the combustion conditions. The process takes advantage of high temperatures, short processing times, and significant gas release to produce well crystalline nanostructured materials with a large specific surface area. This specific surface area is essential for enhancing the performance of electrodes in supercapacitors. Our review focuses on recent publications in this field, specifically examining the relationship between the microstructure of materials and their electrochemical properties. We discuss the findings and suggest potential improvements in the properties and stability of the fabricated composites based on the results