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The human gastrointestinal tract is inhabited by a very diverse symbiotic microbiota, the composition of which depends on host genetics and the environment. Several studies suggested that the host genetics may influence the composition of gut microbiota but no genes involved in host control were proposed. We investigated the effects of the wild type and mutated alleles of the gene, which encodes the protein called pyrin, one of the regulators of innate immunity, on the composition of gut commensal bacteria. Mutations in MEFV lead to the autoinflammatory disorder, familial Mediterranean fever (FMF, MIM249100), which is characterized by recurrent self-resolving attacks of fever and polyserositis, with no clinical signs of disease in remission. A total of 19 FMF patients and eight healthy individuals were genotyped for mutations in the MEFV gene and gut bacterial diversity was assessed by sequencing 16S rRNA gene libraries and FISH analysis. These analyses demonstrated significant changes in bacterial community structure in FMF characterized by depletion of total numbers of bacteria, loss of diversity, and major shifts in bacterial populations within the Bacteroidetes, Firmicutes and Proteobacteria phyla in attack. In remission with no clinical signs of disease, bacterial diversity values were comparable with control but still, the bacterial composition was substantially deviant from the norm. Discriminant function analyses of gut bacterial diversity revealed highly specific, well-separated and distinct grouping, which depended on the allele carrier status of the host. This is the first report that clearly establishes the link between the host genotype and the corresponding shifts in the gut microbiota (the latter confirmed by two independent techniques). It suggests that the host genetics is a key factor in host-microbe interaction determining a specific profile of commensal microbiota in the human gut.

Antiphospholipid antibodies (aPLs) comprise a diverse family of autoantibodies targeted against proteins with the affinity toward negatively charged phospholipids or protein-phospholipid complexes. Their clinical significance, including prothrombotic potential of anti-cardiolipin antibodies (aCLs), anti-β2-glycoprotein I antibodies (aβ2-GPIs), and lupus anti-coagulant (LA), is well-established. However, the ontogeny of these pathogenic aPLs remains less clear. While transient appearance of aPLs could be induced by various environmental factors, in genetically predisposed individuals these factors may eventually lead to the development of the antiphospholipid syndrome (APS). Since the first description of APS, it has been found that a wide variety of microbial and viral agents influence aPLs production and contribute to clinical manifestations of APS. Many theories attempted to explain the pathogenic potential of different environmental factors as well as a phenomenon termed molecular mimicry between β2-GPI molecule and infection-relevant structures. In this review, we summarize and critically assess the pathogenic and non-pathogenic formation of aPLs and its contribution to the development of APS.

Antiphospholipid syndrome (APS) is a systemic autoimmune condition characterized by the persistent presence of antiphospholipid antibodies (aPL), and is commonly associated with thrombosis and pregnancy-related complications. To date, relatively little is known about the potential of NK cells in mediating the pathological effects of APS. While the role of NK cells in controlling immune responses and maintaining tissue homeostasis is relatively clear, the fact that they are also linked to various autoimmune conditions is now being highlighted. Given the impact of NK cells on immune regulation, vascular function, and pregnancy outcomes, the unifying message of a critical role for NK cells in APS emerges. As innate immune cells, NK cells might be activated in an antibody dependent manner and exert antibody-dependent cellular cytotoxicity (ADCC). In this process, NK cells recognize and bind to the Fc portion of antibodies that have attached to target cells. With their immunoregulatory properties in the uterus, NK cells play a crucial role in facilitating endometrial tissue remodeling, supporting vascular function, and contributing to placental formation, all of which are essential for a successful pregnancy. In APS, the presence of aPL may disrupt the delicate balance of NK cell-mediated immune regulation leading to alterations in cell activation, cytokine production, and cytotoxic functions. Given the multifactorial nature of NK cells in peripheral blood and uterus, the review provides insight into the potential underlying mechanisms through which NK cells may contribute to thrombosis and pregnancy complications in APS.

The short lifespan of polymorphonuclear neutrophils (PMNs) in vitro poses challenges, as their limited viability restricts functional assays and experimental manipulations. The HL-60 cell line serves as a valuable model for neutrophil-like differentiation, yet the functional relevance of ATRA- and DMSO-induced differentiation remains incompletely understood. In the present study, we aimed to characterize the differentiation potential of all-trans retinoic acid (ATRA) and dimethyl sulfoxide (DMSO) on HL-60 cells and compare their functionality with primary PMNs. Besides that, we performed profound immunophenotypes of the cells with multicolor cytometry, and evaluated their antitumor capabilities. Our findings indicate that both differentiation conditions yield cells resembling immature neutrophils, exhibiting promyelocyte-like morphology, lacking key maturity markers. However, ATRA-differentiated cells exhibit a more mature phenotype, with higher expression of C/EBPα and reduced proliferation rates, indicating advanced differentiation. Functionally, ATRA-dHL-60 cells displayed limited immune responses, showing minimal phagocytic activity, low ROS production, and a reduced response to LPS. In contrast, DMSO-dHL-60 cells, despite their less mature phenotype, showed enhanced NET formation, and tumor-promoting potential. Additionally, DMSO-dHL-60 cells demonstrated superior adhesion and migration abilities, likely due to increased expression of CD18 and CD31. Overall, different differentiation conditions shape the functional specialization of HL-60 cells, with ATRA promoting a more neutrophil-like maturation and moderate activation, while DMSO results in a more immature phenotype with enhanced NET formation. These distinct properties suggest that ATRA-dHL-60 cells may better model neutrophils in chronic inflammation, whereas DMSO-dHL-60 cells could be more suitable for studying NETosis-driven autoimmune, thrombotic disorders and cancer.

Inflammation has received considerable attention in the pathogenesis of type 2 diabetes mellitus (T2DM). Supporting this concept, enhanced expression of interleukin (IL)-1β and increased infiltration of macrophages are observed in pancreatic islets of patients with T2DM. Although IL-1 receptor antagonist (IL-1Ra) plays a major role in controlling of IL-1β-mediated inflammation, its counteraction effects and epigenetic alterations in T2DM are less studied. Thus, we aimed to analyze the DNA methylation status in IL1RN, RELA (p65) and NFKB1 (p50) genes in peripheral blood mononuclear cells (PBMCs) from treated T2DM patients (n = 35) and age-/sex- matched healthy controls (n = 31). Production of IL-1β and IL-1Ra was analyzed in plasma and supernatants from LPS-induced PBMCs. Immunomodulatory effects of IL-1β and IL-1Ra were studied on THP-1 cells. Average DNA methylation level of IL1RN and NFKB1 gene promoters was significantly decreased in T2DM patients in comparison with healthy controls (P< 0.05), which was associated with the increased IL-1Ra (P< 0.001) and IL-1β (P = 0.039) plasma levels in T2DM patients. Negative association between average methylation of IL1RN gene and IL-1Ra plasma levels were observed in female T2DM patients. Methylation of NFKB1 gene was negatively correlated with IL-1Ra levels in the patients and positively with IL-1β levels in female patients. LPS-stimulated PBMCs from female patients failed to raise IL-1β production, while the cells from healthy females increased IL-1β production in comparison with unstimulated cells (P< 0.001). Taken together, the findings suggest that hypomethylation of IL1RN and NFKB1 gene promoters may promote the increased IL-1β/IL-1Ra production and regulate chronic inflammation in T2DM. Further studies are necessary to elucidate the causal direction of these associations and potential role of IL-1Ra in anti-inflammatory processes in treated patients with T2DM.

Chronic hyperglycemia can contribute to metabolic disorders, disrupting cellular homeostasis and potentially leading to immunological disturbances. As highly adaptable innate immune cells, macrophages can effectively utilize glucose for energy and adjust their activities in response to environmental changes. We hypothesized that hyperglycemia induces distinct effects on M1 and M2 macrophages, thereby promoting their divergent roles in the inflammatory response. For this, we applied an in vitro hyperglycemia model to investigate its impact on M1- and M2-like macrophages differentiated from primary monocytes. M1-like macrophages exhibited diminished capacity to produce reactive oxygen species (ROS), IL-6, TNF-α, as well as reduced antigen presentation and co-stimulatory abilities under long exposure to high glucose. In contrast, M2-like macrophages showed a shift toward M1 polarization, characterized by increased production of ROS and IL-6, upregulation of CD86 and HLA-DR expression, and reduced reparative abilities. We also observed disturbance of endotoxin tolerance evidenced by increased production of TNF-α and diminished phagocytic ability. The results suggest that hyperglycemia disrupts the typical functional dichotomy of M1 and M2 macrophages, which may explain mixed polarization of tissue macrophages in individuals with metabolic syndromes associated with chronic hyperglycemia.

Fas/Fas ligand system was shown to be related to insulin resistance and type 2 diabetes mellitus (T2DM). However, the role of soluble Fas ligand (sFasL) in functioning of immune cells in type 2 diabetes mellitus (T2DM) has not been studied yet. The aim of the present study was to determine in vitro effects of sFasL on neutrophil activation and apoptosis. We demonstrate here that sFasL exhibited proinflammatory effect and induced mRNA levels of caspase-1, NF-κB, IL-1β and CD18 expression. At the same time, sFasL induced reactive oxygen species (ROS) production. Activation of caspase-1 activity abolished sFasL-dependent apoptosis, and suppressed Fas expression and mRNA levels of caspase-3 in neutrophils from T2DM patients. Collectively, our findings identify a novel proinflammatory role of sFasL in T2DM neutrophils that is dependent of caspase activity. Thus, sFasL enhances inflammatory response of neutrophils from T2DM patients without increasing apoptosis suggesting its triggering role in T2DM inflammation.

Familial Mediterranean fever (FMF) is caused by pyrin-encoding MEFV gene mutations and characterized by the self-limiting periods of intense inflammation, which are mainly mediated by a massive influx of polymorphonuclear neutrophils (PMNs) into the inflamed sites. Perturbation of actin polymerization by different pathogens was shown to activate the pyrin inflammasome. Our aim was to test whether cytoskeletal dynamics in the absence of pathogens may cause abnormal activation of PMNs from FMF patients. We also aimed to characterize immunophenotypes of circulating neutrophils and their functional activity. Circulating PMNs displayed heterogeneity in terms of cell size, granularity and immunophenotypes. Particularly, PMNs from the patients in acute flares (FMF-A) exhibited a characteristic of aged/activated cells (small cell size and granularity, up-regulated CXCR4), while PMNs form the patients in remission period (FMF-R) displayed mixed fresh/aged cell characteristics (normal cell size and granularity, up-regulated CD11b, CD49d, CXCR4, and CD62L). The findings may suggest that sterile tissue-infiltrated PMNs undergo reverse migration back to bone marrow and may explain why these PMNs do not cause immune-mediated tissue damage. A multidirectional expression of FcγRs on neutrophils during acute flares was also noteworthy: up-regulation of FcγRI and down-regulation of FcγRII/FcγRIII. We also observed spontaneous and fMPL-induced activation of PMNs from the patients after transmigration through inserts as seen by the increased expression of CD11b and intracellular expression of IL-1β. Our study suggests heightened sensitivity of mutated pyrin inflammasome towards cytoskeletal modifications in the absence of pathogens.

Antiphospholipid syndrome (APS) is associated with recurrent pregnancy morbidity, yet the underlying mechanisms remain elusive. We performed multifaceted characterization of the biological and transcriptomic signatures of mouse placenta and uterine natural killer (uNK) cells in APS. Histological analysis of APS placentas unveiled placental abnormalities, including disturbed angiogenesis, occasional necrotic areas, fibrin deposition, and nucleated red blood cell enrichment. Analyses of APS placentas showed a reduced cell proliferation, lower protein content and thinning of endothelial cells. Disturbances in APS trophoblast cells were linked to a cell cycle shift in cytotrophoblast cells, and a reduced number of spiral artery-associated trophoblast giant cells (SpA-TGC). Transcriptomic profiling of placental tissue highlighted disruptions in cell cycle regulation with notable downregulation of genes involved in developmental or signaling processes. Cellular senescence, metabolic and p53-related pathways were also enriched, suggesting potential mechanisms underlying placental dysfunction in APS. Thrombotic events, though occasionally detected, appeared to have no significant impact on the overall pathological changes. The increased number of dysfunctional uNK cells was not associated with enhanced cytotoxic capabilities. Transcriptomic data corroborated these findings, showing prominent suppression of NK cell secretory capacity and cytokine signaling pathways. Our study highlights the multifactorial nature of APS-associated placental pathologies, which involve disrupted angiogenesis, cell cycle regulation, and NK cell functionality.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are frequently occurring multifactorial diseases affecting joints. OA and RA may share not only tissue locations but also some molecular mechanisms. We compared different pathologies: anti-cyclic citrullinated peptide antibody (ACCP)-positive RA—the classical ‘antigen-driven’ pathology, starting in synovia with no signs of inflammatory process; ACCP-negative RA, starting with synovial inflammation triggered by nonspecific factors, which becomes a chronic process due to inherited innate immune peculiarities; and OA, starting with inadequate chondrocyte functioning and cartilage degradation with inflammation as a driving force. Notable coincidences in RA and OA development were revealed: shared mutations of 29 genes encoding molecules involved in immune-inflammatory processes and in ECM production; unidirectional association of OA and ACCP-negative RA with non-genetic triggers; and overactivation of signaling pathways with the same consequences for RA and OA. Innate and adaptive immune responses were involved in OA development. Similar to that observed in RA, lymphoid nodular aggregates were revealed in 30% of OA synovia. Myeloid, and especially pauci-immune and fibroid synovial pathotypes, are possible in OA. Indistinguishable from that in RA, pannuses were found in OA articular tissues. Thus, these coincidences may be evidence of evolution of some OA variants in RA.