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Annual Review of Medicine Jan 2023Cytokine storm syndrome (CSS), which is frequently fatal, has garnered increased attention with the ongoing coronavirus pandemic. A variety of hyperinflammatory... (Review)
Review
Cytokine storm syndrome (CSS), which is frequently fatal, has garnered increased attention with the ongoing coronavirus pandemic. A variety of hyperinflammatory conditions associated with multiorgan system failure can be lumped under the CSS umbrella, including familial hemophagocytic lymphohistiocytosis (HLH) and secondary HLH associated with infections, hematologic malignancies, and autoimmune and autoinflammatory disorders, in which case CSS is termed macrophage activation syndrome (MAS). Various classification and diagnostic CSS criteria exist and include clinical, laboratory, pathologic, and genetic features. Familial HLH results from cytolytic homozygous genetic defects in the perforin pathway employed by cytotoxic CD8 T lymphocytes and natural killer (NK) cells. Similarly, NK cell dysfunction is often present in secondary HLH and MAS, and heterozygous mutations in familial HLH genes are frequently present. Targeting overly active lymphocytes and macrophages with etoposide and glucocorticoids is the standard for treating HLH; however, more targeted and safer anticytokine (e.g., anti-interleukin-1, -6) approaches are gaining traction as effective alternatives.
Topics: Humans; Cytokine Release Syndrome; Macrophage Activation Syndrome; Lymphohistiocytosis, Hemophagocytic; Killer Cells, Natural; Macrophages
PubMed: 36228171
DOI: 10.1146/annurev-med-042921-112837 -
International Journal of Molecular... Jun 2021Eosinophils are specialized white blood cells, which are involved in the pathology of diverse allergic and nonallergic inflammatory diseases. Eosinophils are... (Review)
Review
Eosinophils are specialized white blood cells, which are involved in the pathology of diverse allergic and nonallergic inflammatory diseases. Eosinophils are traditionally known as cytotoxic effector cells but have been suggested to additionally play a role in immunomodulation and maintenance of homeostasis. The exact role of these granule-containing leukocytes in health and diseases is still a matter of debate. Degranulation is one of the key effector functions of eosinophils in response to diverse stimuli. The different degranulation patterns occurring in eosinophils (piecemeal degranulation, exocytosis and cytolysis) have been extensively studied in the last few years. However, the exact mechanism of the diverse degranulation types remains unknown and is still under investigation. In this review, we focus on recent findings and highlight the diversity of stimulation and methods used to evaluate eosinophil degranulation.
Topics: Cell Degranulation; Eosinophils; Extracellular Traps; Humans; Hypersensitivity
PubMed: 34209362
DOI: 10.3390/ijms22137091 -
Life Sciences Dec 2022Eosinophils are multitasking granulocytes with implications for allergies, host response to helminths and, more recently, described roles in immunomodulation,... (Review)
Review
Eosinophils are multitasking granulocytes with implications for allergies, host response to helminths and, more recently, described roles in immunomodulation, homeostasis and tissue remodeling. Eosinophils secrete their preformed granule proteins by different pathways, especially piecemeal degranulation and cytolysis with granule release. Currently, there are different insights related to eosinophils' functional roles and biology that deserve to be highlighted. Cytolysis with granule release has also been associated with DNA extracellular trap formation, one of the most intriguing, recently described mechanisms of leukocyte activation. Focusing on DNA extracellular trap release, there are lessons to be learned from neutrophils considering the multitasking roles of these structures in inflammation, and the mechanisms involved in their release. This review explores a comparative analysis of the current knowledge considering DNA traps extrusion in neutrophils and eosinophils and update the major findings regarding the presence of these entities in eosinophilic-associated immune responses, inflammation and diseases.
Topics: Humans; Eosinophils; Extracellular Traps; Leukocyte Count; Inflammation; DNA
PubMed: 36379309
DOI: 10.1016/j.lfs.2022.121191 -
International Journal of Medical... Mar 2014PSMs are a recently discovered family of short, amphipathic, α-helical peptides in staphylococci. Several PSMs are key virulence determinants, particularly in highly... (Review)
Review
PSMs are a recently discovered family of short, amphipathic, α-helical peptides in staphylococci. Several PSMs are key virulence determinants, particularly in highly virulent Staphylococcus aureus strains. PSMα peptides of S. aureus facilitate neutrophil lysis after phagocytosis, and are key contributors to several infection types, including skin infection and bacteremia. Furthermore, all PSMs contribute to biofilm structuring and the dissemination of biofilm-associated infection. Cytolytic PSMs as produced by S. aureus appear to have evolved from original functions in the non-infectious lifestyle of staphylococci. The surfactant properties of PSMs, which they all share, are believed to facilitate growth on epithelial surfaces. The basic role of PSMs in staphylococcal physiology is underscored, for example, by their exceptionally strict and direct control by quorum-sensing and the presence of a dedicated secretion system. Targeting PSMs for anti-staphylococcal drug development may be a promising approach to overcome the problems associated with widespread antibiotic resistance in staphylococci.
Topics: Animals; Bacterial Toxins; Biofilms; Humans; Staphylococcus; Surface-Active Agents; Virulence Factors
PubMed: 24447915
DOI: 10.1016/j.ijmm.2013.11.019 -
Cells Jun 2022The presence of eosinophils in the airway is associated with asthma severity and risk of exacerbations. Eosinophils deposit their damaging products in airway tissue,...
The presence of eosinophils in the airway is associated with asthma severity and risk of exacerbations. Eosinophils deposit their damaging products in airway tissue, likely by degranulation and cytolysis. We previously showed that priming blood eosinophils with IL3 strongly increased their cytolysis on aggregated IgG. Conversely, IL5 priming did not result in significant eosinophil cytolysis in the same condition. Therefore, to identify critical events protecting eosinophils from cell cytolysis, we examined the differential intracellular events between IL5- and IL3-primed eosinophils interacting with IgG. We showed that both IL3 and IL5 priming increased the eosinophil adhesion to IgG, phosphorylation of p38, and production of reactive oxygen species (ROS), and decreased the phosphorylation of cofilin. However, autophagic flux as measured by the quantification of SQSTM1-p62 and lipidated-MAP1L3CB over time on IgG, with or without bafilomycin-A1, was higher in IL5-primed compared to IL3-primed eosinophils. In addition, treatment with bafilomycin-A1, an inhibitor of granule acidification and autophagolysosome formation, enhanced eosinophil cytolysis and DNA trap formation in IL5-primed eosinophils. Therefore, this study suggests that increased autophagy in eosinophils protects from cytolysis and the release of DNA, and thus limits the discharge of damaging intracellular eosinophilic contents.
Topics: Autophagy; DNA; Eosinophils; Immunoglobulin G; Interleukin-5
PubMed: 35681515
DOI: 10.3390/cells11111821 -
Immunological Reviews Mar 2023Neutrophils or polymorphonuclear neutrophils (PMNs) are an important component of innate host defense. These phagocytic leukocytes are recruited to infected tissues and... (Review)
Review
Neutrophils or polymorphonuclear neutrophils (PMNs) are an important component of innate host defense. These phagocytic leukocytes are recruited to infected tissues and kill invading microbes. There are several general characteristics of neutrophils that make them highly effective as antimicrobial cells. First, there is tremendous daily production and turnover of granulocytes in healthy adults-typically 10 per day. The vast majority (~95%) of these cells are neutrophils. In addition, neutrophils are mobilized rapidly in response to chemotactic factors and are among the first leukocytes recruited to infected tissues. Most notably, neutrophils contain and/or produce an abundance of antimicrobial molecules. Many of these antimicrobial molecules are toxic to host cells and can destroy host tissues. Thus, neutrophil activation and turnover are highly regulated processes. To that end, aged neutrophils undergo apoptosis constitutively, a process that contains antimicrobial function and proinflammatory capacity. Importantly, apoptosis facilitates nonphlogistic turnover of neutrophils and removal by macrophages. This homeostatic process is altered by interaction with microbes and their products, as well as host proinflammatory molecules. Microbial pathogens can delay neutrophil apoptosis, accelerate apoptosis following phagocytosis, or cause neutrophil cytolysis. Here, we review these processes and provide perspective on recent studies that have potential to impact this paradigm.
Topics: Humans; Aged; Neutrophils; Phagocytosis; Apoptosis; Cell Death; Anti-Infective Agents
PubMed: 36345955
DOI: 10.1111/imr.13163 -
Journal of Family & Reproductive Health Jun 2022In women's health, clinicians are often faced with diagnosing and administering treatment to patients who present with an increased vaginal discharge without much other... (Review)
Review
In women's health, clinicians are often faced with diagnosing and administering treatment to patients who present with an increased vaginal discharge without much other information to work with. It's only once a patient's background is reviewed and lab work is completed that two common reasons behind vaginal discharge with similar symptoms, Lactobacillosis and Cytolytic Vaginitis, can be differentiated and a proper diagnosis can be reached. Now, we understand that Lactobacillosis and Cytolytic Vaginitis are symptomatically confused by patients as well as inexperienced clinicians. Lactobacillosis involves the presence of abnormal, extremely long Lactobacilli, a keystone species for vaginal health, while Cytolytic Vaginitis mainly involves, increased Lactobacilli, pH between 3.5 and 4.5, presence of cytolysis, and a lowered white blood cell count. Both present with similar discharge, leading to their conflation. A microscopic examination of the discharge using a wet mount with normal saline can provide 80% diagnostic sensitivity until further testing can be completed.
PubMed: 36457655
DOI: 10.18502/jfrh.v16i2.9477 -
Frontiers in Immunology 2018Agnathans (lamprey and hagfish) are a group of primitive jawless fish. Jawed vertebrates possess adaptive immunity including immunoglobulins, while agnathans lack... (Review)
Review
Agnathans (lamprey and hagfish) are a group of primitive jawless fish. Jawed vertebrates possess adaptive immunity including immunoglobulins, while agnathans lack immunoglobulins but have alternative adaptive immunity in which variable lymphocyte receptors (VLRs) function as antibodies. The complement system consists of many proteins involved in the elimination of pathogens. In mammals, it is activated the three different pathways, resulting in the generation of C3b followed by the lytic pathway. Complement components including C3, mannose-binding lectin (MBL), and MBL-associated serine proteases (MASP) of the lectin pathway and factor B of the alternative pathway have been identified from lamprey and/or hagfish, while lytic pathway components have not been identified. In mammals, C1q binds to IgM/IgG-antigen complexes and activates the classical pathway in association with C1r and C1s. Lamprey also has C1q (LC1q), but its function differs from that of mammalian C1q. LC1q acts as a lectin and activates C3 in association with MASP the lectin pathway. Furthermore, LC1q may interact with a secreted type of VLR (VLRB) in complex with antigens and mediate activation of C3, potentially MASP, leading to cytolysis. Cytolysis is mediated by a newly identified serum protein named lamprey pore-forming protein (LPFP). In conclusion, lamprey has a complement activation pathway, which could be regarded as the classical pathway and also has a cytolytic system that is distinct from the mammalian lytic pathway. Thus, it appears that the complement system of agnathans is very unique and may have developed independently from jawed vertebrates.
PubMed: 29967624
DOI: 10.3389/fimmu.2018.01405 -
Cureus Apr 2021Leptospirosis is a zoonosis transmitted by an animal vector and caused by the spirochete bacteria Leptospira. Human infection is rare and acquired by exposure to...
Leptospirosis is a zoonosis transmitted by an animal vector and caused by the spirochete bacteria Leptospira. Human infection is rare and acquired by exposure to environmental sources (animal urine, contaminated water, soil, or infected animal tissue). It can have an extremely broad presentation, ranging from asymptomatic to serious illness. We report the case of a 59-year-old man admitted to the hospital with myalgia, fever, and abdominal discomfort. Routine laboratory tests revealed raised inflammatory markers, thrombocytopenia, kidney dysfunction, and hepatic cytolysis and cholestasis. The hypothesis of zoonosis was raised based on symptoms and analytical changes despite the weak epidemiological history to support it. Although leptospira serology tests were negative on admission, a polymerase chain reaction test was requested due to a high degree of suspicion which came back positive. The patient completed eight days of doxycycline with favorable clinical and analytical progression. This case highlights the changing epidemiology of leptospirosis and the importance of having a high degree of suspicion even outside endemic zones. It also highlights the importance of a wise choice of diagnostic tests according to the disease stage.
PubMed: 33968509
DOI: 10.7759/cureus.14295 -
Frontiers in Immunology 2014Eosinophils are tissue-dwelling leukocytes, present in the thymus, and gastrointestinal and genitourinary tracts of healthy individuals at baseline, and recruited, often... (Review)
Review
Eosinophils are tissue-dwelling leukocytes, present in the thymus, and gastrointestinal and genitourinary tracts of healthy individuals at baseline, and recruited, often in large numbers, to allergic inflammatory foci and sites of active tissue repair. The biological significance of eosinophils is vast and varied. In health, eosinophils support uterine and mammary gland development, and maintain bone marrow plasma cells and adipose tissue alternatively activated macrophages, while in response to tissue insult eosinophils function as inflammatory effector cells, and, in the wake of an inflammatory response, promote tissue regeneration, and wound healing. One common mechanism driving many of the diverse eosinophil functions is the regulated and differential secretion of a vast array of eosinophil-derived cytokines. Eosinophils are distinguished from most other leukocytes in that many, if not all, of the over three dozen eosinophil-derived cytokines are pre-synthesized and stored within intracellular granules, poised for very rapid, stimulus-induced secretion. Eosinophils engaged in cytokine secretion in situ utilize distinct pathways of cytokine release that include classical exocytosis, whereby granules themselves fuse with the plasma membrane and release their entire contents extracellularly; piecemeal degranulation, whereby granule-derived cytokines are selectively mobilized into vesicles that emerge from granules, traverse the cytoplasm and fuse with the plasma membrane to release discrete packets of cytokines; and eosinophil cytolysis, whereby intact granules are extruded from eosinophils, and deposited within tissues. In this latter scenario, extracellular granules can themselves function as stimulus-responsive secretory-competent organelles within the tissue. Here, we review the distinctive processes of differential secretion of eosinophil granule-derived cytokines.
PubMed: 25386174
DOI: 10.3389/fimmu.2014.00496