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Critical Care (London, England) Feb 2023Sepsis and septic shock remain drivers for morbidity and mortality in critical illness. The clinical picture of patients presenting with these syndromes evolves rapidly... (Review)
Review
Sepsis and septic shock remain drivers for morbidity and mortality in critical illness. The clinical picture of patients presenting with these syndromes evolves rapidly and may be characterised by: (a) microbial host invasion, (b) establishment of an infection focus, (c) opsonisation of bacterial products (e.g. lipopolysaccharide), (d) recognition of pathogens resulting in an immune response, (e) cellular and humoral effects of circulating pathogen and pathogen products, (f) immunodysregulation and endocrine effects of cytokines, (g) endothelial and organ damage, and (h) organ crosstalk and multiple organ dysfunction. Each step may be a potential target for a specific therapeutic approach. At various stages, extracorporeal therapies may target circulating molecules for removal. In sequence, we could consider: (a) pathogen removal from the circulation with affinity binders and cartridges (specific), (b) circulating endotoxin removal by haemoperfusion with polymyxin B adsorbers (specific), (c) cytokine removal by haemoperfusion with sorbent cartridges or adsorbing membranes (non-specific), (d) extracorporeal organ support with different techniques for respiratory and cardiac support (CO removal or extracorporeal membrane oxygenation), and renal support (haemofiltration, haemodialysis, or ultrafiltration). The sequence of events and the use of different techniques at different points for specific targets will likely require trials with endpoints other than mortality. Instead, the primary objectives should be to achieve the desired action by using extracorporeal therapy at a specific point.
Topics: Humans; Endotoxins; Hemoperfusion; Polymyxin B; Sepsis; Shock, Septic; Extracorporeal Membrane Oxygenation
PubMed: 36750878
DOI: 10.1186/s13054-023-04310-2 -
Frontiers in Cellular and Infection... 2022Host innate and adaptive immunity to infection with is critically dependent on the complement system, demonstrated by the high incidence of invasive infection in... (Review)
Review
Host innate and adaptive immunity to infection with is critically dependent on the complement system, demonstrated by the high incidence of invasive infection in people with inherited deficiency of complement components. The complement system is activated by through multiple mechanisms. The classical complement pathway is activated by recognition of by C-reactive protein, serum amyloid P, C1q, SIGN-R1, or natural or acquired antibody. Some strains are also recognised by ficolins to activate the mannose binding lectin (MBL) activation pathway. Complement activation is then amplified by the alternative complement pathway, which can also be activated by directly. Complement activation results in covalent linkage of the opsonic complement factors C3b and iC3b to the surface which promote phagocytic clearance, along with complement-mediated immune adherence to erythrocytes, thereby protecting against septicaemia. The role of complement for mucosal immunity to is less clear. Given the major role of complement in controlling infection with , it is perhaps unsurprising that has evolved multiple mechanisms of complement evasion, including the capsule, multiple surface proteins, and the toxin pneumolysin. There is considerable variation between capsular serotypes and genotypes with regards to sensitivity to complement which correlates with ability to cause invasive infections. However, at present we only have a limited understanding of the main mechanisms causing variations in complement sensitivity between strains and to non-pathogenic streptococci.
Topics: Complement Activation; Complement System Proteins; Humans; Streptococcus pneumoniae
PubMed: 35967850
DOI: 10.3389/fcimb.2022.929483 -
Cell Aug 2021Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial...
Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.
Topics: Adolescent; Basic Helix-Loop-Helix Transcription Factors; Child; Child, Preschool; Erythroblasts; Erythrocytes; Erythropoiesis; Humans; Interferon Type I; Lupus Erythematosus, Systemic; Mitochondria; Mitophagy; Myeloid Cells; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 34384544
DOI: 10.1016/j.cell.2021.07.021 -
Frontiers in Neurology 2023Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD) is a spectrum of diseases, including optic neuritis, transverse myelitis, acute disseminated... (Review)
Review
Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD) is a spectrum of diseases, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, and cerebral cortical encephalitis. In addition to distinct clinical, radiological, and immunological features, the infectious prodrome is more commonly reported in MOGAD (37-70%) than NMOSD (15-35%). Interestingly, pediatric MOGAD is not more aggressive than adult-onset MOGAD, unlike in multiple sclerosis (MS), where annualized relapse rates are three times higher in pediatric-onset MS. MOGAD pathophysiology is driven by acute attacks during which T cells and MOG antibodies cross blood brain barrier (BBB). MOGAD lesions show a perivenous confluent pattern around the small veins, lacking the radiological central vein sign. Initial activation of T cells in the periphery is followed by reactivation in the subarachnoid/perivascular spaces by MOG-laden antigen-presenting cells and inflammatory CSF milieu, which enables T cells to infiltrate CNS parenchyma. CD4+ T cells, unlike CD8+ T cells in MS, are the dominant T cell type found in lesion histology. Granulocytes, macrophages/microglia, and activated complement are also found in the lesions, which could contribute to demyelination during acute relapses. MOG antibodies potentially contribute to pathology by opsonizing MOG, complement activation, and antibody-dependent cellular cytotoxicity. Stimulation of peripheral MOG-specific B cells through TLR stimulation or T follicular helper cells might help differentiate MOG antibody-producing plasma cells in the peripheral blood. Neuroinflammatory biomarkers (such as MBP, sNFL, GFAP, Tau) in MOGAD support that most axonal damage happens in the initial attack, whereas relapses are associated with increased myelin damage.
PubMed: 36925938
DOI: 10.3389/fneur.2023.1137998 -
Frontiers in Immunology 2021
Topics: Animals; Complement System Proteins; Humans; Nerve Regeneration; Nervous System; Neurogenesis; Neuroimmunomodulation; Signal Transduction
PubMed: 34040618
DOI: 10.3389/fimmu.2021.694810 -
Frontiers in Cellular and Infection... 2022Leishmaniasis presents different types of clinical manifestations that can be divided into cutaneous leishmaniasis and visceral leishmaniasis. The host's immune system,... (Review)
Review
Leishmaniasis presents different types of clinical manifestations that can be divided into cutaneous leishmaniasis and visceral leishmaniasis. The host's immune system, associated with genetic and nutritional factors, is strongly involved in the evolution of the disease or parasite escape. Humoral immunity is characterized by the production of antibodies capable of promoting neutralization, opsonization, and activation of the complement system. In this scenario, B lymphocytes produce antibodies that play an important role in Leishmania infection although neglected for a long time. Thus, relevant aspects in the establishment of Leishmania infection will be addressed, highlighting the importance of humoral immunity during the entire process of Leishmania infection.
Topics: Humans; Leishmaniasis; Leishmaniasis, Visceral; Leishmaniasis, Cutaneous; Immunity, Humoral; Antibodies
PubMed: 36579347
DOI: 10.3389/fcimb.2022.1063291 -
Nanomaterials (Basel, Switzerland) Jul 2022Gold nanoparticles (AuNPs) are continuing to gain popularity in the field of nanotechnology. New methods are continuously being developed to tune the particles'... (Review)
Review
Gold nanoparticles (AuNPs) are continuing to gain popularity in the field of nanotechnology. New methods are continuously being developed to tune the particles' physicochemical properties, resulting in control over their biological fate and applicability to in vivo diagnostics and therapy. This review focuses on the effects of varying particle size on optical properties, opsonization, cellular internalization, renal clearance, biodistribution, tumor accumulation, and toxicity. We review the common methods of synthesizing ultrasmall AuNPs, as well as the emerging constructs termed ultrasmall-in-nano-an approach which promises to provide the desirable properties from both ends of the AuNP size range. We review the various applications and outcomes of ultrasmall-in-nano constructs in vitro and in vivo.
PubMed: 35889699
DOI: 10.3390/nano12142476 -
HemaSphere Jun 2021Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. Although the... (Review)
Review
Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. Although the primary triggering factors of ITP remain unknown, a loss of immune tolerance-mostly represented by a regulatory T-cell defect-allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcγRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. Moreover, the activation of the classical complement pathway participates to platelet opsonization and also to their destruction by complement-dependent cytotoxicity. Platelet destruction is also mediated by a FcγR-independent pathway, involving platelet desialylation that favors their binding to the Ashwell-Morell receptor and their clearance in the liver. Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets. The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes. The better understanding of ITP pathogenesis has provided important therapeutic advances. B cell-targeting therapies and thrombopoietin-receptor agonists (TPO-RAs) have been used for years. New emerging therapeutic strategies that inhibit FcγR signaling, the neonatal Fc receptor or the classical complement pathway, will deeply modify the management of ITP in the near future.
PubMed: 34095758
DOI: 10.1097/HS9.0000000000000574