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The Journal of Histochemistry and... Oct 2014Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have... (Review)
Review
Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role.
Topics: Animals; Disease; Humans; Mast Cells; Phenotype
PubMed: 25062998
DOI: 10.1369/0022155414545334 -
Annual Review of Pathology Jan 2022Autoinflammation describes a collection of diverse diseases caused by indiscriminate activation of the immune system in an antigen-independent manner. The rapid... (Review)
Review
Autoinflammation describes a collection of diverse diseases caused by indiscriminate activation of the immune system in an antigen-independent manner. The rapid advancement of genetic diagnostics has allowed for the identification of a wide array of monogenic causes of autoinflammation. While the clinical picture of these syndromes is diverse, it is possible to thematically group many of these diseases under broad categories that provide insight into the mechanisms of disease and therapeutic possibilities. This review covers archetypical examples of inherited autoinflammatory diseases in five major categories: inflammasomopathy, interferonopathy, unfolded protein/cellular stress response, relopathy, and uncategorized. This framework can suggest where future work is needed to identify other genetic causes of autoinflammation, what types of diagnostics need to be developed to care for this patient population, and which options might be considered for novel therapeutic targeting.
Topics: Autoimmune Diseases; Hereditary Autoinflammatory Diseases; Humans; Inflammation; Syndrome
PubMed: 34699263
DOI: 10.1146/annurev-pathmechdis-030121-041528 -
Nature Medicine Jun 2023Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the...
Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the associations of alcohol consumption with 207 diseases in the 12-year China Kadoorie Biobank of >512,000 adults (41% men), including 168,050 genotyped for ALDH2- rs671 and ADH1B- rs1229984 , with >1.1 million ICD-10 coded hospitalized events. At baseline, 33% of men drank alcohol regularly. Among men, alcohol intake was positively associated with 61 diseases, including 33 not defined by the World Health Organization as alcohol-related, such as cataract (n = 2,028; hazard ratio 1.21; 95% confidence interval 1.09-1.33, per 280 g per week) and gout (n = 402; 1.57, 1.33-1.86). Genotype-predicted mean alcohol intake was positively associated with established (n = 28,564; 1.14, 1.09-1.20) and new alcohol-associated (n = 16,138; 1.06, 1.01-1.12) diseases, and with specific diseases such as liver cirrhosis (n = 499; 2.30, 1.58-3.35), stroke (n = 12,176; 1.38, 1.27-1.49) and gout (n = 338; 2.33, 1.49-3.62), but not ischemic heart disease (n = 8,408; 1.04, 0.94-1.14). Among women, 2% drank alcohol resulting in low power to assess associations of self-reported alcohol intake with disease risks, but genetic findings in women suggested the excess male risks were not due to pleiotropic genotypic effects. Among Chinese men, alcohol consumption increased multiple disease risks, highlighting the need to strengthen preventive measures to reduce alcohol intake.
Topics: Adult; Female; Humans; Male; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; East Asian People; Ethanol; Genotype; Gout; Risk Factors; Disease; China
PubMed: 37291211
DOI: 10.1038/s41591-023-02383-8 -
Frontiers in Immunology 2023Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune... (Review)
Review
Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune responses are dynamically altered at different pathogenic stages. Gasdermins (GSDMs) proteins are pore-forming executors in the membrane, subsequently mediating the release of pro-inflammatory mediators and inflammatory cell death. With the increasing research on GSDMs proteins and sepsis, it is believed that GSDMs protein are one of the most promising therapeutic targets in sepsis in the future. A more comprehensive and in-depth understanding of the functions of GSDMs proteins in sepsis is important to alleviate the multi-organ dysfunction and reduce sepsis-induced mortality. In this review, we focus on the function of GSDMs proteins, the molecular mechanism of GSDMs involved in sepsis, and the regulatory mechanism of GSDMs-mediated signaling pathways, aiming to provide novel ideas and therapeutic strategies for the diagnosis and treatment of sepsis.
Topics: Humans; Gasdermins; Sepsis; Cell Death; Inflammation Mediators; Syndrome
PubMed: 38022612
DOI: 10.3389/fimmu.2023.1203687 -
Handbook of Clinical Neurology 2023Dystonia is a hyperkinetic movement disorder with a unique motor phenomenology that can manifest as an isolated clinical syndrome or combined with other neurological... (Review)
Review
Dystonia is a hyperkinetic movement disorder with a unique motor phenomenology that can manifest as an isolated clinical syndrome or combined with other neurological features. This chapter reviews the characteristic features of dystonia phenomenology and the syndromic approach to evaluating the disorders that may allow us to differentiate the isolated and combined syndromes. We also present the most common types of isolated and combined dystonia syndromes. Since accelerated gene discoveries have increased our understanding of the molecular mechanisms of dystonia pathogenesis, we also present isolated and combined dystonia syndromes by shared biological pathways. Examples of these converging mechanisms of the isolated and combined dystonia syndromes include (1) disruption of the integrated response pathway through eukaryotic initiation factor 2 alpha signaling, (2) disease of dopaminergic signaling, (3) alterations in the cerebello-thalamic pathway, and (4) disease of protein mislocalization and stability. The discoveries that isolated and combined dystonia syndromes converge in shared biological pathways will aid in the development of clinical trials and therapeutic strategies targeting these convergent molecular pathways.
Topics: Humans; Dystonia; Syndrome; Dystonic Disorders; Cerebellum; Dopamine
PubMed: 37620082
DOI: 10.1016/B978-0-323-98817-9.00005-3 -
Clinical Immunology (Orlando, Fla.) Sep 2020The interleukin (IL)-2 - IL-2 receptor (IL-2R) pathway is important in immunity, but is also involved in maintenance of self-tolerance. This paradox is further... (Review)
Review
The interleukin (IL)-2 - IL-2 receptor (IL-2R) pathway is important in immunity, but is also involved in maintenance of self-tolerance. This paradox is further complicated by shedding of the IL-2Rα chain, revealing soluble (s)IL-2R. Binding of IL-2 to sIL-2R may either reduce or enhance responses depending on the target cell being involved in immunity or self-tolerance. Since sIL-2R levels are increasingly measured in clinical practice, it is detrimental for clinical interpretation to understand the possible functional impact of IL-2R shedding. In this review the role of the IL-2 - IL-2R pathway is explored and the conflicting results on the function of sIL-2R are summarized. Finally, the added value of measuring sIL-2R in different types of diseases is being elaborated upon in terms of diagnosis, follow-up, and prognosis. Adequate interpretation of results is hampered by the apparent gap in our knowledge about the functional role of sIL-2R in immunity and tolerance.
Topics: Animals; Disease; Health; Humans; Interleukin-2; Receptors, Interleukin-2; Signal Transduction
PubMed: 32619646
DOI: 10.1016/j.clim.2020.108515 -
Annual Review of Cell and Developmental... Oct 2017In metazoans, removal of cells in situ is involved in larval maturation, metamorphosis, and embryonic development. In adults, such cell removal plays a role in the... (Review)
Review
In metazoans, removal of cells in situ is involved in larval maturation, metamorphosis, and embryonic development. In adults, such cell removal plays a role in the homeostatic maintenance of cell numbers and tissue integrity as well as in the response to cell injury and damage. This removal involves uptake of the whole or fragmented target cells into phagocytes. Depending on the organism, these latter may be near-neighbor tissue cells and/or professional phagocytes such as, in vertebrates, members of the myeloid family of cells, especially macrophages. The uptake processes appear to involve specialized and highly conserved recognition ligands and receptors, intracellular signaling in the phagocytes, and mechanisms for ingestion. The recognition of cells destined for this form of removal is critical and, significantly, is distinguished for the most part from the recognition of foreign materials and organisms by the innate and adaptive immune systems. In keeping with the key role of cell removal in maintaining tissue homeostasis, constant cell removal is normally silent, i.e., does not initiate a local tissue reaction. This article discusses these complex and wide-ranging processes in general terms as well as the implications when these processes are disrupted in inflammation, immunity, and disease.
Topics: Animals; Apoptosis; Disease; Homeostasis; Humans; Intracellular Space; Phagocytes; Phagocytosis
PubMed: 28613937
DOI: 10.1146/annurev-cellbio-111315-125315 -
Developmental Medicine and Child... Mar 2024A neurological deterioration in a child presents a significant worry to the family and often a diagnostic challenge to the clinician. A dysregulated immune response is... (Review)
Review
A neurological deterioration in a child presents a significant worry to the family and often a diagnostic challenge to the clinician. A dysregulated immune response is implicated in a wide and growing spectrum of neurological conditions. In this review we consider the current paradigms in which immune-mediated encephalopathies are considered; the development of paediatric specific diagnostic criteria that facilitate early consideration and treatment of immune-mediated conditions and the limitations and potential developments in diagnostic testing. We consider the expanding phenotype of myelin oligodendrocyte glycoprotein antibody, the spectrum of virus-associated encephalopathy syndromes, and the strategies that have been employed to build an evidence base for the management of these rare conditions. Looking forward we explore the potential for advanced molecular investigations to improve our understanding of immune-mediated encephalitides and guide future treatment strategies. Recently characterized immune-mediated central nervous system disorders include new antibodies causing previously recognized phenotypes. Aggregation of conditions with similar clinical triggers, and characterization of unique imaging features in virus-associated encephalopathy syndromes. Immune treatment iscurrently guided by meta-analysis of individualized patient data and/or multi-national consensus.
Topics: Child; Humans; Autoantibodies; Brain Diseases; Encephalitis; Myelin-Oligodendrocyte Glycoprotein; Nervous System Diseases; Syndrome
PubMed: 37438863
DOI: 10.1111/dmcn.15694 -
Brain : a Journal of Neurology Sep 2017Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory syndrome predominantly...
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory syndrome predominantly affecting the brainstem, cerebellum, and spinal cord. Following its initial description, the salient features of CLIPPERS have been confirmed and expanded upon, but the lack of formalized diagnostic criteria has led to reports of patients with dissimilar features purported to have CLIPPERS. We evaluated clinical, radiological and pathological features of patients referred for suspected CLIPPERS and propose diagnostic criteria to discriminate CLIPPERS from non-CLIPPERS aetiologies. Thirty-five patients were evaluated for suspected CLIPPERS. Clinical and neuroimaging data were reviewed by three neurologists to confirm CLIPPERS by consensus agreement. Neuroimaging and neuropathology were reviewed by experienced neuroradiologists and neuropathologists, respectively, both of whom were blinded to the clinical data. CLIPPERS was diagnosed in 23 patients (18 male and five female) and 12 patients had a non-CLIPPERS diagnosis. CLIPPERS patients' median age of onset was 58 years (interquartile range, 24-72) and were followed a median of 44 months (interquartile range 38-63). Non-CLIPPERS patients' median age of onset was 52 years (interquartile range, 39-59) and were followed a median of 27 months (interquartile range, 14-47). Clinical symptoms of gait ataxia, diplopia, cognitive impairment, and facial paraesthesia did not discriminate CLIPPERS from non-CLIPPERS. Marked clinical and radiological corticosteroid responsiveness was observed in CLIPPERS (23/23), and clinical worsening occurred in all 12 CLIPPERS cases when corticosteroids were discontinued. Corticosteroid responsiveness was common but not universal in non-CLIPPERS [clinical improvement (8/12); radiological improvement (2/12); clinical worsening on discontinuation (3/8)]. CLIPPERS patients had brainstem predominant perivascular gadolinium enhancing lesions on magnetic resonance imaging that were discriminated from non-CLIPPERS by: homogenous gadolinium enhancing nodules <3 mm in diameter without ring-enhancement or mass effect, and homogenous T2 signal abnormality not significantly exceeding the T1 enhancement. Brain neuropathology on 14 CLIPPERS cases demonstrated marked CD3-positive T-lymphocyte, mild B-lymphocyte and moderate macrophage infiltrates, with perivascular predominance as well as diffuse parenchymal infiltration (14/14), present in meninges, white and grey matter, associated with variable tissue destruction, astrogliosis and secondary myelin loss. Clinical, radiological and pathological feature define CLIPPERS syndrome and are differentiated from non-CLIPPERS aetiologies by neuroradiological and neuropathological findings.
Topics: Adrenal Cortex Hormones; Adult; Age of Onset; Aged; Encephalitis; Female; Gadolinium; Humans; Inflammation; Magnetic Resonance Imaging; Male; Middle Aged; Retrospective Studies; Syndrome; Young Adult
PubMed: 29050399
DOI: 10.1093/brain/awx200 -
Journal Der Deutschen Dermatologischen... Mar 2021Autoinflammatory syndromes are a steadily growing group of inflammatory diseases caused by abnormal regulations of the innate immune system. The clinical presentation is...
Autoinflammatory syndromes are a steadily growing group of inflammatory diseases caused by abnormal regulations of the innate immune system. The clinical presentation is multifaceted, but recurrent fever, skin involvement, joint inflammation and other systemic symptoms of inflammation are characteristic. In contrast to classic autoimmune diseases, autoantibodies or specific T cells are not involved in the pathogenesis. In fact, innate immunity plays the most important role in autoinflammation. While activation of the innate immune system is usually self-limiting in healthy individuals, mutations and dysregulation can lead to chronic and excessive activation of innate immune responses and to the development of autoinflammatory diseases.
Topics: Autoimmune Diseases; Humans; Immunity, Innate; Inflammation; Syndrome
PubMed: 33620111
DOI: 10.1111/ddg.14332