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Scandinavian Journal of Immunology Apr 2021SARS-CoV-2 is a novel human coronavirus responsible for the Coronavirus disease 2019 (COVID-19) pandemic. Pneumonia and acute respiratory distress syndrome are the major... (Review)
Review
SARS-CoV-2 is a novel human coronavirus responsible for the Coronavirus disease 2019 (COVID-19) pandemic. Pneumonia and acute respiratory distress syndrome are the major complications of COVID-19. SARS-CoV-2 infection can activate innate and adaptive immune responses and result in massive inflammatory responses later in the disease. These uncontrolled inflammatory responses may lead to local and systemic tissue damage. In patients with severe COVID-19, eosinopenia and lymphopenia with a severe reduction in the frequency of CD4+ and CD8+ T cells, B cells and natural killer (NK) cells are a common feature. COVID-19 severity hinges on the development of cytokine storm characterized by elevated serum levels of pro-inflammatory cytokines. Moreover, IgG-, IgM- and IgA-specific antibodies against SARS-CoV-2 can be detected in most patients, along with the viral RNA, forming the basis for assays that aid in patient diagnosis. Elucidating the immunopathological outcomes due to COVID-19 could provide potential targets for immunotherapy and are important for choosing the best clinical management by consultants. Currently, along with standard supportive care, therapeutic approaches to COVID-19 treatment involve the use of antiviral agents that interfere with the SARS-CoV-2 lifecycle to prevent further viral replication and utilizing immunomodulators to dampen the immune system in order to prevent cytokine storm and tissue damage. While current therapeutic options vary in efficacy, there are several molecules that were either shown to be effective against other viruses such as HIV or show promise in vitro that could be added to the growing arsenal of agents used to control COVID-19 severity and spread.
Topics: Antiviral Agents; COVID-19; COVID-19 Serological Testing; Cytokine Release Syndrome; Humans; Immunologic Factors; Lymphopenia; Pandemics; Respiratory Distress Syndrome; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment
PubMed: 33190302
DOI: 10.1111/sji.12998 -
Circulation Aug 2018The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that antagonism of interleukin (IL)-1β reduces coronary heart disease in patients with a...
BACKGROUND
The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that antagonism of interleukin (IL)-1β reduces coronary heart disease in patients with a previous myocardial infarction and evidence of systemic inflammation, indicating that pathways required for IL-1β secretion increase cardiovascular risk. IL-1β and IL-18 are produced via the NLRP3 inflammasome in myeloid cells in response to cholesterol accumulation, but mechanisms linking NLRP3 inflammasome activation to atherogenesis are unclear. The cholesterol transporters ATP binding cassette A1 and G1 (ABCA1/G1) mediate cholesterol efflux to high-density lipoprotein, and Abca1/g1 deficiency in myeloid cells leads to cholesterol accumulation.
METHODS
To interrogate mechanisms connecting inflammasome activation with atherogenesis, we used mice with myeloid Abca1/g1 deficiency and concomitant deficiency of the inflammasome components Nlrp3 or Caspase-1/11. Bone marrow from these mice was transplanted into Ldlr recipients, which were fed a Western-type diet.
RESULTS
Myeloid Abca1/g1 deficiency increased plasma IL-18 levels in Ldlr mice and induced IL-1β and IL-18 secretion in splenocytes, which was reversed by Nlrp3 or Caspase-1/11 deficiency, indicating activation of the NLRP3 inflammasome. Nlrp3 or Caspase-1/11 deficiency decreased atherosclerotic lesion size in myeloid Abca1/g1-deficient Ldlr mice. Myeloid Abca1/g1 deficiency enhanced caspase-1 cleavage not only in splenic monocytes and macrophages, but also in neutrophils, and dramatically enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques, with reversal by Nlrp3 or Caspase-1/11 deficiency, suggesting that inflammasome activation promotes neutrophil recruitment and neutrophil extracellular trap formation in atherosclerotic plaques. These effects appeared to be indirectly mediated by systemic inflammation leading to activation and accumulation of neutrophils in plaques. Myeloid Abca1/g1 deficiency also activated the noncanonical inflammasome, causing increased susceptibility to lipopolysaccharide-induced mortality. Patients with Tangier disease, who carry loss-of-function mutations in ABCA1 and have increased myeloid cholesterol content, showed a marked increase in plasma IL-1β and IL-18 levels.
CONCLUSIONS
Cholesterol accumulation in myeloid cells activates the NLRP3 inflammasome, which enhances neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques. Patients with Tangier disease, who have increased myeloid cholesterol content, showed markers of inflammasome activation, suggesting human relevance.
Topics: ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; Animals; Atherosclerosis; Case-Control Studies; Caspase 1; Caspases; Caspases, Initiator; Cholesterol; Cytokines; Disease Models, Animal; Extracellular Traps; Humans; Inflammasomes; Inflammation; Mice, Knockout; Myeloid Cells; NLR Family, Pyrin Domain-Containing 3 Protein; Plaque, Atherosclerotic; Receptors, LDL; Spleen; Tangier Disease
PubMed: 29588315
DOI: 10.1161/CIRCULATIONAHA.117.032636 -
Frontiers in Immunology 2022Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infections and regulates the innate and acquired immune response. IL-18 is... (Review)
Review
Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infections and regulates the innate and acquired immune response. IL-18 is produced by both hematopoietic and non-hematopoietic cells, including monocytes, macrophages, keratinocytes and mesenchymal cell. IL-18 could potentially induce inflammatory and cytotoxic immune cell activities leading to autoimmunity. Its elevated levels have been reported in the blood of patients with some immune-related diseases, including rheumatoid arthritis, systemic lupus erythematosus, type I diabetes mellitus, atopic dermatitis, psoriasis, and inflammatory bowel disease. In the present review, we aimed to summarize the biological properties of IL-18 and its pathological role in different autoimmune diseases. We also reported some monoclonal antibodies and drugs targeting IL-18. Most of these monoclonal antibodies and drugs have only produced partial effectiveness or complete ineffectiveness , and human studies. The ineffectiveness of these drugs targeting IL-18 may be largely due to the loophole caused by the involvement of other cytokines and proteins in the signaling pathway of many inflammatory diseases besides the involvement of IL-18. Combination drug therapies, that focus on IL-18 inhibition, in addition to other cytokines, are highly recommended to be considered as an important area of research that needs to be explored.
Topics: Antibodies, Monoclonal; Autoimmune Diseases; Cytokines; Humans; Immunity; Inflammation; Interleukin-18
PubMed: 36032110
DOI: 10.3389/fimmu.2022.919973 -
Journal of Atherosclerosis and... Aug 2021Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a... (Review)
Review
Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings are orange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available, so early identification of patients and preventing atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally, treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells has occasionally been reported.
Topics: Disease Management; Humans; Japan; Tangier Disease
PubMed: 33994407
DOI: 10.5551/jat.RV17053 -
JPMA. the Journal of the Pakistan... May 2022'Lipokathexis' is derived from the term 'Lipo' meaning fat and 'kathexis' which means retention. We propose this name for describing a clinical situation wherein despite...
'Lipokathexis' is derived from the term 'Lipo' meaning fat and 'kathexis' which means retention. We propose this name for describing a clinical situation wherein despite excessive stores of fat are noted in the body but lower levels of circulating lipids are present in the blood. Different disease conditions that express such a phenotype including Tangier's disease, metabolic healthy obesity and those coming under the domain of obesity paradox have been described in this manuscript. This paper will invoke the readers interest on different facets of lipid metabolism in context of metabolic medicine and explore this concept of "Fat Paradox".
Topics: Humans; Obesity
PubMed: 35713075
DOI: 10.47391/JPMA.22-65 -
Journal of Neuromuscular Diseases 2021Generally, neuropathies of peripheral nerves are a frequent condition (prevalence 2-3%) and most frequently due to alcoholism, diabetes, renal insufficiency, malignancy,... (Review)
Review
OBJECTIVES
Generally, neuropathies of peripheral nerves are a frequent condition (prevalence 2-3%) and most frequently due to alcoholism, diabetes, renal insufficiency, malignancy, toxins, or drugs. However, the vast majority of neuropathies has orphan status. This review focuses on the etiology, frequency, diagnosis, and treatment of orphan neuropathies.
METHODS
Literature reviewResults:Rareness of diseases is not uniformly defined but in the US an orphan disease is diagnosed if the prevalence is <1:200000, in Europe if <5:10000. Most acquired and hereditary neuropathies are orphan diseases. Often the causative variant has been reported only in a single patient or family, particularly the ones that are newly detected (e.g. SEPT9, SORD). Among the complex neuropathies (hereditary multisystem disorders with concomitant neuropathies) orphan forms have been reported among mitochondrial disorders (e.g. NARP, MNGIE, SANDO), spinocerebellar ataxias (e.g. TMEM240), hereditary spastic paraplegias (e.g UBAP1), lysosomal storage disease (e.g. Schindler disease), peroxisomal disorders, porphyrias, and other types (e.g. giant axonal neuropathy, Tangier disease). Orphan acquired neuropathies include the metabolic neuropathies (e.g. vitamin-B1, folic acid), toxic neuropathies (e.g. copper, lithium, lead, arsenic, thallium, mercury), infectious neuropathies, immune-mediated (e.g. Bruns-Garland syndrome), and neoplastic/paraneoplastic neuropathies.
CONCLUSIONS
Though orphan neuropathies are rare per definition they constitute the majority of neuropathies and should be considered as some of them are easy to identify and potentially treatable, as clarification of the underlying cause may contribute to the knowledge about etiology and pathophysiology of these conditions, and as the true prevalence may become obvious only if all ever diagnosed cases are reported.
Topics: Humans; Peripheral Nervous System Diseases; Rare Diseases
PubMed: 32986679
DOI: 10.3233/JND-200518 -
Scandinavian Journal of Immunology May 2021T helper 22 (Th22) cell populations are a newly identified subset of CD4 T cells that primarily mediate biological effects on the epithelial barrier through... (Review)
Review
T helper 22 (Th22) cell populations are a newly identified subset of CD4 T cells that primarily mediate biological effects on the epithelial barrier through interleukin (IL)-22. Although, new studies showed that both Th22 and IL-22 are closely associated with the pathogenesis of inflammatory, autoimmune and allergic disease as well as malignancies. In this review, we aim to describe the development and characteristics of Th22 cells as well as their roles in the immunopathogenesis of immune-related disorders and cancer.
Topics: Autoimmune Diseases; Humans; Hypersensitivity; Inflammation; Interleukins; Lymphocyte Subsets; Neoplasms; T-Lymphocytes, Helper-Inducer; Interleukin-22
PubMed: 33576072
DOI: 10.1111/sji.13030