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Annual Review of Animal Biosciences Feb 2020Immunoglobulins (Igs), as one of the hallmarks of adaptive immunity, first arose approximately 500 million years ago with the emergence of jawed vertebrates. Two events... (Review)
Review
Immunoglobulins (Igs), as one of the hallmarks of adaptive immunity, first arose approximately 500 million years ago with the emergence of jawed vertebrates. Two events stand out in the evolutionary history of Igs from cartilaginous fish to mammals: () the diversification of Ig heavy chain (IgH) genes, resulting in Ig isotypes or subclasses associated with novel functions, and () the diversification of genetic and structural strategies, leading to the creation of the antibody repertoire we know today. This review first gives an overview of the IgH isotypes identified in jawed vertebrates to date and then highlights the implications or applications of five new recent discoveries arising from comparative studies of Igs derived from different vertebrate species.
Topics: Adaptive Immunity; Animals; Antibodies; Evolution, Molecular; Immunoglobulin Heavy Chains; Immunoglobulin Isotypes; Immunoglobulins; Vertebrates
PubMed: 31846352
DOI: 10.1146/annurev-animal-021419-083720 -
Gene Jul 2018The MYH9 gene encodes the heavy chain of non-muscle myosin IIA, a widely expressed cytoplasmic myosin that participates in a variety of processes requiring the... (Review)
Review
The MYH9 gene encodes the heavy chain of non-muscle myosin IIA, a widely expressed cytoplasmic myosin that participates in a variety of processes requiring the generation of intracellular chemomechanical force and translocation of the actin cytoskeleton. Non-muscle myosin IIA functions are regulated by phosphorylation of its 20 kDa light chain, of the heavy chain, and by interactions with other proteins. Variants of MYH9 cause an autosomal-dominant disorder, termed MYH9-related disease, and may be involved in other conditions, such as chronic kidney disease, non-syndromic deafness, and cancer. This review discusses the structure of the MYH9 gene and its protein, as well as the regulation and physiologic functions of non-muscle myosin IIA with particular reference to embryonic development. Moreover, the review focuses on current knowledge about the role of MYH9 variants in human disease.
Topics: Animals; Cell Line; Deafness; Hearing Loss, Sensorineural; Humans; Mice; Molecular Motor Proteins; Mutation; Myosin Heavy Chains; Neoplasms; Nonmuscle Myosin Type IIA; Phosphorylation; Renal Insufficiency, Chronic; Thrombocytopenia
PubMed: 29679756
DOI: 10.1016/j.gene.2018.04.048 -
Journal of the American Society of... Jul 2018Monoclonal gammopathies are characterized by the overproduction of monoclonal Ig (MIg) detectable in the serum or urine resulting from a clonal proliferation of plasma... (Review)
Review
Monoclonal gammopathies are characterized by the overproduction of monoclonal Ig (MIg) detectable in the serum or urine resulting from a clonal proliferation of plasma cells or B lymphocytes. The underlying hematologic conditions range from malignant neoplasms of plasma cells or B lymphocytes, including multiple myeloma and B-cell lymphoproliferative disorders, to nonmalignant small clonal proliferations. The term MGUS implies presence of an MIg in the setting of a "benign" hematologic condition without renal or other end organ damage. The term MGRS was recently introduced to indicate monoclonal gammopathy with MIg-associated renal disease in the absence of hematologic malignancy. Most MIg-associated renal diseases result from the direct deposition of nephrotoxic MIg or its light- or heavy-chain fragments in various renal tissue compartments. Immunofluorescence microscopy is essential to identify the offending MIg and define its tissue distribution. Mass spectrometry is helpful in difficult cases. Conditions caused by direct tissue deposition of MIg include common disorders, such as cast nephropathy, amyloidosis, and MIg deposition diseases, as well as uncommon disorders, such as immunotactoid glomerulopathy, proliferative GN with MIg deposits, light-chain proximal tubulopathy, and the rare entities of crystal-storing histiocytosis and crystalglobulinemia. Indirect mechanisms of MIg-induced renal disease can cause C3 glomerulopathy or thrombotic microangiopathy without tissue MIg deposits. Treatment of MIg-associated renal disease is aimed at eliminating the clonal plasma cell or B-cell population as appropriate. Both the renal and the underlying hematologic disorders influence the management and prognosis of MIg-associated renal diseases.
Topics: Amyloidosis; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Laser Capture Microdissection; Mass Spectrometry; Paraproteinemias; Terminology as Topic
PubMed: 29703839
DOI: 10.1681/ASN.2017121319 -
Science Advances Nov 2021Artificial enzymes have attracted wide interest in disease diagnosis and biotechnology due to high stability, easy synthesis, and cost effectiveness. Unfortunately,...
Artificial enzymes have attracted wide interest in disease diagnosis and biotechnology due to high stability, easy synthesis, and cost effectiveness. Unfortunately, their catalytic rate is limited to surface electron transfer, affecting the catalytic and biological activity. Here, we report an oligomeric nanozyme (O-NZ) with ultrafast electron transfer, achieving ultrahigh catalytic activity. O-NZ shows electron transfer of 1.8 nanoseconds in internal cores and 1.2 picoseconds between core and ligand molecule, leading to ultrahigh superoxidase dismutase–like and glutathione peroxidase–like activity (comparable with natural enzyme, Michaelis constant = 0.87 millimolars). Excitingly, O-NZ can improve the 1-month survival rate of mice with acute brain trauma from 50 to 90% and promote the recovery of long-term neurocognition. Biochemical experiments show that O-NZ can decrease harmful peroxide and superoxide via in vivo catalytic chain reaction and reduce acute neuroinflammation via nuclear factor erythroid-2 related factor 2–mediated up-regulation of heme oxygenase-1 expression.
PubMed: 34757781
DOI: 10.1126/sciadv.abk1210 -
MAbs 2015Linking the heavy chain (HC) and light chain (LC) genes required for monoclonal antibodies (mAb) production on a single cassette using 2A peptides allows control of LC...
Linking the heavy chain (HC) and light chain (LC) genes required for monoclonal antibodies (mAb) production on a single cassette using 2A peptides allows control of LC and HC ratio and reduces non-expressing cells. Four 2A peptides derived from the foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A), respectively, were compared for expression of 3 biosimilar IgG1 mAbs in Chinese hamster ovary (CHO) cell lines. HC and LC were linked by different 2A peptides both in the absence and presence of GSG linkers. Insertion of a furin recognition site upstream of 2A allowed removal of 2A residues that would otherwise be attached to the HC. Different 2A peptides exhibited different cleavage efficiencies that correlated to the mAb expression level. The relative cleavage efficiency of each 2A peptide remains similar for expression of different IgG1 mAbs in different CHO cells. While complete cleavage was not observed for any of the 2A peptides, GSG linkers did enhance the cleavage efficiency and thus the mAb expression level. T2A with the GSG linker (GT2A) exhibited the highest cleavage efficiency and mAb expression level. Stably amplified CHO DG44 pools generated using GT2A had titers 357, 416 and 600 mg/L for the 3 mAbs in shake flask batch cultures. Incomplete cleavage likely resulted in incorrectly processed mAb species and aggregates, which were removed with a chromatin-directed clarification method and protein A purification. The vector and methods presented provide an easy process beneficial for both mAb development and manufacturing.
Topics: Animals; Antibodies, Monoclonal; CHO Cells; Cricetinae; Cricetulus; Humans; Immunoglobulin G; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Peptides; Proteolysis; Recombinant Fusion Proteins; Viral Proteins
PubMed: 25621616
DOI: 10.1080/19420862.2015.1008351 -
Klinicka Onkologie : Casopis Ceske a... 2020Gamma-heavy chain disease is a rare disease, described so far in approximately 150 cases. The aim of this work was laboratory dia-gnostics of immunoglobulin heavy chain...
BACKGROUND
Gamma-heavy chain disease is a rare disease, described so far in approximately 150 cases. The aim of this work was laboratory dia-gnostics of immunoglobulin heavy chain disease.
MATERIALS AND METHODS
A 60-year-old patient was referred to the University Hospital in Ostrava for suspected marginal zone lymphoma from gastric bio-psy. Staging examinations including bone marrow trepanobio-psy and PET/CT were added; special examinations required serum protein electrophoresis, immunofixation electrophoresis, determination of polyclonal immunoglobulins, free light chains, and immunoglobulin heavy/light chain pairs. Isoelectric focusing in agarose gel followed by affinity immunoblotting and SDS electrophoresis was added due to unclear findings.
RESULTS
0.1 % of plasma cells were found in the bone marrow, of which 87 % were clonal (pathological) plasma cells, followed by the cyt cytotype LAMBDA + CD38 + CD138 + CD45 + CD19 + CD56- CD27 + CD81- CD117-. Monoclonal heavy chains were found in the patients serum. No monoclonal immunoglobulin heavy or light chains were detected in urine. The PET/CT examination showed generalized lymphadenopathy, splenomegaly and inhomogeneous accumulation of fluorodeoxyglucose in axillary and appendicular skeleton, but without the presence of typical osteolytic lesions.
CONCLUSION
Monoclonal heavy chains of immunoglobulins are a rare disease. In contrast to the detection of a complete paraprotein molecule, additional methods must be used to confirm them. The finding of monoclonal heavy chain gamma in the serum of the study patient is related to the presence of marginal zone lymphoma, which was proven from a gastric bio-psy. The study was supported by the project of MH CZ - DRO - FNOs /2017 (Biobank in Teaching Hospital Ostrava) The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Topics: Heavy Chain Disease; Humans; Immunoglobulin gamma-Chains; Male; Middle Aged; Prognosis
PubMed: 32894957
DOI: 10.14735/amko2020280 -
Nature Apr 2019The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner....
The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner. LAT1, an antiporter of the amino acid-polyamine-organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as L-3,4-dihydroxyphenylalanine across membranes. Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs. LAT1 forms a heteromeric amino acid transporter complex with 4F2 cell-surface antigen heavy chain (4F2hc; also known as SLC3A2)-a type II membrane glycoprotein that is essential for the stability of LAT1 and for its localization to the plasma membrane. Despite extensive cell-based characterization of the LAT1-4F2hc complex and structural determination of its homologues in bacteria, the interactions between LAT1 and 4F2hc and the working mechanism of the complex remain largely unknown. Here we report the cryo-electron microscopy structures of human LAT1-4F2hc alone and in complex with the inhibitor 2-amino-2-norbornanecarboxylic acid at resolutions of 3.3 Å and 3.5 Å, respectively. LAT1 exhibits an inward open conformation. Besides a disulfide bond association, LAT1 also interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side. Biochemical analysis reveals that 4F2hc is essential for the transport activity of the complex. Together, our characterizations shed light on the architecture of the LAT1-4F2hc complex, and provide insights into its function and the mechanisms through which it might be associated with disease.
Topics: Amino Acids; Binding Sites; Biological Transport; Carboxylic Acids; Cryoelectron Microscopy; Disulfides; Fusion Regulatory Protein 1, Heavy Chain; Humans; Large Neutral Amino Acid-Transporter 1; Models, Molecular; Multiprotein Complexes; Norbornanes; Protein Binding; Protein Conformation
PubMed: 30867591
DOI: 10.1038/s41586-019-1011-z -
Leukemia & Lymphoma Mar 2023Chronic lymphocytic leukemia (CLL) has a heterogeneous biological behavior, which is highly influenced by its immunogenetic, epigenetic, and genomic properties. The... (Review)
Review
Chronic lymphocytic leukemia (CLL) has a heterogeneous biological behavior, which is highly influenced by its immunogenetic, epigenetic, and genomic properties. The remarkably variable clinical course of the disease has been associated with genetic features such as chromosomal abnormalities, the presence of either high or low numbers of somatic hypermutations (SHM) in the variable region of the immunoglobulin heavy chain locus (), and somatic mutations of several specific driver genes. Next-generation sequencing (NGS) technologies have provided a comprehensive characterization of the genomic and epigenomic landscape in CLL, elucidating important underlying mechanisms of the disease's biology. The scope of this review is to summarize the most recent discoveries about novel genetic and epigenetic alterations, discussing their impact on clinical outcomes and response to currently available therapy.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Epigenomics; Epigenesis, Genetic; Mutation
PubMed: 36503384
DOI: 10.1080/10428194.2022.2153359 -
Theranostics 2023Atherosclerosis (AS) is still the major cause of cardiovascular disease (CVD) as well as stroke. Endothelial metabolic disorder has been found to be activated and then...
Atherosclerosis (AS) is still the major cause of cardiovascular disease (CVD) as well as stroke. Endothelial metabolic disorder has been found to be activated and then promote endothelial cells (ECs) injury, which is regarded to initiate AS progression. N-acetylneuraminic acid (Neu5Ac), a metabolite produced by hexosamine-sialic acid pathway branching from glucose metabolism, was presented as a notable biomarker of CVD and is positively correlated with ECs function. However, few studies explain whether Neu5Ac regulate AS progression by affecting EC function as well as its involved mechanisms are still unknown. Here, we mimicked an animal model in mice which displaying similar plasma Neu5Ac levels with AS model to investigate its effect on AS progression. We found that Neu5Ac exacerbated plaques area and increased lipids in plasma in absence of HFD feeding, and ECs inflammatory injury was supposed as the triggering factor upon Neu5Ac treatment with increasing expression of IL-1β, ICAM-1, and promoting ability of monocyte adhesion to ECs. Mechanistic studies showed that Neu5Ac facilitated SLC3A2 binding to ubiquitin and then triggered P62 mediated degradation, further leading to accumulation of lipid peroxidation in ECs. Fer-1 could inhibit ECs injury and reverse AS progression induced by Neu5Ac in mice. Interestingly, mitochondrial dysfunction was also partly participated in ECs injury after Neu5Ac treatment and been reversed by Fer-1. Together, our study unveils a new mechanism by which evaluated metabolite Neu5Ac could promote SLC3A2 associated endothelial ferroptosis to activate ECs injury and AS plaque progression, thus providing a new insight into the role of Neu5Ac-ferroptosis pathway in AS. Also, our research revealed that pharmacological inhibition of ferroptosis may provide a novel therapeutic strategy for premature AS.
Topics: Animals; Mice; Atherosclerosis; Endothelial Cells; Ferroptosis; Plaque, Atherosclerotic; Mice, Knockout, ApoE; Fusion Regulatory Protein 1, Heavy Chain
PubMed: 37771765
DOI: 10.7150/thno.87968 -
Nature Communications Jul 2023Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which...
Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes individuals to mount qualitatively and quantitatively different antibody responses. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function, and dynamics of the antibody response in disease.
Topics: Humans; Genes, Immunoglobulin Heavy Chain; Genes, Immunoglobulin; Alleles; Germ-Line Mutation; Immunoglobulin Heavy Chains
PubMed: 37479682
DOI: 10.1038/s41467-023-40070-x