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1.
The pockets guide to HLA class I molecules.
Nguyen, AT, Szeto, C, Gras, S
Biochemical Society transactions. 2021;(5):2319-2331
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Abstract
Human leukocyte antigens (HLA) are cell-surface proteins that present peptides to T cells. These peptides are bound within the peptide binding cleft of HLA, and together as a complex, are recognised by T cells using their specialised T cell receptors. Within the cleft, the peptide residue side chains bind into distinct pockets. These pockets ultimately determine the specificity of peptide binding. As HLAs are the most polymorphic molecules in humans, amino acid variants in each binding pocket influences the peptide repertoire that can be presented on the cell surface. Here, we review each of the 6 HLA binding pockets of HLA class I (HLA-I) molecules. The binding specificity of pockets B and F are strong determinants of peptide binding and have been used to classify HLA into supertypes, a useful tool to predict peptide binding to a given HLA. Over the years, peptide binding prediction has also become more reliable by using binding affinity and mass spectrometry data. Crystal structures of peptide-bound HLA molecules provide a means to interrogate the interactions between binding pockets and peptide residue side chains. We find that most of the bound peptides from these structures conform to binding motifs determined from prediction software and examine outliers to learn how these HLAs are stabilised from a structural perspective.
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2.
Single nucleotide polymorphisms in ZNRD1-AS1 increase cancer risk in an Asian population.
Wang, PY, Li, JH, Liu, YM, Lv, Q, Xie, N, Zhang, HH, Xie, SY
Oncotarget. 2017;(6):10064-10070
Abstract
Single nucleotide polymorphisms (SNPs) in human zinc ribbon domain containing 1 antisense RNA 1 (ZNRD1-AS1) have been associated with cancer development. In this meta-analysis, we more precisely estimated the associations between three expression quantitative trait loci SNPs in ZNRD1-AS1 (rs3757328, rs6940552, and rs9261204) and cancer susceptibility. The data for three SNPs were extracted from eligible studies, which included 5,293 patients and 5,440 controls. Overall, no significant associations between SNPs in ZNRD1-AS1 (rs3757328, rs6940552, and rs9261204) and cancer risk were observed. However, in further subgroup analyses based on cancer type, we found that the A allele of rs3757328 increased the risk of some cancer in both allele contrast (OR = 1.15, 95% CI = 1.05 - 1.25) and recessive models (OR = 1.79; 95% CI = 1.33 - 2.41). The A allele of rs6940552 and the G allele of rs9261204 also increased the risk of some cancer in an Asian population in allele contrast (OR = 1.17, 95% CI = 1.08 - 1.26, and OR = 1.25, 95% CI = 1.16 - 1.34, respectively) and recessive models (OR = 1.44, 95% CI = 1.18 - 1.77, and OR = 1.49; 95% CI = 1.23 - 1.80, respectively). Thus, rs3757328, rs6940552, and rs9261204 in ZNRD1-AS1 are all associated with increased some cancer risk in an Asian population.
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3.
Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.
Sasazuki, T, Inoko, H, Morishima, S, Morishima, Y
Advances in immunology. 2016;:175-249
Abstract
The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases. The genomic diversity analysis in the HLA region facilitated by next-generation sequencing will pave the way to molecular understanding of linkage disequilibrium structure, population diversity, histocompatibility in transplantation, and associations with autoimmune diseases. The 4-digit DNA genotyping of HLA for six HLA loci, HLA-A through DP, in the patients with Graves' disease (GD) and Hashimoto thyroiditis (HT) identified six susceptible and three resistant HLA alleles. Their epistatic interactions in controlling the development of these diseases are shown. Four susceptible and one resistant HLA alleles are shared by GD and HT. Two HLA alleles associated with GD or HT control the titers of autoantibodies to thyroid antigens. All these observations led us to propose a new model for the development of GD and HT. Hematopoietic stem cell transplantation from unrelated donor (UR-HSCT) provides a natural experiment to elucidate the role of allogenic HLA molecules in immune response. Large cohort studies using HLA allele and clinical outcome data have elucidated that (1) HLA locus, allele, and haplotype mismatches between donor and patient, (2) specific amino acid substitution at specific positions of HLA molecules, and (3) ethnic background are all responsible for the immunological events related to UR-HSCT including acute graft-versus-host disease (GVHD), chronic GVHD, graft-versus-leukemia (GvL) effect, and graft failure.
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4.
Iron and the liver.
Pietrangelo, A
Liver international : official journal of the International Association for the Study of the Liver. 2016;:116-23
Abstract
Humans have evolved to retain iron in the body and are exposed to a high risk of iron overload and iron-related toxicity. Excess iron in the blood, in the absence of increased erythropoietic needs, can saturate the buffering capacity of serum transferrin and result in non-transferrin-bound highly reactive forms of iron that can cause damage, as well as promote fibrogenesis and carcinogenesis in the parenchymatous organs. A number of hereditary or acquired diseases are associated with systemic or local iron deposition or iron misdistribution in organs or cells. Two of these, the HFE- and non-HFE hemochromatosis syndromes represent the paradigms of genetic iron overload. They share common clinical features and the same pathogenic basis, in particular, a lack of synthesis or activity of hepcidin, the iron hormone. Before hepcidin was discovered, the liver was simply regarded as the main site of iron storage and, as such, the main target of iron toxicity. Now, as the main source of hepcidin, it appears that the loss of the hepcidin-producing liver mass or genetic and acquired factors that repress hepcidin synthesis in the liver may also lead to iron overload. Usually, there is low-grade excess iron which, through oxidative stress, is sufficient to worsen the course of the underlying liver disease or other chronic diseases that are apparently unrelated to iron, such as chronic metabolic and cardiovascular diseases. In the future, modulation of hepcidin synthesis and activity or hepcidin hormone-replacing strategies may become therapeutic options to cure iron-related disorders.
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5.
Diagnosis and management of hereditary hemochromatosis.
Salgia, RJ, Brown, K
Clinics in liver disease. 2015;(1):187-98
Abstract
Hereditary hemochromatosis is a rare genetic disorder that can have significant clinical consequences. Hemochromatosis is associated with iron overload, and can initially be recognized through laboratory testing for serum ferritin and transferrin saturation. Genetic testing for the HFE mutation can be performed in patients with elevated iron indices and a suspicion for hemochromatosis or liver disease. The main pathway resulting in iron overload is through altered hepcidin levels. Treatment of patients with the clinical phenotype of hereditary hemochromatosis is commonly through phlebotomy for removal of excess iron stores. This article highlights the current information and data regarding the diagnosis and management of hemochromatosis.
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6.
Recent advances in hemochromatosis: a 2015 update : a summary of proceedings of the 2014 conference held under the auspices of Hemochromatosis Australia.
Ekanayake, D, Roddick, C, Powell, LW
Hepatology international. 2015;(2):174-82
Abstract
This review focuses on iron metabolism, the genetics of hemochromatosis, current treatment protocols and various screening methods. Even though the most common form of hereditary hemochromatosis, C282Y gene mutations in the HFE gene, has been extensively studied, novel mutations in both HFE and non-HFE genes have been implicated in this disease. These have important implications for the Asia-Pacific region. In overload, deposition of iron in various body tissues leads to toxic damage. Patients commonly present with non-specific symptoms of malaise and lethargy. Biochemical, imaging and genetic testing can be carried out to confirm diagnosis. Venesection forms the mainstay of treatment and at present cascade screening of affected families is recommended over population-level screening.
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7.
Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies.
Li, M, Wang, L, Wang, W, Qi, XL, Tang, ZY
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2014;(3):215-22
Abstract
Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in the HFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS) through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFE in ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D). For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005) and the dominant model (YY+CY vs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006). No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.
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8.
Importance of TAP-independent processing pathways.
Oliveira, CC, van Hall, T
Molecular immunology. 2013;(2):113-6
Abstract
The majority of peptides presented in MHC class I at the cell surface originate from the conventional antigen processing pathway, involving the proteasome and TAP peptide transporter. Alternative pathways, however, certainly contribute to the diversity of the total peptide repertoire. The importance of such TAP-independent processing pathways is nicely illustrated by the finding that individuals with an inherited deficiency in this peptide transporter still sufficiently mount T cell responses against viruses. Although defects in TAP do result in strongly decreased surface display of MHC class I molecules, the residual levels are capable to educate and elicit T cell immunity. In our work, we have shown that a broad repertoire of peptides is presented on processing-deficient cells. The characterization of these peptides, which we called TEIPP - "T-cell epitopes associated with impaired peptide processing", showed that they derive from housekeeping proteins, are diverse in length and amino-acid composition, and are not presented on normal cells. So, TAP-deficiency promotes the emergence of neo-antigens. These TAP-independent peptides might be processed via the two already known pathways, signal sequence liberation or furin-mediated cleavage in the Golgi, or via yet other routes. Our study on TEIPP antigens reveals that there is a world to be discovered in the alternative antigen processing field. Autophagy, vesicular routing, membrane-associated proteolysis, invariant chain involvement and recycling of MHC class I molecules all might come to the stage in this interesting research area.
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9.
[Diagnosis and treatment of genetic haemochromatosis].
Milman, NT
Ugeskrift for laeger. 2013;(16):1109-12
Abstract
Genetic haemochromatosis is a complex disorder/disease, which can be caused by a multiplicity of mutations in genes involved in iron metabolism being located on different chromosomes. In Caucasians, mutations in the HFE-gene account for the most common form of haemochromatosis (type 1). Non-HFE-haemochromatoses are less frequent and consist of juvenile haemochromatosis (type 2A and 2B) and TRF2-related haemochromatosis (type 3), which all respond to phlebotomies. The others comprise ferroportin disease (type 4A) atypical ferroportin disease (type 4B), acoeruloplasminaemia, atransferrinaemia and DMT1-associated haemochromatosis.
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10.
Iron storage disease in Asia-Pacific populations: the importance of non-HFE mutations.
McDonald, CJ, Wallace, DF, Crawford, DH, Subramaniam, VN
Journal of gastroenterology and hepatology. 2013;(7):1087-94
Abstract
Hereditary hemochromatosis (HH) is a widely recognized and well-studied condition in European populations. This is largely due to the high prevalence of the C282Y mutation of HFE. Although less common than in Europe, HH cases have been reported in the Asia-Pacific region because of mutations in both HFE and non-HFE genes. Mutations in all of the currently known genes implicated in non-HFE HH (hemojuvelin, hepcidin, transferrin receptor 2, and ferroportin) have been reported in patients from the Asia-Pacific region. This review discusses the molecular basis of HH and the genes and mutations known to cause non-HFE HH with particular reference to the Asia-Pacific region. Challenges in the genetic diagnosis of non-HFE HH are also discussed and how new technologies such as next generation sequencing may be informative in the future.