ABSTRACT
Two different single nucleotide substitutions in intron 2 give rise to novel HLA-DQB1*03:02:01 alleles.
Subject(s)
Alleles , HLA-DQ beta-Chains , Introns , Humans , Histocompatibility Testing , HLA-DQ beta-Chains/genetics , Polymorphism, Single NucleotideABSTRACT
Two nucleotide substitutions in intronic regions give rise to the novel alleles: HLA-B*35:01:01:39 and -B*35:03:01:32.
Subject(s)
Genes, MHC Class I , HLA-B Antigens , Humans , Alleles , HLA-B Antigens/genetics , Introns , High-Throughput Nucleotide SequencingABSTRACT
HLA-DPA1*02:01:25 differs from DPA1*02:01:01:02 by a synonymous transition in exon 2.
Subject(s)
HLA-DP alpha-Chains , High-Throughput Nucleotide Sequencing , Humans , Alleles , HLA-DP alpha-Chains/genetics , Exons/geneticsABSTRACT
Seven different single nucleotide substitutions in non-coding regions gave rise to novel HLA-DPA1*01:03:01 variants.
Subject(s)
HLA-DP alpha-Chains , High-Throughput Nucleotide Sequencing , Humans , Alleles , HLA-DP alpha-Chains/genetics , Histocompatibility TestingABSTRACT
Characterization by next-generation sequencing of four novel HLA alleles: C*17:03:01:07, C*16:01:01:39, B*15:17:01:07, and B*44:03:01:57.
Subject(s)
High-Throughput Nucleotide Sequencing , Nucleotides , Humans , 3' Untranslated Regions , AllelesABSTRACT
Three nucleotide substitutions in intronic regions give rise to the novel alleles: HLA-DQB1*03:01:01:54, -DQB1*03:01:01:56, -DQB1*03:01:01:58.
Subject(s)
High-Throughput Nucleotide Sequencing , Humans , Alleles , HLA-DQ beta-Chains/genetics , IntronsABSTRACT
HLA-DQA1*05:71, the first HLA-DQA1 allele with Aspartic Acid at residue 208 in the transmembrane domain.
Subject(s)
Aspartic Acid , Humans , Aspartic Acid/genetics , Alleles , Sequence Analysis, DNA , HLA-DQ alpha-Chains/geneticsABSTRACT
The novel HLA-DQB1*03:02:01:14 was likely generated by a recombination event between DQB1*03:02:01:01 and DQB1*03:03:02:01.
Subject(s)
High-Throughput Nucleotide Sequencing , Recombination, Genetic , Humans , Alleles , HLA-DQ beta-Chains/geneticsABSTRACT
Two transitions in intronic regions give rise to the novel alleles: HLA-DQB1*05:02:01:13 and HLA-DQB1*05:02:01:14.
Subject(s)
High-Throughput Nucleotide Sequencing , Humans , Alleles , HLA-DQ beta-Chains/genetics , IntronsABSTRACT
A missense nucleotide substitution in codon -17 in the leader peptide results in the novel HLA-DRB1*04:354 allele.
Subject(s)
Nucleotides , Valine , Humans , HLA-DRB1 Chains/genetics , Alleles , Valine/genetics , Exons/geneticsABSTRACT
The failure to identify HLA null alleles in bone marrow transplantation could be life-threatening because this could result in an HLA mismatch with the ability to trigger the graft-vs-host disease (GVHD) and to reduce patient's survival. In this report we describe the identification and characterization of the novel HLA-DPA1*02:66:02N allele with a non-sense codon in exon 2. This new allele was discovered in two unrelated bone marrow donors during routine HLA-typing using next-generation sequencing (NGS). DPA1*02:66:02N is homologous to DPA1*02:01:01:03 with a single nucleotide difference in exon 2, codon 50, where the replacement of C located at genomic position 3825 by T, causes the formation of a premature stop codon (TGA), resulting in a null allele. This description illustrates the benefits of HLA typing by NGS since it permits to reduce ambiguities, identify new alleles, analyze multiple HLA loci and improve transplantation outcome.
Subject(s)
Codon, Nonsense , HLA-DP alpha-Chains , Humans , Alleles , HLA-DP alpha-Chains/genetics , Exons/genetics , Codon , Histocompatibility Testing/methodsABSTRACT
A synonymous substitution in exon 2 and intronic insertion results in the novel HLA-DQA1*01:04:07 allele.
Subject(s)
HLA-DQ Antigens , Humans , HLA-DQ Antigens/genetics , Alleles , HLA-DQ alpha-Chains/genetics , ExonsABSTRACT
A nonsynonymous nucleotide substitution in exon 1 results in the novel HLA-DQB1*03:493 allele.
Subject(s)
Glutamic Acid , Protein Sorting Signals , Humans , Alleles , Glutamic Acid/genetics , Base Sequence , HLA-DQ beta-Chains/geneticsABSTRACT
The novel HLA class I allele, HLA-B*49:78, was detected in a Spanish Caucasian individual.
Subject(s)
HLA-B Antigens , High-Throughput Nucleotide Sequencing , Alleles , Exons/genetics , Genes, MHC Class I , HLA-B Antigens/genetics , HumansABSTRACT
BACKGROUND AND PURPOSE: Short-chain fatty acids (SCFAs) can have pro- or anti-inflammatory properties, but their relationship with multiple sclerosis (MS) relapses during pregnancy remains unknown. This study aimed to explore SCFA profiles in MS patients during pregnancy and to assess their association with the appearance of relapses during pregnancy and postpartum. METHODS: We prospectively included 53 pregnant MS patients and 21 healthy control women. Patients were evaluated during pregnancy and puerperium. SCFAs were measured by liquid chromatography-mass spectrometry. RESULTS: Sixteen patients (32%) had relapses during pregnancy or puerperium, and 37 (68%) did not. All MS patients showed significant increases in acetate levels during pregnancy and the postpartum period compared to non-MS women. However, propionate and butyrate values were associated with disease activity. Their values were higher in nonrelapsing patients and remained similar to the control group in relapsing patients. The variable that best identified active patients was the propionate/acetate ratio. Ratios of <0.36 during the first trimester were associated with higher inflammatory activity (odds ratio = 165, 95% confidence interval = 10.2-239.4, p < 0.01). Most nonrelapsing patients showed values of >0.36, which were similar to those in healthy pregnant women. CONCLUSIONS: Low propionate/acetate ratio values during the first trimester of gestation identified MS patients at risk of relapses during pregnancy and the postpartum period.
Subject(s)
Multiple Sclerosis , Fatty Acids, Volatile , Female , Humans , Odds Ratio , Pregnancy , Prospective Studies , RecurrenceABSTRACT
Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.
Subject(s)
Immunosenescence/immunology , Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Oligoclonal Bands/immunology , Activins/cerebrospinal fluid , Adolescent , Adult , Aged , Antibodies, Viral/blood , B-Lymphocytes/immunology , B7-H1 Antigen/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Chitinase-3-Like Protein 1/cerebrospinal fluid , Female , Humans , Linear Models , Male , Middle Aged , Multivariate Analysis , T-Lymphocytes/immunology , Young AdultABSTRACT
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.
Subject(s)
Astrocytes/physiology , Cell Communication , Central Nervous System/pathology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Microglia/physiology , Multiple Sclerosis/physiopathology , Single-Cell Analysis , Animals , Antigens, CD/metabolism , Brain/pathology , Brain/physiopathology , Central Nervous System/physiopathology , Encephalomyelitis, Autoimmune, Experimental/pathology , Ephrin-B3/metabolism , Herpesvirus 1, Suid/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Multiple Sclerosis/pathology , NF-kappa B/metabolism , Nerve Tissue Proteins/metabolism , RNA-Seq , Reactive Oxygen Species/metabolism , Receptor, EphB3/antagonists & inhibitors , Receptor, EphB3/metabolism , Receptors, Cell Surface/metabolism , Semaphorins/metabolism , Signal Transduction , T-Lymphocytes/physiology , TOR Serine-Threonine Kinases/metabolismABSTRACT
Epstein-Barr virus (EBV), human herpesvirus 6A/B (HHV-6A/B) and multiple sclerosis (MS)-associated retrovirus (MSRV) have been described as possible MS triggers. We analysed antibody titres against EBV and HHV-6, and MSRV envelope (env) mRNA expression, in the serum of pregnant multiple sclerosis patients (P-MS) to study their possible link to the clinical activity of MS during pregnancy and postpartum and their possible role as relapse predictors. For that purpose, serum samples were collected from 71 pregnant women (50 pregnant MS and 21 pregnant healthy controls-P-HC) during pregnancy and postpartum. Relating to antibody titres, IgM antibody titres against HHV-6A/B were significantly higher in P-MS than in P-HC both in each pregnancy trimester and in the postpartum period. Moreover, IgM antibody titres against HHV-6A/B were higher in P-MS who suffered a relapse during the postpartum. Regarding MSRV env mRNA expression, the prevalence in the first trimester of pregnancy was significantly higher in P-MS who suffered relapses during pregnancy. Summing it up, high IgM antibody titres against HHV-6A/B and MSRV env mRNA expression during the first trimester of pregnancy could act as relapse predictors for the gestation/postpartum periods.
