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2.
J Autoimmun ; 94: 70-82, 2018 11.
Article in English | MEDLINE | ID: mdl-30064915

ABSTRACT

Genetic investigations on ancient human remains affected by rheumatological pathologies are a research field of particular interest for identifying the pathogenesis of diseases, especially those having an autoimmune background such as spondyloarthopaties (SpA). Reliable studies concerning this topic require collaboration between multiple disciplines, usually starting from paleopathologic observations up to molecular genetic screening. Here, we focused our investigation in a medieval necropolis in the Basque Country (13th-15th century, N = 163), which presents a high frequency of joint pathologies through two approaches: on the one hand, the analysis of joint manifestations for the differential diagnosis of the SpA and, on the other hand, the determination of the alleles of the HLA-B gene. The morphological analysis allowed determining that 30% of the individuals had rheumatic bone manifestations, with SpA being the most frequent (45%). The genetic analysis of individuals with and without pathologies, based on the study of the HLA-B gene, allowed finding 17 alleles for this gene, with HLA-B40, HLA-B27 and HLA-B35 being the most frequent. Although these alleles have been traditionally described as genetic markers associated to the development of SpA, in this study they were also found in individuals with other rheumatic diseases (osteoarthritis and rheumatoid arthritis) and even in individuals without pathologies. These data confirm the complexity of the relationship of the HLA-B gene variants with SpA, since it is not possible to establish a diagnosis of SpA with these variants alone. However, we suggest that allele HLA-B40, in combination with some specific rheumatic bone manifestations, facilitates the diagnosis of SpA.


Subject(s)
Arthritis, Rheumatoid/diagnosis , HLA-B27 Antigen/genetics , HLA-B35 Antigen/genetics , HLA-B40 Antigen/genetics , Osteoarthritis/diagnosis , Polymorphism, Genetic , Spondylarthropathies/diagnosis , Alleles , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Body Remains , Bone and Bones/immunology , Bone and Bones/pathology , Climate , Cold Temperature , DNA, Ancient/analysis , Diagnosis, Differential , Female , Genetic Predisposition to Disease , HLA-B27 Antigen/immunology , HLA-B35 Antigen/immunology , HLA-B40 Antigen/immunology , History, Medieval , Humans , Joints/immunology , Joints/pathology , Male , Osteoarthritis/genetics , Osteoarthritis/immunology , Osteoarthritis/pathology , Paleopathology/methods , Spain , Spondylarthropathies/genetics , Spondylarthropathies/immunology , Spondylarthropathies/pathology
6.
Blood ; 129(21): 2908-2916, 2017 05 25.
Article in English | MEDLINE | ID: mdl-28232583

ABSTRACT

To identify HLA alleles closely involved in the autoantigen presentation in acquired aplastic anemia (AA), we studied the HLA allelic loss frequencies of 312 AA patients, including 43 patients with loss of heterozygosity of 6p chromosome (6pLOH). An analysis of the HLA alleles contained in the lost haplotype revealed HLA-B*40:02 to be the most frequently lost allele. When we examined 28 AA (12 6pLOH[+] and 16 6pLOH[-]) patients with HLA-B*40:02 for the presence of leukocytes lacking HLA-B4002 (B4002-) using a new monoclonal antibody specific to this allele, B4002- granulocytes were detected not only in all 6pLOH(+) patients but also in 9 (56%) of the 16 6pLOH(-) patients. Furthermore, 10 (83%) of the 12 6pLOH(+) patients possessed 1.0% to 78% B4002- granulocytes that retained the HLA-A allele on the same haplotype (B4002-A+), suggesting the frequent coexistence of granulocytes that underwent mutations restricted to HLA-B*40:02 with 6pLOH(+) (B4002-A-) granulocytes. Deep sequencing of the HLA-B*40:02 of sorted B4002-A+ granulocytes revealed various somatic mutations, such as frameshift, nonsense, and splice site mutations, in all 15 patients studied. Surprisingly, missense mutations in the α-3 domain of HLA-B*40:02 that are not involved in the antigen presentation were detected exclusively in the B4002+ granulocytes of 3 patients possessing B4002- granulocytes. The markedly high prevalence of leukocytes lacking HLA-B4002 as a result of either 6pLOH or structural gene mutations, or both, suggests that antigen presentation by hematopoietic stem/progenitor cells to cytotoxic T cells via the HLA-B allele plays a critical role in the pathogenesis of AA.


Subject(s)
Alleles , Anemia, Aplastic , Antigen Presentation/genetics , Autoantigens , HLA-A Antigens , HLA-B40 Antigen , Adolescent , Adult , Aged , Aged, 80 and over , Anemia, Aplastic/genetics , Anemia, Aplastic/immunology , Anemia, Aplastic/pathology , Autoantigens/genetics , Autoantigens/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Female , Granulocytes/immunology , Granulocytes/pathology , HLA-A Antigens/genetics , HLA-A Antigens/immunology , HLA-B40 Antigen/genetics , HLA-B40 Antigen/immunology , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/pathology , Humans , Male , Middle Aged
8.
HLA ; 87(6): 461-2, 2016 06.
Article in English | MEDLINE | ID: mdl-27140171

ABSTRACT

HLA-B*40:01:47 differs from HLA-B*40:01:01 by one nucleotide exchange at position 420 in exon 3.


Subject(s)
Alleles , Exons , HLA-B40 Antigen/genetics , Point Mutation , Base Sequence , Cloning, Molecular , Codon/chemistry , Genotype , HLA-B40 Antigen/immunology , Histocompatibility Testing , Humans , Polymerase Chain Reaction , Sequence Alignment , Sequence Analysis, DNA
10.
HLA ; 87(3): 179-80, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26924358

ABSTRACT

One nucleotide replacement at residue 147 of HLA-B*40:01:01 results in a new allele, HLA-B*40:01:44.


Subject(s)
Alleles , Exons , HLA-B40 Antigen/genetics , Point Mutation , Base Sequence , Bone Marrow Transplantation , Codon , Genotype , HLA-B40 Antigen/immunology , Histocompatibility Testing , Humans , Sequence Alignment , Sequence Analysis, DNA , Taiwan , Unrelated Donors
12.
Tissue Antigens ; 86(4): 301-2, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26302685

ABSTRACT

The novel HLA-B*40:229 allele shows one nucleotide difference from B*40:02:01 in exon 2 at nucleotide position 97 (C → T).


Subject(s)
Alleles , HLA-B40 Antigen/genetics , Point Mutation , Base Sequence , Bone Marrow Transplantation , China , Codon , Exons , Genotype , HLA-B40 Antigen/immunology , Histocompatibility Testing , Humans , Molecular Sequence Data , Sequence Alignment , Sequence Analysis, DNA , Tissue Donors
15.
Mol Cell Proteomics ; 13(2): 462-74, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24366607

ABSTRACT

Human leukocyte antigen (HLA) class I molecules bind peptides derived from the intracellular degradation of endogenous proteins and present them to cytotoxic T lymphocytes, allowing the immune system to detect transformed or virally infected cells. It is known that HLA class I-associated peptides may harbor posttranslational modifications. In particular, phosphorylated ligands have raised much interest as potential targets for cancer immunotherapy. By combining affinity purification with high-resolution mass spectrometry, we identified more than 2000 unique ligands bound to HLA-B40. Sequence analysis revealed two major anchor motifs: aspartic or glutamic acid at peptide position 2 (P2) and methionine, phenylalanine, or aliphatic residues at the C terminus. The use of immobilized metal ion and TiO2 affinity chromatography allowed the characterization of 85 phosphorylated ligands. We further confirmed every sequence belonging to this subset by comparing its experimental MS2 spectrum with that obtained upon fragmentation of the corresponding synthetic peptide. Remarkably, three phospholigands lacked a canonical anchor residue at P2, containing phosphoserine instead. Binding assays showed that these peptides bound to HLA-B40 with high affinity. Together, our data demonstrate that the peptidome of a given HLA allotype can be broadened by the presentation of peptides with posttranslational modifications at major anchor positions. We suggest that ligands with phosphorylated residues at P2 might be optimal targets for T-cell-based cancer immunotherapy.


Subject(s)
Antigen Presentation , Antigenic Variation , HLA-B40 Antigen/metabolism , Peptide Fragments/immunology , Peptide Fragments/metabolism , Phosphoproteins/immunology , Phosphoproteins/metabolism , Amino Acid Sequence , Binding Sites , Epitope Mapping , HLA-B40 Antigen/immunology , Humans , Ligands , Peptide Fragments/chemistry , Phosphoproteins/chemistry , Phosphorylation , Protein Interaction Mapping , Proteome/analysis , Proteome/immunology , Proteome/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism
16.
Immunol Lett ; 156(1-2): 1-6, 2013.
Article in English | MEDLINE | ID: mdl-24029662

ABSTRACT

Limited reports are available on association of HLA-B with HIV infection from India, a home to the third largest population of HIV infected people in the world. This emphasizes the need to have more information specifically the genetic constitution of HIV serodiscordant couples (DCs), where one spouse is seropositive (HSP) while the other remains seronegative (HSN) even after repeated exposure. Hence, aim of this study was to document association of HLA-B with HIV infection in DCs living in Mumbai, India. A cohort was designed to enroll DCs attending the ICTC/Shakti Clinic of KEM Hospital, Mumbai. A group of unexposed volunteers were also enrolled as healthy controls (HC). HLA-B alleles were typed using sequence-specific oligonucleotide probes. Allele frequency comparison was done using 2×2 contingency tables. Results were considered significant, when p<0.05 with two-tailed Fisher's exact test. At HLA-B locus, the frequencies of HLA-B*40;-B*35;-B*07;-B*15;-B*51;-B*44;-B*52;-B*37 and -B*57 were found in decreasing order in the population. Frequency of HLA-B*35 allele was significantly higher (HSP vs HSN; p<0.02 and HSP vs HC; p<0.04) in HSP. HLA-B*40 (HSN vs HSP; p<0.01 and HC vs HSP; p<0.01) and HLA-B*18 (HSN vs HSP; p<0.02) were significantly associated with HSN. Both HSN and HC had similar HLA-B*35 and -B*40 allele frequency. HLA-B*57 allele was observed in 15 individuals (3.69%). However, HLA-B*57:01 which is known to be associated with adverse reactions against Abacavir was observed in 7 of them. HLA-B*39 was observed exclusively in HSP. Our observation in DCs confirmed the association of HLA-B*35 with susceptibility while HLA-B*40 (specifically *B40:06), -B*18 with protection. These identified alleles can be used as possible marker associated with HIV transmission. In India, HLA screening is not carried out before initiation of HIV treatment. However, the presence of HLA-B*57:01 in the population emphasizes the importance of such screening to predict/avoid Abacavir hypersensitivity.


Subject(s)
HIV Infections/immunology , HIV Seronegativity/immunology , HIV Seropositivity/immunology , HIV-1/immunology , HLA-B Antigens/immunology , Alleles , Cohort Studies , Female , Gene Frequency , HIV Infections/genetics , HIV Infections/virology , HIV Seronegativity/genetics , HIV Seropositivity/genetics , HIV Seropositivity/virology , HIV-1/physiology , HLA-B Antigens/genetics , HLA-B18 Antigen/genetics , HLA-B18 Antigen/immunology , HLA-B35 Antigen/genetics , HLA-B35 Antigen/immunology , HLA-B40 Antigen/genetics , HLA-B40 Antigen/immunology , Histocompatibility Testing/methods , Host-Pathogen Interactions/immunology , Humans , India , Male , Spouses
17.
Eur J Immunol ; 43(11): 3038-50, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23893393

ABSTRACT

The low frequency of antigen-specific naïve T cells has challenged numerous laboratories to develop various techniques to study the naïve T-cell repertoire. Here, we combine the generation of naïve repertoire-derived antigen-specific T-cell lines based on MHC-tetramer staining and magnetic-bead enrichment with in-depth functional assessment of the isolated T cells. Cytomegalovirus (CMV) specific T-cell lines were generated from seronegative individuals. Generated T-cell lines consisted of a variety of immunodominant CMV-epitope-specific oligoclonal T-cell populations restricted to various HLA-molecules (HLA-A1, A2, B7, B8, and B40), and the functional and structural avidity of the CMV-specific T cells was studied. Although all CMV-specific T cells were isolated based on their reactivity toward a specific peptide-MHC complex, we observed a large variation in the functional avidity of the MHC-tetramer positive T-cell populations, which correlated with the structural avidity measured by the recently developed Streptamer koff -rate assay. Our data demonstrate that MHC-tetramer staining is not always predictive for specific T-cell reactivity, and challenge the sole use of MHC-tetramers as an indication of the peripheral T-cell repertoire, independent of the analysis of functional activity or structural avidity parameters.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cytomegalovirus/immunology , Lymphocyte Activation/immunology , Receptors, Antigen, T-Cell/immunology , Cell Line , Epitopes, T-Lymphocyte/immunology , HLA-A1 Antigen/immunology , HLA-A2 Antigen/immunology , HLA-B40 Antigen/immunology , HLA-B7 Antigen/immunology , HLA-B8 Antigen/immunology , Humans , Interferon-gamma/biosynthesis , T-Lymphocyte Subsets/immunology
19.
Tissue Antigens ; 80(4): 383-4, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22803579

ABSTRACT

The new allele B*40:186 shows a one nucleotide substitution compared with B*40:01:02 at codon 56 (GGG → AGG) resulting in coding change, Gly to Arg.


Subject(s)
Alleles , HLA-B40 Antigen/genetics , Nucleotides/genetics , Amino Acid Substitution , Asian People , Base Sequence , Codon , Exons , Genetic Loci , HLA-B40 Antigen/immunology , Histocompatibility Testing , Humans , Introns , Molecular Sequence Data , Protein Isoforms/genetics , Protein Isoforms/immunology , Sequence Analysis, DNA , Sequence Homology, Nucleic Acid
20.
Haematologica ; 97(8): 1196-204, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22419570

ABSTRACT

BACKGROUND: Patients with hematologic malignancies can be successfully treated with donor lymphocyte infusion after HLA-matched allogeneic hematopoietic stem cell transplantation. The effect of donor lymphocyte infusion is mediated by donor T cells recognizing minor histocompatibility antigens. T cells recognizing hematopoietic restricted minor histocompatibility antigens may induce selective graft-versus-leukemia reactivity, whereas broadly-expressed antigens may be targeted in graft-versus-host disease. DESIGN AND METHODS: We analyzed in detail CD8(+) T-cell immunity in a patient with relapsed chronic myelogenous leukemia who responded to donor lymphocyte infusion with minimal graft-versus-host disease of the skin. CD8(+) T-cell clones specific for 4 HLA-B*40:01 restricted minor histocompatibility antigens were isolated which were identified by screening a plasmid cDNA library and whole genome association scanning. Detailed T-cell reactivity and monitoring experiments were performed to estimate the clinical and therapeutic relevance of the novel antigens. RESULTS: Three antigens were demonstrated to be expressed on primary leukemic cells of various origins as well as subtypes of non-malignant hematopoietic cells, whereas one antigen was selectively recognized on malignant hematopoietic cells with antigen presenting cell phenotype. Skin derived fibroblasts were only recognized after pre-treatment with IFN-γ by two T-cell clones. CONCLUSIONS: Our data show evidence for different roles of the HLA-B*40:01 restricted minor histocompatibility antigens in the onset and execution of the anti-tumor response. All antigens may have contributed to a graft-versus-leukemia effect, and one minor histocompatibility antigen (LB-SWAP70-1Q) has specific therapeutic value based on its in vivo immunodominance and strong presentation on leukemic cells of various origins, but absence of expression on cytokine-treated fibroblasts.


Subject(s)
Graft vs Host Disease/genetics , Graft vs Host Disease/immunology , HLA-B40 Antigen/genetics , HLA-B40 Antigen/immunology , Minor Histocompatibility Antigens/genetics , Minor Histocompatibility Antigens/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Female , Gene Expression Profiling , Gene Expression Regulation , Gene Library , Hematopoietic Stem Cell Transplantation , Humans , Leukemia/genetics , Leukemia/immunology , Leukemia/therapy , Middle Aged , Polymorphism, Single Nucleotide , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transplantation, Homologous
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