RESUMO
Bullous pemphigoid (BP), although a rare disease, is the most frequent subepidermal autoimmune disorder. Treatment with gliptins, used for type 2 diabetes, was reported as associated with BP onset. To identify HLA alleles that may reflect a higher susceptibility to BP in the Italian population, we analysed 30 patients affected by idiopathic bullous pemphigoid (IBP) and 86 gliptin-associated BP (GABP) patients. A significant association between HLA-DQB1*03:01 allele and IBP and GABP patients was found. Of note, both IBP and GABP were significantly associated with one of the following haplotypes: DRB1*11:01, DRB3*02:02, DQA1*05:05, DQB1*03:01 or DRB1*11:04, DRB3*02:02, DQA1*05:05 and DQB1*03:01. These data identify, for the first time, potential markers of susceptibility to BP in the Italian population, especially when associated with gliptin intake.
Assuntos
Alelos , Predisposição Genética para Doença , Haplótipos , Penfigoide Bolhoso , Humanos , Penfigoide Bolhoso/genética , Penfigoide Bolhoso/induzido quimicamente , Itália , Feminino , Masculino , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cadeias beta de HLA-DQ/genética , Pessoa de Meia-Idade , Frequência do Gene , Idoso de 80 Anos ou maisRESUMO
The novel HLA-DPA1*02:110:02 allele differs from HLA-DPA1*02:01:01:06 by one nucleotide substitution in exon 4.
Assuntos
Cadeias alfa de HLA-DP , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Alelos , Teste de Histocompatibilidade , Cadeias alfa de HLA-DP/genéticaRESUMO
HLA-DRB3*02:192 differs from DRB3*02:02:01:02 by one nucleotide substitution in codon 204 in exon 4.
RESUMO
HLA-DQA1*05:05:14 differs from HLA-DQA1*05:05:01:04 by one nucleotide substitution in codon -8 in exon 1.
Assuntos
Alelos , Humanos , Cadeias alfa de HLA-DQ/genética , Análise de Sequência de DNA , CódonRESUMO
HLA-DPA1*01:03:40 differs from HLA-DPA1*01:03:01:02 by one nucleotide substitution in codon 60 in exon 2.
Assuntos
Cadeias alfa de HLA-DP , Alelos , Cadeias alfa de HLA-DP/genética , Teste de Histocompatibilidade , Humanos , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
The novel allele HLA-B*07:422 differs from HLA-B*07:02:01:01 by one nucleotide substitution in exon 4.
Assuntos
Antígeno HLA-B7 , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , HumanosRESUMO
HLA-DQA1*01:02:11 differs from HLA-DQA1*01:02:01:10 by one nucleotide substitution in codon 201 in exon 4.
Assuntos
Alelos , Cadeias alfa de HLA-DQ , Éxons/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Análise de Sequência de DNARESUMO
HLA-DQA1*01:58 differs from HLA-DQA1*01:02:01:06 by one nucleotide substitution in codon 46 in exon 2.
Assuntos
Cadeias alfa de HLA-DQ , Alelos , Éxons/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Análise de Sequência de DNARESUMO
The novel allele HLA-B*35:481 differs from HLA-B*35:05:01 by two nucleotide substitution in exon 3.
Assuntos
Genes MHC Classe I , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Antígenos HLA-B/genética , HumanosRESUMO
HLA-DQA1*03:01:06 differs from HLA-DQA1*03:01:01:01 by one nucleotide substitution in codon 9 in exon 2.
Assuntos
Alelos , Éxons/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Análise de Sequência de DNARESUMO
The novel allele HLA-DQA1*01:26 differs from HLA-DQA1*01:01:01:01 by one nucleotide substitution in exon 2.
Assuntos
Alelos , Éxons/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Análise de Sequência de DNARESUMO
HLA-DRB3*02:02:23 differs from HLA-DRB3*02:02:01:02 by one nucleotide substitution in codon 218 in exon 4.
Assuntos
Cadeias HLA-DRB3 , Alelos , Códon , Éxons , Cadeias HLA-DRB3/genética , HumanosRESUMO
HLA-DRB3*02:96 differs from HLA-DRB3*02:02:01:01 by one nucleotide substitution in codon 189 in exon 4.
Assuntos
Códon/genética , Éxons/genética , Cadeias HLA-DRB3/genética , Teste de Histocompatibilidade/métodos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Alelos , Substituição de Aminoácidos , Sequência de Bases , Humanos , Homologia de SequênciaRESUMO
HLA-DRB3*02:02:17 differs from HLA-DRB3*02:02:01:01 by one nucleotide substitution in codon 179 in exon 3.
Assuntos
Alelos , Cadeias HLA-DRB3/genética , Teste de Histocompatibilidade , Sequência de Bases , Éxons/genética , HumanosRESUMO
HLA-C*07:708 differs from HLA-C*07:01:01:01 by one nucleotide substitution at codon 258 in exon 4.
Assuntos
Códon , Éxons , Antígenos HLA-C/genética , Mutação Puntual , Teste de Histocompatibilidade , Humanos , Análise de Sequência de DNARESUMO
HLA-DRB3*02:02:11 differs from HLA-DRB3*02:02:01:01 by a single synonymous substitution in exon 3'.
Assuntos
Alelos , Éxons , Cadeias HLA-DRB3/genética , Polimorfismo de Nucleotídeo Único , Sequência de Bases , Criança , Códon/química , Feminino , Expressão Gênica , Genótipo , Cadeias HLA-DRB3/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Itália , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , TransplantadosRESUMO
In a cohort of ß-Thalassemia (ß-Thal) transplanted with haploidentical-HSCT we identified one transplanted patient characterized by persistent mixed chimerism (PMC) for several months after HSCT. In this unique ß-Thal patient we assessed the donor engraftment overtime after transplantation, the potential loss of the non-shared HLA haplotype, and the presence of CD49b(+)LAG-3(+) T regulatory type 1 (Tr1) cells, previously demonstrated to be associated with PMC after HLA-related HSCT for ß-Thal. The majority of the patient's erythrocytes were of donor origin, whereas T cells were initially mostly derived from the recipient, no HLA loss, but an increased frequency of circulating Tr1 cells were observed. For the first time, we showed that when the proportion of residual donor cells decreases, the frequency of CD49b(+)LAG-3(+) Tr1 cells declines, reaching the levels present in healthy subjects. These findings confirm previous results obtained in transplant related settings for ß-Thal, and supported the central role of Tr1 cells in promoting and maintaining PMC after allo-HSCT.
Assuntos
Quimerismo , Transplante de Células-Tronco Hematopoéticas , Linfócitos T Reguladores/citologia , Talassemia beta/genética , Talassemia beta/terapia , Estudos de Coortes , Haplótipos , Teste de Histocompatibilidade , Humanos , Linfócitos T Reguladores/metabolismoRESUMO
Previous studies have shown that a stable presence of both donor and recipient haematopoietic derived cells after allogeneic haematopoietic stem cell transplantation (HSCT) occurs in approximately ten percent of the patients affected by ß-Thalassemia. Once achieved this condition, defined as persistent mixed chimerism (PMC), the patients do not require additional red blood cells (RBCs) support and, regardless of the presence in some cases of an extremely low percentage of donor-derived nucleated cells, they are clinically cured by an incomplete, but functional graft. Most of the published papers have, however, investigated the impact of donor engraftment in the nucleated cells rather than in the mature erythrocytes. We have recently published a paper showing that in four long-term transplanted patients affected by hemoglobinopathies, characterized by the presence of few donor engrafted nucleated cells-both in the peripheral blood and in the bone marrow-the majority of the erythrocytes were of donor origin. Moreover we showed that the proportion of donor-derived erythroid precursors, determined by analyzing singularly picked-up burst-forming unit erythroid colonies, was equivalent to that observed in the mature nucleated cells rather than in the red blood cells. These results suggest that in patients characterized by the presence of PMC after HSCT a selective advantage of the donor erythroid precursors maturation might successfully contrast the problems bound to the recipient ineffective erythropoiesis. When genetically modified HSCT will be a possible option for treating Thalassemia Major, the co-existence of the repaired cells with those still expressing the genetic defect will be an expected scenario, not in an allogeneic, but in an autologous environment.
RESUMO
BACKGROUND: Persistent mixed chimerism represents a state in which recipient and donor cells stably co-exist after hematopoietic stem cell transplantation. However, since in most of the studies reported in literature the engraftment state was observed in the nucleated cells, in this study we determined the donor origin of the mature erythrocytes of patients with persistent mixed chimerism after transplantation for hemoglobinopathies. Results were compared with the engraftment state observed in singly picked out burst-forming unit - erythroid colonies and in the nucleated cells collected from the peripheral blood and from the bone marrow. DESIGN AND METHODS: The donor origin of the erythrocytes was determined analyzing differences on the surface antigens of the erythrocyte suspension after incubation with anti-ABO and/or anti-C, -c, -D, -E and -e monoclonal antibodies by a flow cytometer. Analysis of short tandem repeats was used to determine the donor origin of nucleated cells and burst-forming unit - erythroid colonies singly picked out after 14 days of incubation. RESULTS: The proportions of donor-derived nucleated cells in four transplanted patients affected by hemoglobinopathies were 71%, 46%, 15% and 25% at day 1364, 1385, 1314 and 932, respectively. Similar results were obtained for the erythroid precursors, analyzing the donor/recipient origin of the burst-forming unit - erythroid colonies. In contrast, on the same days of observation, the proportions of donor-derived erythrocytes in the four patients with persistent mixed chimerism were 100%, 100%, 73% and 90%. Conclusions Our results showed that most of the erythrocytes present in four long-term transplanted patients affected by hemoglobinopathies and characterized by the presence of few donor engrafted nucleated cells were of donor origin. The indication that small proportions of donor engrafted cells might be sufficient for clinical control of the disease in patients affected by hemoglobinopathies is relevant, although the biological mechanisms underlying these observations need further investigation.
Assuntos
Anemia Falciforme/terapia , Transplante de Medula Óssea , Núcleo Celular/patologia , Quimerismo , Eritrócitos/patologia , Hemoglobinopatias/etiologia , Talassemia beta/terapia , Adolescente , Adulto , Anemia Falciforme/complicações , Criança , Pré-Escolar , Eritrócitos/metabolismo , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Doadores de Tecidos , Adulto Jovem , Talassemia beta/complicaçõesRESUMO
BACKGROUND: Thalassemia major can be cured with allogeneic hematopoietic stem cell transplantation. Persistent mixed chimerism develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood. DESIGN AND METHODS: The presence of interleukin-10-producing T cells in the peripheral blood of eight patients with persistent mixed chimerism and five with full donor chimerism was investigated. A detailed characterization was then performed, by T-cell cloning, of the effector and regulatory T-cell repertoire of one patient with persistent mixed chimerism, who developed stable split erythroid/lymphoid chimerism after a hematopoietic stem cell transplant from an HLA-matched unrelated donor. RESULTS: Higher levels of interleukin-10 were produced by peripheral blood mononuclear cells from patients with persistent mixed chimerism than by the same cells from patients with complete donor chimerism or normal donors. T-cell clones of both host and donor origin could be isolated from the peripheral blood of one, selected patient with persistent mixed chimerism. Together with effector T-cell clones reactive against host or donor alloantigens, regulatory T-cell clones with a cytokine secretion profile typical of type 1 regulatory cells were identified at high frequencies. Type 1 regulatory cell clones, of both donor and host origin, were able to inhibit the function of effector T cells of either donor or host origin in vitro. CONCLUSIONS: Overall these results suggest that interleukin-10 and type 1 regulatory cells are associated with persistent mixed chimerism and may play an important role in sustaining long-term tolerance in vivo. These data provide new insights into the mechanisms of peripheral tolerance in chimeric patients and support the use of cellular therapy with regulatory T cells following hematopoietic stem cell transplantation.