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[PMID]: 29385200 [Au] Autor: Rout ED; Burnett RC; Labadie JD; Yoshimoto JA; Avery AC [Ad] Endereço: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America. [Ti] Título: Preferential use of unmutated immunoglobulin heavy variable region genes in Boxer dogs with chronic lymphocytic leukemia. [So] Source: PLoS One;13(1):e0191205, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Human chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease, and immunoglobulin heavy variable region (IGHV) gene mutational status is an important prognostic marker. IGHV mutational status has not been previously examined in canine CLL. We sequenced the IGHV-D-J rearrangements from 55 canine patients with CLL, including 36 non-Boxer and 19 Boxer dogs. The majority of non-Boxers (75%) had mutated IGHV genes, whereas the majority of Boxers (79%) had unmutated IGHV genes. IGHV3-41 and IGHV3-67 gene usage was significantly higher in Boxers with CLL compared to non-Boxers. Additionally, 11 Boxers with large B-cell lymphoma and the normal IGHV repertoire of six control dogs (three Boxers and three non-Boxers) were sequenced. IGHV3-41 was preferentially used in Boxers with other forms of lymphoma and without lymphoproliferative disease. However, preferential use of unmutated IGHV genes was unique to Boxers with CLL, suggesting Boxers may be a valuable model to investigate unmutated CLL. [Mh] Termos MeSH primário: Doenças do Cão/genética Doenças do Cão/imunologia Genes de Cadeia Pesada de Imunoglobulina Região Variável de Imunoglobulina/genética Leucemia Linfocítica Crônica de Células B/veterinária [Mh] Termos MeSH secundário: Animais Sequência de Bases Estudos de Casos e Controles Análise Mutacional de DNA DNA de Neoplasias/genética Cães Feminino Rearranjo Gênico de Cadeia Pesada de Linfócito B Leucemia Linfocítica Crônica de Células B/genética Leucemia Linfocítica Crônica de Células B/imunologia Masculino Mutação Homologia de Sequência do Ácido Nucleico Especificidade da Espécie Éxons VDJ [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DNA, Neoplasm); 0 (Immunoglobulin Variable Region) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180201 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191205

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[PMID]: 28682481 [Au] Autor: Moody S; Escudero-Ibarz L; Wang M; Clipson A; Ochoa Ruiz E; Dunn-Walters D; Xue X; Zeng N; Robson A; Chuang SS; Cogliatti S; Liu H; Goodlad J; Ashton-Key M; Raderer M; Bi Y; Du MQ [Ad] Endereço: Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK. [Ti] Título: Significant association between TNFAIP3 inactivation and biased immunoglobulin heavy chain variable region 4-34 usage in mucosa-associated lymphoid tissue lymphoma. [So] Source: J Pathol;243(1):3-8, 2017 Sep. [Is] ISSN: 1096-9896 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Both antigenic drive and genetic change play critical roles in the development of mucosa-associated lymphoid tissue (MALT) lymphoma, but neither alone is sufficient for malignant transformation, and lymphoma development critically depends on their cooperation. However, which of these different events concur and how they cooperate in MALT lymphomagenesis is totally unknown. To explore this, we investigated somatic mutations of 17 genes and immunoglobulin heavy chain variable region (IGHV) usage in 179 MALT lymphomas from various sites. We showed that: (1) there was a significant association between the biased usage of IGHV4-34 (binds to the carbohydrate I/i antigens) and inactivating mutation of TNFAIP3 [encoding a global negative regulator of the canonical nuclear factor-κB (NF-κB) pathway] in ocular adnexal MALT lymphoma; (2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of the salivary gland, but was not associated with mutation in any of the 17 genes investigated; and (3) MALT lymphoma lacked mutations that are frequently seen in other B-cell lymphomas characterized by constitutive NF-κB activities, including mutations in CD79B, CARD11, MYD88, TNFRSF11A, and TRAF3. Our findings show, for the first time, a significant association between biased usage of autoreactive IGHV and somatic mutation of NF-κB regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic B-cell receptor signalling and driving oncogenesis in lymphoma development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [Mh] Termos MeSH primário: Biomarcadores Tumorais/genética Neoplasias Oculares/genética Rearranjo Gênico Inativação Gênica Genes de Cadeia Pesada de Imunoglobulina Região Variável de Imunoglobulina/genética Linfoma de Zona Marginal Tipo Células B/genética Mutação Neoplasias de Anexos e de Apêndices Cutâneos/genética Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética [Mh] Termos MeSH secundário: Biomarcadores Tumorais/imunologia Análise Mutacional de DNA Neoplasias Oculares/imunologia Neoplasias Oculares/patologia Predisposição Genética para Doença Seres Humanos Região Variável de Imunoglobulina/imunologia Linfoma de Zona Marginal Tipo Células B/imunologia Linfoma de Zona Marginal Tipo Células B/patologia Neoplasias de Anexos e de Apêndices Cutâneos/imunologia Neoplasias de Anexos e de Apêndices Cutâneos/patologia Fenótipo Proteína 3 Induzida por Fator de Necrose Tumoral alfa/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers, Tumor); 0 (Immunoglobulin Variable Region); EC 3.4.19.12 (TNFAIP3 protein, human); EC 3.4.19.12 (Tumor Necrosis Factor alpha-Induced Protein 3) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170707 [St] Status: MEDLINE [do] DOI: 10.1002/path.4933

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[PMID]: 28502113 [Au] Autor: Dong Y; Wu C; Zhao X; Zhang P; Zhang H; Zheng M; Li S; Jiao J; Yu X; Lv Z; Ji Y [Ad] Endereço: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China. [Ti] Título: Epigenetic modifications of the V region after DJ recombination in Pro-B cells. [So] Source: Immunology;152(2):218-231, 2017 Oct. [Is] ISSN: 1365-2567 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The variable region of murine immunoglobulin heavy chain (Igh) is assembled by sequential D -J and V -DJ recombination. The accessibility of the Igh locus determines the order of rearrangement. Because of the large number of V genes and the lack of a suitable model, the epigenetic modifications of V genes after DJ recombination have not previously been characterized. Here, we employed two v-Abl pro-B cell lines, in which the Igh locus is in germline and DJ -recombined configurations, respectively. The DJ junction displays the characteristics of a recombination centre, such as high levels of activation-associated histone modifications and recombination-activating gene protein (RAG) binding in DJ -rearranged pro-B cells, which extend the recombination centre model proposed for the germline Igh locus. The different domains of the V region have distinct epigenetic characteristics after DJ recombination. Distal V genes have higher levels of active histone modifications, germline transcription and Pax5 binding, and good quality recombination signal sequences. Proximal V genes are relatively close to the DJ recombination centre, which partially compensates for the low levels of the above active epigenetic modifications. DJ recombination centre might serve as a cis-acting element to regulate the accessibility of the V region. Furthermore, we demonstrate that RAG weakly binds to functional V genes, which is the first detailed assessment of RAG dynamic binding to V genes. We provide a way for V -DJ recombination in which the V gene is brought into close proximity with the DJ recombination centre for RAG binding by a Pax5-dependent chromosomal compaction event, and held in this position for subsequent cleavage and V -DJ joining. [Mh] Termos MeSH primário: Epigênese Genética Rearranjo Gênico do Linfócito B Genes de Cadeia Pesada de Imunoglobulina Região Variável de Imunoglobulina/genética Células Precursoras de Linfócitos B/imunologia [Mh] Termos MeSH secundário: Acetilação Animais Linhagem Celular Transformada Imunoprecipitação da Cromatina Proteínas de Ligação a DNA/imunologia Proteínas de Ligação a DNA/metabolismo Genes abl Células HEK293 Histonas/metabolismo Proteínas de Homeodomínio/imunologia Proteínas de Homeodomínio/metabolismo Seres Humanos Região de Junção de Imunoglobulinas/genética Região de Junção de Imunoglobulinas/imunologia Região Variável de Imunoglobulina/imunologia Região Variável de Imunoglobulina/metabolismo Metilação Camundongos Camundongos Endogâmicos C57BL Fator de Transcrição PAX5/genética Fator de Transcrição PAX5/metabolismo Células Precursoras de Linfócitos B/metabolismo Ligação Proteica Processamento de Proteína Pós-Traducional Transcrição Genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DNA-Binding Proteins); 0 (Histones); 0 (Homeodomain Proteins); 0 (Immunoglobulin Joining Region); 0 (Immunoglobulin Variable Region); 0 (PAX5 Transcription Factor); 0 (Pax5 protein, mouse); 0 (Rag2 protein, mouse); 128559-51-3 (RAG-1 protein) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171002 [Lr] Data última revisão: 171002 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170515 [St] Status: MEDLINE [do] DOI: 10.1111/imm.12758

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[PMID]: 28438896 [Au] Autor: Longo NS; Rogosch T; Zemlin M; Zouali M; Lipsky PE [Ad] Endereço: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. [Ti] Título: Mechanisms That Shape Human Antibody Repertoire Development in Mice Transgenic for Human Ig H and L Chain Loci. [So] Source: J Immunol;198(10):3963-3977, 2017 May 15. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: To determine the impact of the milieu on the development of the human B cell repertoire, we carried out a comprehensive analysis of productive and nonproductive Ig gene rearrangements from transgenic mice engineered to express single copies of the unrearranged human H chain and L chain Ig gene loci. By examining the nonproductive repertoire as an indication of the immediate product of the rearrangement machinery without an impact of selection, we discovered that the distribution of human rearrangements arising in the mouse was generally comparable to that seen in humans. However, differences between the distribution of nonproductive and productive rearrangements that reflect the impact of selection suggested species-specific selection played a role in shaping the respective repertoires. Although expression of some VH genes was similar in mouse and human (IGHV3-23, IGHV3-30, and IGHV4-59), other genes behaved differently (IGHV3-33, IGHV3-48, IGHV4-31, IGHV4-34, and IGHV1-18). Gene selection differences were also noted in L chains. Notably, nonproductive human VH rearrangements in the transgenic mice expressed shorter CDRH3 with less N addition. Even the CDRH3s in the productive rearrangements were shorter in length than those of the normal human productive repertoire. Amino acids in the CDRH3s in both species showed positive selection of tyrosines and glycines, and negative selection of leucines. The data indicate that the environment in which B cells develop can affect the expressed Ig repertoire by exerting influences on the distribution of expressed VH and VL genes and by influencing the amino acid composition of the Ag binding site. [Mh] Termos MeSH primário: Linfócitos B/imunologia Rearranjo Gênico de Cadeia Pesada de Linfócito B Rearranjo Gênico do Linfócito B Genes de Imunoglobulinas Cadeias Pesadas de Imunoglobulinas/genética Região Variável de Imunoglobulina/genética [Mh] Termos MeSH secundário: Aminoácidos/análise Animais Animais Geneticamente Modificados Genes de Cadeia Pesada de Imunoglobulina Seres Humanos Cadeias Pesadas de Imunoglobulinas/química Cadeias Pesadas de Imunoglobulinas/imunologia Imunoglobulina M Região Variável de Imunoglobulina/química Região Variável de Imunoglobulina/imunologia Camundongos Família Multigênica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acids); 0 (Immunoglobulin Heavy Chains); 0 (Immunoglobulin M); 0 (Immunoglobulin Variable Region) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170919 [Lr] Data última revisão: 170919 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170426 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1700133

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[PMID]: 28422925 [Au] Autor: Gao B; Gu Y; Rong C; Moore C; Porcheray F; Wong W; Preffer F; Saidman SL; Fu Y; Cosimi B; Sachs DH; Kawai T; Sykes M; Zorn E [Ad] Endereço: 1 Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 2 Transplant Center, The First Hospital of Jilin University, Changchun, China. 3 Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY. 4 The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China. 5 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. [Ti] Título: Dynamics of B Cell Recovery In Kidney/Bone Marrow Transplant Recipients. [So] Source: Transplantation;101(11):2722-2730, 2017 Nov. [Is] ISSN: 1534-6080 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Previous studies identified B cell gene signatures and predominance of specific B cell subsets as a marker of operational tolerance after kidney transplantation. These findings suggested a role for B cells in the establishment or maintenance of tolerance. Here we analyzed B cell recovery in 4 subjects, 3 of whom achieved tolerance after combined kidney/bone marrow transplantation. METHODS: Peripheral B cell subsets were examined longitudinally by flow cytometry. Immunoglobulin heavy chain repertoire analysis was performed using next-generation sequencing. Lastly, the patients' serum reactivity to HLA was assessed by Luminex. RESULTS: B cell counts recovered approximately 1 year posttransplant except for 1 subject who experienced delayed reconstitution. This subject resumed immunosuppression for acute rejection at 10 months posttransplant and underwent preemptive retransplantation at 3 years for chronic rejection. B cell recovery was accompanied by a high frequency of CD20 + CD24CD38 transitional B cells and a diversified clonal repertoire. However, all 4 subjects showed prevalence of CD20 + CD27+ memory B cells around 6 months posttransplant when B cell counts were still low and the clonal B cell repertoire very limited. The predominance of memory B cells was also associated with high levels of somatically mutated immunoglobulin heavy chain variable sequences and transient serum reactivity to HLA. CONCLUSIONS: Our observations reveal the presence of memory B cells early posttransplant that likely escaped the preparative regimen at a time consistent with the establishment of tolerance. Further studies are warranted to characterize the functional properties of these persisting memory cells and evaluate their potential contribution to tolerance induction. [Mh] Termos MeSH primário: Linfócitos B/imunologia Transplante de Medula Óssea Proliferação Celular Transplante de Rim [Mh] Termos MeSH secundário: Linfócitos B/metabolismo Biomarcadores/sangue Boston Feminino Genes de Cadeia Pesada de Imunoglobulina Sobrevivência de Enxerto Antígenos HLA/imunologia Hospitais Gerais Seres Humanos Memória Imunológica Isoanticorpos/sangue Contagem de Linfócitos Masculino Mutação Fenótipo Recuperação de Função Fisiológica Fatores de Tempo Tolerância ao Transplante Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 0 (HLA Antigens); 0 (Isoantibodies) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171106 [Lr] Data última revisão: 171106 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170420 [St] Status: MEDLINE [do] DOI: 10.1097/TP.0000000000001789

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[PMID]: 28419517 [Au] Autor: Cavalli M; De Novi LA; Della Starza I; Cappelli LV; Nunes V; Pulsoni A; Del Giudice I; Guarini A; Foà R [Ad] Endereço: Haematology, Department of Cellular Biotechnologies and Haematology, Policlinico Umberto I, Sapienza University, Rome, Italy. [Ti] Título: Comparative analysis between RQ-PCR and digital droplet PCR of BCL2/IGH gene rearrangement in the peripheral blood and bone marrow of early stage follicular lymphoma. [So] Source: Br J Haematol;177(4):588-596, 2017 May. [Is] ISSN: 1365-2141 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BCL2/IGH rearrangements were analysed by polymerase chain reaction (PCR) at diagnosis in paired peripheral blood (PB) and bone marrow (BM) samples from 67 patients with stage I/II follicular lymphoma (FL). Real time quantitative PCR (RQ-PCR) and digital droplet PCR (ddPCR) were performed in cases with a major breakpoint region (MBR+) at diagnosis and after localized radiotherapy and rituximab administration in order to investigate the applicability of ddPCR. The overall ddPCR/RQ-PCR concordance was 81·9% (113/138 samples) and 97·5% in the 40/138 with quantifiable disease (RQ-PCR≥10 ). At baseline, ddPCR allowed the recovery of a MBR+ marker in 8/18 (44·4%) samples that resulted MBR-negative/minor cluster region-negative/minor BCL2-negative by qualitative PCR. Moreover, the tumour burden at diagnosis significantly predicted progression-free survival (PSF) only when quantified by ddPCR. Paired PB and BM samples analysis demonstrated a high concordance in the detection of BCL2/IGH+ cells by qualitative and quantitative methods; in particular, 40/62 samples were positive by ddPCR (25 PB+/BM+; 9 PB+/BM-; 6 PB-/BM+), with 34/40 (85%) identified by the study of PB only. In conclusion, in localized FL, ddPCR is a promising tool for monitoring minimal residual disease (MRD) that is at least comparable to RQ-PCR and potentially more accurate. PB is a suitable source for serial BCL2/IGH MRD assessments, regardless of the methodology utilized. [Mh] Termos MeSH primário: Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética Genes de Cadeia Pesada de Imunoglobulina/genética Genes bcl-2/genética Linfoma Folicular/genética [Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico Medula Óssea/fisiologia Terapia Combinada Seres Humanos Leucócitos Mononucleares/fisiologia Linfoma Folicular/diagnóstico Linfoma Folicular/terapia Neoplasia Residual/genética Reação em Cadeia da Polimerase em Tempo Real/métodos Rituximab/uso terapêutico Translocação Genética [Pt] Tipo de publicação: COMPARATIVE STUDY; EVALUATION STUDIES; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 4F4X42SYQ6 (Rituximab) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170731 [Lr] Data última revisão: 170731 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170419 [St] Status: MEDLINE [do] DOI: 10.1111/bjh.14616

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[PMID]: 28388445 [Au] Autor: Kirik U; Greiff L; Levander F; Ohlin M [Ad] Endereço: Dept. of Immunotechnology, Lund University, Lund, Sweden. [Ti] Título: Parallel antibody germline gene and haplotype analyses support the validity of immunoglobulin germline gene inference and discovery. [So] Source: Mol Immunol;87:12-22, 2017 Jul. [Is] ISSN: 1872-9142 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Analysis of antibody repertoire development and specific antibody responses important for e.g. autoimmune conditions, allergy, and protection against disease is supported by high throughput sequencing and associated bioinformatics pipelines that describe the diversity of the encoded antibody variable domains. Proper assignment of sequences to germline genes are important for many such processes, for instance in the analysis of somatic hypermutation. Germline gene inference from antibody-encoding transcriptomes, by using tools such as TIgGER or IgDiscover, has a potential to enhance the quality of such analyses. These tools may also be used to identify germline genes not previously known. In this study, we exploited such software for germline gene inference and define aspects of analysis settings and pre-existing knowledge of germline genes that affect the outcome of gene inference. Furthermore, we demonstrate the capacity of IGHJ and IGHD haplotype inference, whenever subjects are heterozygous with respect to such genes, to lend support to IGHV gene inference in general, and to the identification of novel alleles presently not recognized by germline gene reference directories. We propose that such haplotype analysis shall, whenever possible, be used in future best practice to support the outcome of germline gene inference. IGHJ-directed haplotype inference was also used to identify haplotypes not expressing some IGHV germline genes. In particular, we identified a haplotype that did not express several major germline genes such as IGHV1-8, IGHV3-9, IGHV3-15, IGHV1-18, IGHV3-21, and IGHV3-23. We envisage that haplotype analysis will provide an efficient approach to identify subjects for further studies of the link between the available immunoglobulin repertoire and outcomes of immune responses. [Mh] Termos MeSH primário: Anticorpos/genética Genes de Cadeia Pesada de Imunoglobulina/genética Genes de Imunoglobulinas/genética Haplótipos/genética [Mh] Termos MeSH secundário: Alelos Seres Humanos Cadeias Pesadas de Imunoglobulinas/genética Região Variável de Imunoglobulina/genética Família Multigênica/genética Mutação/genética Transcriptoma/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies); 0 (Immunoglobulin Heavy Chains); 0 (Immunoglobulin Variable Region) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170912 [Lr] Data última revisão: 170912 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170408 [St] Status: MEDLINE

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[PMID]: 28386906 [Au] Autor: Strati P; Parikh SA; Chaffee KG; Achenbach SJ; Slager SL; Call TG; Ding W; Jelinek DF; Hanson CA; Kay NE; Shanafelt TD [Ad] Endereço: Mayo Clinic College of Medicine, Rochester, MN, USA. [Ti] Título: CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with chronic lymphocytic leukaemia. [So] Source: Br J Haematol;178(1):99-105, 2017 Jul. [Is] ISSN: 1365-2141 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: CD49d is a surface integrin that is expressed on chronic lymphocytic leukaemia (CLL) cells, and strongly correlates with more aggressive disease. Given its association with cell-cell adhesion and leucocyte trafficking, we hypothesized that patients with high CD49d expression would experience a clinical course dominated by lymphadenopathy. CD49d expression was measured by flow cytometry and considered positive if expressed by ≥30% of CLL cells. The study included 797 newly diagnosed CLL/small lymphocytic leukaemia patients; 279 (35%) were CD49d positive. CD49d-positive patients were more likely to present with lymphadenopathy (P < 0·001); a finding that persisted after adjusting for fluorescence in situ hybridisation (FISH) and IGHV mutation status [odds ratio (OR) 2·51; 95% confidence interval (CI) 1·64-3·83; P < 0·001]. Among CLL Rai 0 patients, CD49d positivity was associated with shorter time to development of lymphadenopathy (3·2 years vs not reached, P < 0·01). This association was maintained after adjusting for either FISH [hazard ratio (HR) 2·18; 95% CI 1·25-3·81; P = 0·006) or IGHV status (HR 2·02; 95% CI 1·11-3·69; P = 0·02) individually, but was attenuated when adjusting by both (HR 1·72; 95% CI 0·88-3·38; P = 0·11).These data demonstrate that CD49d-positive CLL patients experience a disease course dominated by lymphadenopathy. These findings could have implications for therapy selection and disease monitoring. [Mh] Termos MeSH primário: Biomarcadores Tumorais/sangue Genes de Cadeia Pesada de Imunoglobulina/genética Integrina alfa4/sangue Leucemia Linfocítica Crônica de Células B/diagnóstico Linfadenopatia/diagnóstico [Mh] Termos MeSH secundário: Adulto Idoso Idoso de 80 Anos ou mais Progressão da Doença Feminino Seguimentos Seres Humanos Região Variável de Imunoglobulina/genética Leucemia Linfocítica Crônica de Células B/genética Leucemia Linfocítica Crônica de Células B/patologia Linfadenopatia/genética Masculino Meia-Idade Mutação Estadiamento de Neoplasias Prognóstico Fatores de Tempo Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers, Tumor); 0 (Immunoglobulin Variable Region); 143198-26-9 (Integrin alpha4) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170906 [Lr] Data última revisão: 170906 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170408 [St] Status: MEDLINE [do] DOI: 10.1111/bjh.14647

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[PMID]: 28255762 [Au] Autor: Medvedeva EV; Dmitrieva VG; Limborska SA; Myasoedov NF; Dergunova LV [Ad] Endereço: Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, 123182, Russia. medvedevaekaterina@yandex.ru. [Ti] Título: Semax, an analog of ACTH , regulates expression of immune response genes during ischemic brain injury in rats. [So] Source: Mol Genet Genomics;292(3):635-653, 2017 Jun. [Is] ISSN: 1617-4623 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Brain stroke continues to claim the lives of million people every year. To build the effective strategies for stroke treatment it is necessary to understand the neuroprotective mechanisms that are able to prevent the ischemic injury. Consisting of the ACTH fragment and the tripeptide Pro-Gly-Pro (PGP), the synthetic peptide Semax effectively protects brain against ischemic stroke. However, the molecular mechanisms underlying its neuroprotection and participation of PGP in them are still needed to be clarified. To reveal biological processes and signaling pathways, which are affected by Semax and PGP, we performed the transcriptome analysis of cerebral cortex of rats with focal cerebral ischemia treated by these peptides. The genome-wide biochip data analysis detected the differentially expressed genes (DEGs) and bioinformatic web-tool Ingenuity iReport found DEGs associations with several biological processes and signaling pathways. The immune response is the process most markedly affected by the peptide: Semax enhances antigen presentation signaling pathway, intensifies the effect of ischemia on the interferon signaling pathways and affects the processes for synthesizing immunoglobulins. Semax significantly increased expression of the gene encoding the immunoglobulin heavy chain, highly affects on cytokine, stress response and ribosomal protein-encoding genes after occlusion. PGP treatment of rats with ischemia attenuates the immune activity and suppresses neurotransmission in the CNS. We suppose that neuroprotective mechanism of Semax is realized via the neuroimmune crosstalk, and the new properties of PGP were found under ischemia. Our results provided the basis for further proteomic investigations in the field of searching Semax neuroprotection mechanism. [Mh] Termos MeSH primário: Hormônio Adrenocorticotrópico/análogos & derivados Isquemia Encefálica/imunologia Isquemia Encefálica/prevenção & controle Genes de Cadeia Pesada de Imunoglobulina/efeitos dos fármacos Cadeias Pesadas de Imunoglobulinas/genética Fármacos Neuroprotetores/uso terapêutico Oligopeptídeos/uso terapêutico Fragmentos de Peptídeos/uso terapêutico Prolina/análogos & derivados [Mh] Termos MeSH secundário: Hormônio Adrenocorticotrópico/uso terapêutico Animais Apresentação do Antígeno/efeitos dos fármacos Apresentação do Antígeno/imunologia Isquemia Encefálica/genética Modelos Animais de Doenças Perfilação da Expressão Gênica Cadeias Pesadas de Imunoglobulinas/biossíntese Masculino Artéria Cerebral Média/cirurgia Prolina/uso terapêutico Ratos Ratos Wistar Estresse Fisiológico/efeitos dos fármacos Estresse Fisiológico/imunologia Transcriptoma/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Immunoglobulin Heavy Chains); 0 (Neuroprotective Agents); 0 (Oligopeptides); 0 (Peptide Fragments); 0 (prolyl-glycyl-proline); 80714-61-0 (ACTH (4-7), Pro-Gly-Pro-); 9002-60-2 (Adrenocorticotropic Hormone); 9DLQ4CIU6V (Proline) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171007 [Lr] Data última revisão: 171007 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170304 [St] Status: MEDLINE [do] DOI: 10.1007/s00438-017-1297-1

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MEDLINE

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[PMID]: 28249016 [Au] Autor: García-Álvarez M; Alcoceba M; López-Parra M; Puig N; Antón A; Balanzategui A; Prieto-Conde I; Jiménez C; Sarasquete ME; Chillón MC; Gutiérrez ML; Corral R; Alonso JM; Queizán JA; Vidán J; Pardal E; Peñarrubia MJ; Bastida JM; García-Sanz R; Marín L; González M [Ad] Endereço: Department of Hematology, University Hospital of Salamanca (HUS-IBSAL), Salamanca, Spain. [Ti] Título: HLA specificities are associated with prognosis in IGHV-mutated CLL-like high-count monoclonal B cell lymphocytosis. [So] Source: PLoS One;12(3):e0172978, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: INTRODUCTION: Molecular alterations leading progression of asymptomatic CLL-like high-count monoclonal B lymphocytosis (hiMBL) to chronic lymphocytic leukemia (CLL) remain poorly understood. Recently, genome-wide association studies have found 6p21.3, where the human leukocyte antigen (HLA) system is coded, to be a susceptibility risk region for CLL. Previous studies have produced discrepant results regarding the association between HLA and CLL development and outcome, but no studies have been performed on hiMBL. AIMS: We evaluated the role of HLA class I (-A, -B and -C) and class II (-DRB1 and -DQB1) in hiMBL/CLL susceptibility, hiMBL progression to CLL, and treatment requirement in a large series of 263 patients diagnosed in our center with hiMBL (n = 156) or Binet A CLL (n = 107). RESULTS: No consistent association between HLA specificities and hiMBL or CLL susceptibility was found. With a median follow-up of 7.7 years, 48/156 hiMBLs (33%) evolved to asymptomatic CLLs, while 16 hiMBLs (10%) and 44 CLLs (41%) required treatment. No HLA specificities were found to be significantly associated with hiMBL progression or treatment in the whole cohort. However, within antigen-experienced immunoglobulin heavy-chain (IGHV)-mutated hiMBLs, which represents the highest proportion of hiMBL cases (81%), the presence of HLA-DQB1*03 showed a trend to a higher risk of progression to CLL (60% vs. 26%, P = 0.062). Moreover, HLA-DQB1*02 specificity was associated with a lesser requirement for 15-year treatment (10% vs. 36%, P = 0.012). CONCLUSION: In conclusion, our results suggest a role for HLA in IGHV-mutated hiMBL prognosis, and are consistent with the growing evidence of the influence of 6p21 on predisposition to CLL. Larger non-biased series are required to enable definitive conclusions to be drawn. [Mh] Termos MeSH primário: Genes de Cadeia Pesada de Imunoglobulina Antígenos de Histocompatibilidade Classe I/genética Linfocitose/genética Mutação [Mh] Termos MeSH secundário: Adulto Idoso Idoso de 80 Anos ou mais Linfócitos B/patologia Cromossomos Humanos Par 6/genética Feminino Seres Humanos Contagem de Linfócitos Linfocitose/sangue Masculino Meia-Idade Prognóstico [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Histocompatibility Antigens Class I) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170302 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0172978

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