IMGT/3Dstructure-DB and IMGT/DomainGapAlign: a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF

Ehrenmann, François; Kaas, Quentin; Lefranc, Marie‐Paule

doi:10.1093/nar/gkp946

Cited by 227 publications

(294 citation statements)

References 35 publications

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“…Accumulating evidence from the recent literature, 35,36 combined with our experience from similar analyses, led us to adopt more stringent subset-defining criteria than we did previously, so that the identified primary amino acid sequence relatedness may correspond to actual structural similarity. 37,38 The revised criteria mainly related to (1) VH CDR3 length, known to be a critical determinant of the structure of the Ag recognition loop, 39 and (2) the exact location of the shared pattern within the VH CDR3 region, given ample evidence that the positioning of certain amino acids may affect Ig structure stabilization. 40,41 For these reasons and to ensure maximum accuracy, we followed a conservative approach and required for same-subset assignment at the ground level no less than total identity in VH CDR3 length and offset of shared patterns.…”

Section: Discussionmentioning

confidence: 99%

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

Agathangelidis

Darzentas

Hadzidimitriou

et al. 2012

Blood

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341

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Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotypedBCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset. (Blood. 2012;119(19):4467-4475) IntroductionThe analysis of the Ig genes in chronic lymphocytic leukemia (CLL) has contributed significantly toward deciphering the molecular pathogenesis of the disease. Studies from the 1990s provided the first indications for a possible role of Ag(s) in selecting the CLL progenitor cells, through the discovery of a biased Ig heavy variable (IGHV) gene repertoire, different from that of normal B cells, as well as distinctive Ag-binding sites among unrelated cases. [1][2][3][4][5] By the late 1990s, it emerged that the mutational status of the rearranged IGHV genes directly correlated with patient survival. In particular, patients with unmutated IGHV genes were found to follow a more aggressive clinical course and have significantly shorter survival than patients carrying mutated IGHV genes. 6,7 Yet, there were exceptions to this rule: cases using the IGHV3-21 gene, although mostly expressing mutated Ig, had a survival similar to that of unmutated cases. 8 Intriguingly, approximately half of the IGHV3-21 cases were found to display restricted and, in some instances, essentially identical variable heavy complementarity determining region 3 (VH CDR3) sequences and identical light chains, strongly suggesting recognition of a common antigenic determinant. 9 Soon thereafter, the study of Ig sequences in CLL by groups in both Europe and the United States led to the identification of several other subsets of cases carrying highly similar BCR Igs among both mutated and unmutated cases (stereotyped BCR). [10][11][12][13][14] The identification of stereotypy among unrelated and geographically distant cases was widely accepted as evidence for the Submitted November 26, 2011; accepte...

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Section: Discussionmentioning

confidence: 99%

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

Agathangelidis

Darzentas

Hadzidimitriou

et al. 2012

Blood

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341

383

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“…Three-dimensional molecular modelling of ternary TCR/DRB1*0301/peptide complexes Vα2.3/Vβ22 TCR sequences were retrieved from the IMGT (International ImMunoGeneTics Information System) database [21], and all modelling was performed manually using the COOT program [22]. A detailed description of the modelling procedure is provided in the online data supplement.…”

Section: Discussionmentioning

confidence: 99%

T-cell receptor–HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis

et al. 2015

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In pulmonary sarcoidosis, CD4+ T-cells expressing T-cell receptor Vα2.3 accumulate in the lungs of HLA-DRB1*03 + patients. To investigate T-cell receptor-HLA-DRB1*03 interactions underlying recognition of hitherto unknown antigens, we performed detailed analyses of T-cell receptor expression on bronchoalveolar lavage fluid CD4 + T-cells from sarcoidosis patients. Pulmonary sarcoidosis patients (n=43) underwent bronchoscopy with bronchoalveolar lavage. T-cell receptor α and β chains of CD4 + T-cells were analysed by flow cytometry, DNA-sequenced, and threedimensional molecular models of T-cell receptor-HLA-DRB1*03 complexes generated.Simultaneous expression of Vα2.3 with the Vβ22 chain was identified in the lungs of all HLA-DRB1*03 + patients. Accumulated Vα2.3/Vβ22-expressing T-cells were highly clonal, with identical or near-identical Vα2.3 chain sequences and inter-patient similarities in Vβ22 chain amino acid distribution. Molecular modelling revealed specific T-cell receptor-HLA-DRB1*03-peptide interactions, with a previously identified, sarcoidosis-associated vimentin peptide, (Vim)429-443 DSLPLVDTHSKRTLL, matching both the HLA peptide-binding cleft and distinct T-cell receptor features perfectly.We demonstrate, for the first time, the accumulation of large clonal populations of specific Vα2.3/Vβ22 T-cell receptor-expressing CD4 + T-cells in the lungs of HLA-DRB1*03 + sarcoidosis patients. Several distinct contact points between Vα2.3/Vβ22 receptors and HLA-DRB1*03 molecules suggest presentation of prototypic vimentin-derived peptides. @ERSpublications Clonal CD4 + lung T-cells associating with HLA-DRB1*03 molecules indicate specific antigens in pulmonary sarcoidosis

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“…Relevant identified peptide sequences were determined by base peak interrogation as described previously (49) and aligned to the IMGT numbering system (16,17,45) with the IMGT/DomainGapAlign tool (88). Missing sequence patches were identified via inverse interrogation of the PEAKS results and LC-MS/MS data.…”

Section: Methodsmentioning

confidence: 99%

Aggregation of Full-length Immunoglobulin Light Chains from Systemic Light Chain Amyloidosis (AL) Patients Is Remodeled by Epigallocatechin-3-gallate

Andrich

Hegenbart

Kimmich

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserIntervention into amyloid deposition with anti-amyloid agents like the polyphenol epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and multiple myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL do they form amyloid deposits in vivo. We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms. We isolated nine LC from the urine of AL and MM patients. We quantified their thermodynamic stabilities and monitored their aggregation under physiological conditions by thioflavin T fluorescence, light scattering, SDS stability, and atomic force microscopy. LC from all patients formed amyloid-like aggregates, albeit with individually different kinetics. LC existed as dimers, ϳ50% of which were linked by disulfide bridges. Our results suggest that cleavage into LC monomers is required for efficient amyloid formation. The kinetics of AL LC displayed a transition point in concentration dependence, which MM LC lacked. The lack of concentration dependence of MM LC aggregation kinetics suggests that conformational change of the light chain is rate-limiting for these proteins. Aggregation kinetics displayed two distinct phases, which corresponded to the formation of oligomers and amyloid fibrils, respectively. EGCG specifically inhibited the second aggregation phase and induced the formation of SDS-stable, non-amyloid LC aggregates. Our data suggest that EGCG intervention does not depend on the individual LC sequence and is similar to the mechanism observed for amyloid-␤ and ␣-synuclein. Systemic light chain amyloidosis (AL)2 is the most common form of systemic amyloidosis (1), but it is still a rare disease with an incidence of 6 -7 in 1,000,000 people (2). Underlying AL pathology is a clonal plasma cell disorder, which produces an immunoglobulin light chain in the bone marrow with a unique sequence. These light chains are released into the blood (monoclonal gammopathy). When elevated LC levels in serum overwhelm renal absorption, LC is also found in the urine. Fulllength LC can be isolated from the urine of these patients (3-5).Clonal plasma cell disorders can present different types of pathologies; light chains form amyloid deposits in AL patients. Here, LC fibrils adopt a conformation characterized by highly stable, intramolecular cross-␤-sheets that stain with Congo red (6) and thioflavin T (ThT) (7-9).In contrast, amyloid deposits are not observed in patients suffering from multiple myeloma (MM), a malignant disease characterized by bone marrow failure and bone destruction. The two contrasting pathologies of LC gammopathies raise the question of which factors determine amyloid formation. Amyloid formation could be initiated (a) by the sequences of the individual light chains, (b) by high levels of light chain expression, (c) by p...

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IMGT/3Dstructure-DB and IMGT/DomainGapAlign: a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF

Cited by 227 publications

References 35 publications

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

T-cell receptor–HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis

Aggregation of Full-length Immunoglobulin Light Chains from Systemic Light Chain Amyloidosis (AL) Patients Is Remodeled by Epigallocatechin-3-gallate

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