Systematic analysis of sequences of anti-DNA antibodies—relevance                 to theories of origin and pathogenicity

Rahman, Anisur; Giles, Ian; Haley, Joanna; Isenberg, David

doi:10.1191/0961203302lu302rr

Cited by 46 publications

(36 citation statements)

References 74 publications

(104 reference statements)

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“…44 From a biological perspective, this may be an oversimplification, as a low mutational 'burden', even a single amino-acid replacement, can be functionally relevant. 8,45,46 For this reason, we adopted a different approach and separated the truly unmutated cases (100% identity) from the remaining cases showing any level of SHM and, thus, considered as mutated. For statistical purposes, mutated cases were further subdivided according to their IGHV gene mutational status into 'borderline/minimally mutated' (97 --99.9% identity to germline) and 'significantly mutated' subgroups (o97% identity).…”

Section: Discussionmentioning

confidence: 99%

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

et al. 2012

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We performed an immunogenetic analysis of 345 IGHV --IGHD --IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; 12.8%; 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele *04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2*04 peaked at 31%. The IGHV1-2*04 rearrangements carried significantly longer complementaritydetermining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2*04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97 --99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2*04 allele.

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Section: Discussionmentioning

confidence: 99%

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

et al. 2012

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“…From a biologic perspective, this may be an oversimplification, in view of ample evidence from normal, autoreactive and malignant B-cell clones where even a low mutational "burden" can be functionally relevant. 9,21,22 Here, we performed a detailed immunogenetic analysis of the IG receptors from 807 cases with MCL, by far the largest series to date. Our aim was to obtain a comprehensive view of the IG gene repertoire, with a special focus on SHM targeting and the configuration of the antigen-binding site.…”

Section: Introductionmentioning

confidence: 99%

Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases

Hadzidimitriou

Agathangelidis

Darzentas

et al. 2011

Blood

148

133

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We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eightyfour of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementaritydetermining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23.Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases. (Blood. 2011; 118(11):3088-3095) IntroductionMantle cell lymphoma (MCL) is an aggressive B-cell malignancy that represents 5%-10% of non-Hodgkin lymphomas. The median overall survival is 3-5 years, and at present, conventional treatment is not curative and long-term remission is rare. However, subsets of MCL patients follow a more indolent clinical course without disease progression for a relatively long period. 1 The cytogenetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32). This aberration leads to the juxtaposition of the CCDN1 locus on chromosome 11 to the immunoglobulin heavy chain (IGH) locus on chromosome 14. As a consequence, cyclin D1 is constitutively overexpressed, causing gross cell cycle deregulation. 2 In addition to the primary t(11;14), several secondary genomic aberrations can be identified in most MCL cases, 2,3 supporting early findings that cyclin D1 overexpression must be accompanied by other genetic abnormalities to promote lymphomagenesis. 2,4 Various gene expression changes that may cooperate with cyclin D1 deregulation also have been described in MCL, mainly involved in DNA repair pathways and the control of cell cycle and apoptosis. 4,5 That notwithstanding, alterations in the local tumor microenvironment also may play an important role in regulating the growth and survival of MCL neoplastic cells. 2,5,6 In B-cell malignancies, immunogenetic analysis of the clonogenic B-cell receptors (BcRs) offers valuable insight into both the ontogenetic derivation and the possible involvement of antigen selection. In particular, a biased repertoire of immunoglobulin heavy variable (IGHV) genes is generally considered as evid...

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“…Several authors have noted a preponderance of R, N, and K residues at the antigen-binding sites of human and murine anti-dsDNA antibodies (13,14,16). Using a database of 1,875 antibody sequences, Collis et al (39) showed that both R and N, but not K, are significantly overrepresented in the combining sites of antibodies that bind nucleotide antigens, in comparison with antibodies binding other types of antigen.…”

Section: Lambrianides Et Almentioning

confidence: 99%

Arginine mutation alters binding of a human monoclonal antibody to antigens linked to systemic lupus erythematosus and the antiphospholipid syndrome

Lambrianides¹,

Giles²,

Ioannou³

et al. 2007

Arthritis & Rheumatism

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Objective. Previous studies have shown the importance of somatic mutations and arginine residues in the complementarity-determining regions (CDRs) of pathogenic anti-double-stranded DNA (anti-dsDNA) antibodies in human and murine lupus, and in studies of murine antibodies, a role of mutations at position 53 in V H CDR2 has been demonstrated. We previously demonstrated in vitro expression and mutagenesis of the human IgG1 monoclonal antibody B3. The present study was undertaken to investigate, using this expression system, the importance of the arginine residue at position 53 (R53) in B3 V H .Methods. R53 was altered, by site-directed mutagenesis, to serine, asparagine, or lysine, to create 3 expressed variants of V H . In addition, the germline sequence of the V H 3-23 gene (from which B3 V H is derived) was expressed either with or without arginine at position 53. These 5 new heavy chains, as well as wild-type B3 V H , were expressed with 4 different light chains, and the resulting antibodies were assessed for their ability to bind to nucleosomes, ␣-actinin, cardiolipin, ovalbumin, ␤ 2 -glycoprotein I (␤ 2 GPI), and the N-terminal domain of ␤ 2 GPI (domain I), using direct binding assays.Results. The presence of R53 was essential but not sufficient for binding to dsDNA and nucleosomes. Conversely, the presence of R53 reduced binding to ␣-actinin, ovalbumin, ␤ 2 GPI, and domain I of ␤ 2 GPI. The combination B3 (R53S) V H /B3 V L bound human, but not bovine, ␤ 2 GPI.Conclusion. The fact that the R53S substitution significantly alters binding of B3 to different clinically relevant antigens, but that the alteration is in opposite directions depending on the antigen, implies that this arginine residue plays a critical role in the affinity maturation of antibody B3.

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Systematic analysis of sequences of anti-DNA antibodies—relevance to theories of origin and pathogenicity

Cited by 46 publications

References 74 publications

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases

Arginine mutation alters binding of a human monoclonal antibody to antigens linked to systemic lupus erythematosus and the antiphospholipid syndrome

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