Serological and genetic characterization of a human monoclonal immunoglobulin G anti-DNA idiotype.

Ehrenstein, Michael R.; Longhurst, Celia M.; Latchman, David S.; Isenberg, David

doi:10.1172/jci117164

Cited by 46 publications

(21 citation statements)

References 32 publications

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“…[38][39][40][41][42] The usage of the germline genes which may encode autoantibodies is also a distinctive feature of low grade MALT lymphomas of the gastrointestinal tract and salivary glands. 15,17,43,44 It has been well documented that low grade MALT lymphomas may produce antibodies that bind selfantigens.…”

Section: Discussionmentioning

confidence: 99%

Primary diffuse large B cell lymphoma of the stomach: analysis of somatic mutations in the rearranged immunoglobulin heavy chain variable genes indicates antigen selection

et al. 1999

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Gastric low grade MALT lymphomas show a pattern of somatic mutations in their rearranged immunoglobulin genes, indicative of antigen selection. This provides evidence for antigen stimulation in the lymphomagenesis. Gastric diffuse large B cell lymphomas develop secondary to low grade MALT lymphoma or de novo. To study whether antigen-selection is also a feature of primary diffuse large B cell lymphomas, we analysed somatic mutations in the rearranged immunoglobulin heavy chain (IgH) variable genes (VH). The rearranged VH genes of six cases of gastric primary diffuse large B cell lymphoma were amplified from genomic or complementary DNA by a VH gene family-specific polymerase chain reaction method. The PCR products were directly sequenced and were compared to published germline sequences to analyse somatic mutations. Similarly to low grade MALT lymphomas 5/6 primary diffuse large B cell lymphomas show a pattern of somatic mutation in their rearranged VH genes, indicative of antigen selection and suggesting a role for antigens in lymphomagenesis. One case showed bi-allelic VH gene rearrangements, which were nonfunctional due to extensive deletions. Antigen selection could not be demonstrated or excluded. Antigen selection is a common feature in most analysed primary diffuse large B cell lymphomas, although some heterogeneity in the mechanisms involved in the lymphomagenesis of gastric primary diffuse large B cell lymphomas has not been excluded entirely (case 4).

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Section: Discussionmentioning

confidence: 99%

Primary diffuse large B cell lymphoma of the stomach: analysis of somatic mutations in the rearranged immunoglobulin heavy chain variable genes indicates antigen selection

et al. 1999

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“…IS4 was derived from a primary antiphospholipid syndrome patient and binds to CL in the presence of bovine and human ␤2GPI and to human ␤2GPI alone (28). B3 (29) and UK4 (30) were isolated from patients with SLE, and B3 binds nucleosomes, CL, and histones (29,31,32). UK4 binds negatively charged (but not neutral) PL in the absence of ␤2GPI and does not bind DNA (30).…”

Section: Human Mabsmentioning

confidence: 99%

“…The sequences of IS4, B3, and UK4 have all been described in detail previously (25,29). All three Abs contain L chains encoded by the germline V gene 2a2.…”

Section: Sequences Of Expressed Ab Variable Regionsmentioning

confidence: 99%

Arginine Residues Are Important in Determining the Binding of Human Monoclonal Antiphospholipid Antibodies to Clinically Relevant Antigens

Giles

Lambrianides

Pattni

et al. 2006

The Journal of Immunology

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In the antiphospholipid syndrome (APS), antiphospholipid Abs (aPL) bind to anionic phospholipids (PL) and various associated proteins, especially β2-glycoprotein I (β2GPI) and prothrombin. In the present study, we show that altering specific Arg residues in the H chain of a human pathogenic β2GPI-dependent aPL, IS4, has major effects on its ability to bind these clinically important Ags. We expressed whole human IgG in vitro by stable transfection of Chinese hamster ovary cells with expression plasmids containing different VH and VL sequences. VH sequences were derived from IS4 by altering the number of Arg residues in CDR3. VL sequences were those of IS4, B3 (anti-nucleosome Ab), and UK4 (β2GPI-independent aPL). Binding of the expressed H/L chain combinations to a range of anionic, neutral, and zwitterionic PL, as well as prothrombin, β2GPI, dsDNA, and chicken OVA, was determined by ELISA. Of four Arg residues in IS4VH CDR3 substituted to Ser, two at positions 100 and 100g, reduced binding to all Ags, while two at positions 96 and 97 reduced binding to β2GPI but increased or decreased binding to different PL. Eleven of 14 H/L chain combinations displayed weak binding to OVA with Arg to Ser replacements of all four Arg residues enhancing binding to this Ag. Only one H/L chain combination bound neutral PL and none bound dsDNA; hence, these effects are particularly relevant to Ags important in antiphospholipid syndrome. We hypothesize that these four Arg residues have developed as a result of somatic mutations driven by an Ag containing both PL and β2GPI.

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“…Our initial studies have therefore been focused on the cloning and overexpression of the Fab of a well characterized human anti-DNA antibody B3 (14) in a heterologous cell expression system. We now describe construction of novel vectors pAGP2 () and Blunt zeo that allow cloning of virtually any human lambda antibody.…”

Section: Systemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

“…The final expression vector pAWtac is based on pCTR008 (25) involving the secretion of L and H chains under the direction of OmpA signal sequence and involves co-translational coupling between the cistrons (26). The cDNA encoding the variable (V /V H ) domains of L and H chains of the B3 antibody (14) were amplified by PCR (95°C, 2 min; 62°C, 2 min; 72°C, 30 s; 30 cycles) using Vent DNA polymerase (New England Biolabs, Hitchin, UK) for cloning into the above described vectors. However, the original CellTech vector pAGP2 contains L chain with kappa constant region.…”

Section: Cloning Of B3 Fabmentioning

confidence: 99%

Molecular Cloning and Expression of the Fabs of Human Autoantibodies in Escherichia coli

Kumar¹,

Kalsi²,

Ravirajan³

et al. 2000

Journal of Biological Chemistry

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Serological and genetic characterization of a human monoclonal immunoglobulin G anti-DNA idiotype.

Cited by 46 publications

References 32 publications

Primary diffuse large B cell lymphoma of the stomach: analysis of somatic mutations in the rearranged immunoglobulin heavy chain variable genes indicates antigen selection

Primary diffuse large B cell lymphoma of the stomach: analysis of somatic mutations in the rearranged immunoglobulin heavy chain variable genes indicates antigen selection

Arginine Residues Are Important in Determining the Binding of Human Monoclonal Antiphospholipid Antibodies to Clinically Relevant Antigens

Molecular Cloning and Expression of the Fabs of Human Autoantibodies in Escherichia coli

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