Secondary Heavy Chain Rearrangement

Sekiguchi, Debora R.; Eisenberg, Robert A.; Weigert, Martin

doi:10.1084/jem.20020737

Cited by 58 publications

(16 citation statements)

References 39 publications

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“…Like any recombination process, V H replacement is a random process that can generate non-functional IgH genes or IgH genes encoding autoreactive antibodies. Previous studies have shown that V H replacement products generated through replacing the knocked-in anti-DNA IgH genes can produce high affinity anti-DNA antibodies during chronic graft-versus-host (cGVH) response [56]. Theoretically, after V H replacement recombination, the newly generated IgH genes should be subjected to strict negative selection again to eliminate B cells expressing autoreactive BCRs.…”

Section: Discussionmentioning

confidence: 99%

Contribution of VH Replacement Products in Mouse Antibody Repertoire

Huang

Lange

et al. 2013

PLoS ONE

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VH replacement occurs through RAG-mediated recombination between the cryptic recombination signal sequence (cRSS) near the 3′ end of a rearranged VH gene and the 23-bp RSS from an upstream unrearranged VH gene. Due to the location of the cRSS, VH replacement leaves a short stretch of nucleotides from the previously rearranged VH gene at the newly formed V-D junction, which can be used as a marker to identify VH replacement products. To determine the contribution of VH replacement products to mouse antibody repertoire, we developed a Java-based VH Replacement Footprint Analyzer (VHRFA) program and analyzed 17,179 mouse IgH gene sequences from the NCBI database to identify VH replacement products. The overall frequency of VH replacement products in these IgH genes is 5.29% based on the identification of pentameric VH replacement footprints at their V-D junctions. The identified VH replacement products are distributed similarly in IgH genes using most families of VH genes, although different families of VH genes are used differentially. The frequencies of VH replacement products are significantly elevated in IgH genes derived from several strains of autoimmune prone mice and in IgH genes encoding autoantibodies. Moreover, the identified VH replacement footprints in IgH genes from autoimmune prone mice or IgH genes encoding autoantibodies preferentially encode positively charged amino acids. These results revealed a significant contribution of VH replacement products to the diversification of antibody repertoire and potentially, to the generation of autoantibodies in mice.

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Section: Discussionmentioning

confidence: 99%

Contribution of VH Replacement Products in Mouse Antibody Repertoire

Huang

Lange

et al. 2013

PLoS ONE

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“…In the GVHD model, no foreign ag is administered, therefore only self-ag reactive B cells will encounter endogenous signal 1 and become autoantibody secreting cells. IgG anti-ssDNA ab appear early (days 10–14) [17] and after this initial B cell expansion a second ag-driven phase ensues at >1 month of disease [15] characterized by detection of lupus-specific auto-antibodies not seen earlier e.g., anti-dsDNA, Sm, chromatin [18,19] and poly(ADP-ribose) polymerase-1 (PARP-1) depending on the P→F1 combinations used [20]. Clinical renal disease becomes demonstrable at approximately 2 months.…”

Section: Lupus Development In the Parent-into-f1 (P→f1) Model Of Lmentioning

confidence: 99%

Therapeutic potential of CD8+ cytotoxic T lymphocytes in SLE

Puliaeva

Puliaev

Via

2009

Autoimmunity Reviews

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Recent evidence supports the idea that following a break in tolerance, CD8 cytotoxic T lymphocytes (CTL) may be an important but unrecognized mechanism for limiting expansion of autoreactive B cells. Failure of this mechanism could allow persistence of CD4 T cell driven polyclonal B cell activation resulting in clinical lupus. Although CD8 CTL failure may occur early in disease, work in mice supports the concept that therapeutic CTL enhancement may be both practical and beneficial in lupus. Devising such therapy for humans will first require an understanding of the in vivo mechanisms critical in CTL expansion and down regulation, particularly in the lupus setting which may differ from CTL generation in other clinical settings (e.g. tumors, infections).

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“…Another possibility is that the editing defect in B6.Aec1/2 mice is significant, but that its effects on the 56R transgene are insufficient to limit autoreactivity, even in wild type mice. Indeed, B6.56R and even B6 mice spontaneously break tolerance to dsDNA, so clearly editing is not a panacea (49, 61, 70). Even when antibody light chains are edited in B6.56R mice, most do not fully negate the autoreactive specificity of the 56R heavy chain.…”

Section: Discussionmentioning

confidence: 99%

B-Cell Tolerance Defects in the B6.Aec1/2 Mouse Model of Sjögren’s Syndrome

Meng

Xue

et al. 2012

J Clin Immunol

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Purpose Primary Sjögren’s syndrome (SjS) is an autoimmune disorder characterized by lymphocytic infiltration of the salivary and lacrimal glands, B-cell clonal expansions and an increased risk of lymphoma. In order to understand the role of B cells in this disorder, the antibody repertoire and B-cell maturation were studied in a mouse model of SjS called B6.Aec1/2. Methods B6.Aec1/2 serum was analyzed for (auto)antibodies by ELISA and immunoprecipitation, B-cell development by flow cytometry, antibody gene rearrangements by CDR3 spectratyping and quantitative PCR. In order to test the functional consequences of the observed defects, B6.Aec1/2 mice were crossed with anti-dsDNA antibody heavy chain knock-in mice (B6.56R). Results B6.Aec1/2 mice exhibit B-cell clonal expansions, have altered serum immunoglobulin levels and spontaneously produce multireactive autoantibodies. B6.Aec1/2 mice also have decreased numbers of bone marrow pre-B cells and decreased frequencies of kappa light chain gene deletion. These findings suggest that B6.Aec1/2 mice have a defective early B-cell tolerance checkpoint. B6.56R.Aec1/2 mice unexpectedly had lower anti-dsDNA antibody levels than B6.56R mice and less salivary gland infiltration than B6.Aec1/2 mice. Conclusions These data suggest that the early tolerance checkpoint defect in B6.Aec1/2 mice is not sufficient to promulgate disease in mice with pre-formed autoantibodies, such as B6.56R. Rather, B6.Aec1/2 mice may require a diverse B-cell repertoire for efficient T-B-cell collaboration and disease propagation. These findings imply that therapies aimed at reducing B-cell diversity or T-B interactions may be helpful in treating SjS.

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Secondary Heavy Chain Rearrangement

Cited by 58 publications

References 39 publications

Contribution of VH Replacement Products in Mouse Antibody Repertoire

Contribution of VH Replacement Products in Mouse Antibody Repertoire

Therapeutic potential of CD8+ cytotoxic T lymphocytes in SLE

B-Cell Tolerance Defects in the B6.Aec1/2 Mouse Model of Sjögren’s Syndrome

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