The Role of Rearrangement at the Second Ig Heavy Chain Locus in Maintaining B Cell Tolerance to DNA

Liu, Yang; Li, Lisa; Mohan, Chandra

doi:10.4049/jimmunol.180.11.7721

Cited by 4 publications

(1 citation statement)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further studies will be required to more directly address these issues. Finally, in agreement with a previous report in which B cell development was assessed in mice expressing two copies of the 3H9/56R antichromatin BCR (32), H chain editing does not seem to play a predominant role in the development of either HKIR +/+ /V κ 10 or HKIR +/+ B cells, since hybridomas derived from such B cells express mAbs with canonical V H -dependent idiotopes, RNA derived from the intact HKIR locus, or both.…”

Section: Discussionsupporting

confidence: 92%

Influence of B Cell Antigen Receptor Expression Level on Pathways of B Cell Tolerance Induction

Liu

Shen

Manser

2009

The Journal of Immunology

View full text Add to dashboard Cite

We have described an Igtransgenic, autoreactive B cell clonotype that undergoes a novel tolerance pathway. Early in development this clonotype expresses average BCR levels, but these levels are progressively down-regulated as development proceeds efficiently to the mature, follicular compartment. This clonotype does not display conventional features of anergy and can be induced to undergo apoptosis and receptor editing in in vitro bone marrow cultures, but these pathways are not taken in vivo. These data suggested that autoantigen-driven down-regulation of BCR levels and, hence, avidity for autoantigen allows this clonotype to bypass conventional tolerance mechanisms. To test this idea, we enforced elevated levels of expression of BCR in this clonotype by making the transgenic Igh locus homozygous. This resulted in retarded clonotype development and L chain receptor editing in vivo. These data support a pivotal role for adaptive, autoantigen-induced adjustment of BCR expression levels in the regulation of primary B cell development and tolerance.

show abstract

Section: Discussionsupporting

confidence: 92%

Influence of B Cell Antigen Receptor Expression Level on Pathways of B Cell Tolerance Induction

Liu

Shen

Manser

2009

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

Alternative mechanisms of receptor editing in autoreactive B cells

Kalinina

Doyle-Cooper

Miksanek

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Pathogenic anti-DNA antibodies expressed in systemic lupus erythematosis bind DNA mainly through electrostatic interactions between the positively charged Arg residues of the antibody complementarity determining region (CDR) and the negatively charged phosphate groups of DNA. The importance of Arg in CDR3 for DNA binding has been shown in mice with transgenes coding for anti-DNA V H regions; there is also a close correlation between arginines in CDR3 of antibodies and DNA binding. Codons for Arg can readily be formed by V(D)J rearrangement; thereby, antibodies that bind DNA are part of the preimmune repertoire. Anti-DNAs in healthy mice are regulated by receptor editing, a mechanism that replaces κ light (L) chains compatible with DNA binding with κ L chains that harbor aspartic residues. This negatively charged amino acid is thought to neutralize Arg sites in the V H . Editing by replacement is allowed at the κ locus, because the rearranged VJ is nested between unrearranged Vs and Js. However, neither λ nor heavy (H) chain loci are organized so as to allow such second rearrangements. In this study, we analyze regulation of anti-DNA H chains in mice that lack the κ locus, κ-/κ-mice. These mice show that the endogenous preimmune repertoire does indeed include a high frequency of antibodies with Arg in their CDR3s (putative anti-DNAs) and they are associated mainly with the editor L chain λx. The editing mechanisms in the case of λ-expressing B cells include L chain allelic inclusion and V H replacement.autoimmunity | tolerance A nti-DNA antibodies bind DNA mainly through electrostatic interactions between the positively charged Arg (R) residues of the antibody complementarity determining regions (CDRs) and the negatively charged DNA phosphodiester backbone (1). Arg enrichment has been demonstrated in the protein sequences of anti-DNA antibody heavy (H) chains (2, 3). In addition, reverse mutagenesis of an H chain Arg to a germline amino acid weakened DNA binding, whereas forward mutagenesis with additional Arg residues enhanced DNA binding (1). The predominant occurrence of Arg residues in the V H -encoded CDRs of anti-DNA antibodies indicates a dominant role for V H in DNA binding, and the DNA specificity of these H chains persists when paired with a wide variety of light (L) chains (4-6). There are exceptional L chains (4 Vκ L chains of 95 functional Vκ genes and 1 Vλ L chain of 4 functional Vλ L chains) of the mouse that modify or veto the DNA-binding quality of 7,8). These editor L chains are characterized by a high content of aspartate, a negatively charged amino acid that efficiently neutralizes the positively charged Arg residues of anti-DNA H chains (4). B cells that express an anti-DNA V H with a noneditor L chain can undergo further L chain rearrangement. If the original L chain is replaced by an editor L chain, the B cell will be tolerized (4, 7). Similarly, MHC class I-reactive B cells (found in 3-83μ transgenic mice) that encounter autoantigen in the bone marrow continue rearrangement and change rece...

show abstract

Central B-Cell Tolerance: Where Selection Begins

Pelanda

Torres²

2012

Cold Spring Harbor Perspectives in Biology

View full text Add to dashboard Cite

The Role of Rearrangement at the Second Ig Heavy Chain Locus in Maintaining B Cell Tolerance to DNA

Cited by 4 publications

References 30 publications

Influence of B Cell Antigen Receptor Expression Level on Pathways of B Cell Tolerance Induction

Influence of B Cell Antigen Receptor Expression Level on Pathways of B Cell Tolerance Induction

Alternative mechanisms of receptor editing in autoreactive B cells

Central B-Cell Tolerance: Where Selection Begins

Contact Info

Product

Resources

About