Selection of Immunoglobulin Variable Regions in Autoimmunity to DNA

Marion, Tony N.; Tillman, David M.; Jou, Nainn-Tsyr; Hill, Robert J.

doi:10.1111/j.1600-065x.1992.tb00835.x

Cited by 97 publications

(68 citation statements)

References 56 publications

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“…However, besides the changes reported in Table I, no further residue usage differences were noted in the CDR3 regions of ANA LCs. For instance, previous studies have suggested that R residues at L96 arising as a consequence of V-J1 joining were particularly prominent among anti-dsDNA Abs (8,40,41). However, in the present analysis, the frequency of R at L96 was almost identical between anti-dsDNA Abs and the non-ANA controls, arising in both cases as a consequence of rearrangement to J1.…”

Section: Discussioncontrasting

confidence: 79%

Molecular Signatures of Anti-nuclear Antibodies: Contributions of Specific Light Chain Residues and a Novel New Zealand BlackVκ1Germline Gene

Liang

Mohan

2003

The Journal of Immunology

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Although the Ig H chains of anti-nuclear Abs (ANA) have been described to possess certain shared molecular signatures, it remains unclear whether the L chains of these Abs also possess distinctive molecular features. The present study examines this by generating and analyzing two comprehensive murine Ig L chain databases, one consisting of 264 monoclonal ANAs and the other consisting of 145 non-ANAs, drawn from previously published work. Importantly, clonal replicates were represented only once each, so as to minimize bias. ANAs and non-ANAs did not differ in Vκ family or Jκ gene usage, nor in their mutation frequencies. Interestingly, the L chains of ANAs exhibited differential usage of certain complementarity-determining region residues, arising almost entirely from the increased usage of certain Vκ germline genes, notably, Vκ ai4 among anti-dsDNA ANAs, Vκ23–45 among anti-ssDNA ANAs, and Vκ21–12 among non-ANAs. Finally, prompted by the increased prevalence of a particular Vκ1 family sequence among ANAs, we proceeded to clone a novel New Zealand Black Vκ1 germline gene, named bb1.1, which appears to be frequently used to encoded anti-ssDNA Abs. Collectively, these studies underline the potential contribution of particular Vκ germline genes in promoting or thwarting DNA binding.

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Section: Discussioncontrasting

confidence: 79%

Molecular Signatures of Anti-nuclear Antibodies: Contributions of Specific Light Chain Residues and a Novel New Zealand BlackVκ1Germline Gene

Liang

Mohan

2003

The Journal of Immunology

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“…Numerous studies have shown that the autoantibodies produced in systemic autoimmune disease states, particular to nuclear autoantigens, bear the hallmarks of transit through the GC/memory pathway: heavily somatically mutated V regions and recurrent types of mutations that increase affinity for cognate autoantigen (e.g., resulting in the introduction of arginines in CDRs) (62,63). If Fc␥RIIB does not directly participate in the negative selection of autoreactive B cells during the GC/memory B cell pathway how, then, can the pivotal contribution of a deficiency of this receptor to the development of autoimmune disease on certain mouse and human genetic backgrounds be explained?…”

Section: Discussionmentioning

confidence: 99%

FcγRIIB Regulates Autoreactive Primary Antibody-Forming Cell, but Not Germinal Center B Cell, Activity

Rahman

Alabyev

Manser

2007

The Journal of Immunology

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The low-affinity FcR for IgG FcγRIIB suppresses the development of IgG autoantibodies and autoimmune disease in normal individuals, but how this effect is mediated is incompletely understood. To investigate this issue, we created FcγRIIB-deficient versions of two previously described targeted BCR-transgenic lines of mice that contain follicular B cells with specificity for the hapten arsonate, but with different levels of antinuclear autoantigen reactivity. The primary development and tolerance of both types of B cells were unaltered by the absence of FcγRIIB. Moreover, the reduced p-azophenylarsonate-driven germinal center and memory responses characteristic of the highly autoreactive clonotype were not reversed by an intrinsic FcγRIIB deficiency. In contrast, the p-azophenylarsonate-driven primary Ab-forming cell responses of both clonotypes were equivalently increased by such a deficiency. In total, our data do not support the idea that FcγRIIB directly participates in the action of primary or germinal center tolerance checkpoints. In contrast, this receptor apparently contributes to the prevention of autoimmunity by suppressing the production of autoreactive IgGs from B cells that have breached tolerance checkpoints and entered the Ab-forming cell pathway due to spontaneous, or cross-reactive, Ag-mediated activation.

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“…The nucleotide sequences contributing to DNA binding have been a subject of intense study in recent years (12,(28)(29)(30). The basic amino acids arginine (R) and lysine (K) are capable of interacting with DNA or with its deoxyribose phosphate backbone.…”

Section: Discussionmentioning

confidence: 99%

The double edged sword of the immune response: mutational analysis of a murine anti-pneumococcal, anti-DNA antibody.

Putterman¹,

Limpanasithikul²,

Edelman³

et al. 1996

J. Clin. Invest.

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Anti-double-stranded (ds) DNA antibodies are not only an important diagnostic marker for SLE, but also play an important role in tissue injury. Microbial antigen may be a stimulus for the production of these antibodies. We isolated 99D.7E, an IgG2b monoclonal antibody from a nonautoimmune BALB/c mouse that is cross-reactive with both ds-DNA and phosphorylcholine, the dominant hapten on the pneumococcal cell wall. While partially protective against a bacterial challenge, 99D.7E is also pathogenic to the kidney. To identify those molecular motifs that confer on anti-PC antibodies the potential for autoreactivity, we created a panel of 99D.7E mutants with single amino acid substitutions in the heavy chain, and examined the changes in antigen binding and renal deposition. Our results support the hypothesis that charge and affinity for dsDNA are not adequate predictors of the pathogenicity of anti-DNA antibodies. Differential renal damage from anti-dsDNA antibodies may be due to differences in fine specificity, rather than differential affinity for dsDNA. Importantly, high affinity IgG antibodies cross-reactive with bacterial and self antigen exist and can display pathogenic potential, suggesting that defects in peripheral regulation of B cells, activated by foreign antigen but cross-reactive with self antigen, might lead to autoimmune disorders. ( J. Clin. Invest. 1996. 97:2251-2259.)

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Selection of Immunoglobulin Variable Regions in Autoimmunity to DNA

Cited by 97 publications

References 56 publications

Molecular Signatures of Anti-nuclear Antibodies: Contributions of Specific Light Chain Residues and a Novel New Zealand BlackVκ1Germline Gene

Molecular Signatures of Anti-nuclear Antibodies: Contributions of Specific Light Chain Residues and a Novel New Zealand BlackVκ1Germline Gene

FcγRIIB Regulates Autoreactive Primary Antibody-Forming Cell, but Not Germinal Center B Cell, Activity

The double edged sword of the immune response: mutational analysis of a murine anti-pneumococcal, anti-DNA antibody.

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