Molecular characterization of a somatically mutated anti-DNA antibody bearing two systemic lupus erythematosus-related idiotypes.

Davidson, Anne; Manheimer-Lory, A; Aranow, Cynthia; Peterson, Reece L.; Hannigan, Noreen R.; Diamond, Betty

doi:10.1172/jci114584

Cited by 93 publications

(32 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, the F4 idiotype may be encoded with the VDJ junction and represent a particular D region gene sequence. We do not favor this hypothesis as the D region of the H2F antibody reported in this study differs substantially from that ofthe 2A4 antibody (8).…”

Section: Discussioncontrasting

confidence: 78%

“…Sequences of F4-reactive myeloma proteins revealed more than one VH family. A detailed molecular study of one 3I-positive, F4-positive anti-DNA antibody, 2A4, revealed the acquisition of somatic mutations in complementarity-determining regions of the heavy chain (8). These mutations lead to an accumulation of positive charges and generate the amino acids arginine and asparagine, which have been postulated to be involved in DNA-protein interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas two lines were derived from the patient with myeloma, neither line is producing the myeloma protein. Both lines produce a VKl-encoded light chain, whereas the myeloma protein is a VK3 encoded light chain (8).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Generation and analysis of clonal IgM- and IgG-producing human B cell lines expressing an anti-DNA-associated idiotype.

Manheimer-Lory¹,

Davidson²,

Watkins³

et al. 1991

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

This study describes a methodology for generating stable, cloned, EBV-transformed IgG-and IgM-producing human B cell lines. Using these lines we have characterized immunoglobulin V gene utilization in an anti-DNA-associated idiotypic system. The 31 anti-DNA-associated idiotype is encoded preferentially by the VKl gene family, and, in all probability, reflects a germ line gene-encoded framework determinant. Analysis of these lines indicates that the DNA-binding antibodies produced by B cell lines from SLE patients may differ from DNA binding myeloma proteins and from natural autoantibodies. (J. Clin. Invest. 1991. 87:1519-1525.) Key words: clonal EBV lines * anti-DNA idiotype * systemic lupus erythematosus * autoantibody Introduction Little is known about the etiology of autoantibody production in systemic lupus erythematosus (SLE),I and animal models of the disease have led to disparate views. Many ofthe manipulations performed in studies of lupus-prone mice clearly cannot be undertaken in studies ofthe human disease; nonetheless, the study of the autoantibodies themselves can be very revealing. Serologic studies of SLE have employed idiotypic analyses to identify and characterize subsets of autoantibodies that bind DNA and structurally related antibodies that do not bind DNA. One approach has been to generate antiidiotypic reagents to monoclonal anti-DNA antibodies. However, it is not clear how closely the selected monoclonal autoantibodies mirror the pathogenic anti-DNA antibodies in disease. The approach favored by our laboratory has been to generate antiidiotypes to the heterogenous anti-DNA antibodies present in the serum and kidneys of individuals with SLE. The 3I antiidiotype recognizes a determinant on kappa light chains of anti-DNA antibodies (1). High titered expression of31-reactive antibodies is present in -80% of SLE patients with anti-DNA activity. We studied expression of the 31 idiotype in the serum ofrelatives ofSLE patients, as well as on monoclonal immunoglobulins in the serum of individuals with monoclonal gammopathies (1, 2) to obtain structural and genetic information

show abstract

Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Generation and analysis of clonal IgM- and IgG-producing human B cell lines expressing an anti-DNA-associated idiotype.

Manheimer-Lory¹,

Davidson²,

Watkins³

et al. 1991

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

show abstract

“…No serum was available from this patient. Lymphocytes were obtained by Ficoll-Hypaque separation of whole blood and transformed using EBV as described previously (6,8).…”

Section: Generation Of F4mentioning

confidence: 99%

Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Manheimer-Lory

Zandman‐Goddard²,

Davidson³

et al. 1997

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

The F4 idiotype is a heavy chain determinant expressed almost exclusively on IgG immunoglobulins and is highly associated with specificity for double-stranded DNA. Since high-titered F4 expression is present predominantly in sera of patients with systemic lupus erythematosus (SLE), we thought F4ϩ IgG antibodies might constitute a useful subset of immunoglobulins in which to investigate lupus-specific alterations in variable (V) region gene expression or in the process of somatic mutation. This molecular analysis of F4 ϩ B cell lines generated from lupus patients demonstrates that despite the strong association of F4 reactivity with specificity for native DNA, there is no apparent V H gene restriction. Furthermore, V H gene segments encoding these antibodies are also used in protective immune responses.An examination of the process of somatic mutation in F4 ϩ antibodies showed no abnormality in frequency of somatic mutation nor in the distribution of mutations in complementarity-determining regions or framework regions. However, there was a decrease in targeting of mutations to putative mutational hot spots. This subtle difference in mutations present in these antibodies may reflect an intrinsic defect in mutational machinery or, more likely, altered state of B cell activation that affects the mutational process and perhaps also negative selection. (

show abstract

“…In human SLE, the evidence implicating T cells is indirect. The pathogenic antibodies are of the IgG isotype and are encoded by immunoglobulin genes that have undergone somatic mutation (5).…”

Section: Introductionmentioning

confidence: 99%

Autoantigen-specific T cell proliferation induced by the ribosomal P2 protein in patients with systemic lupus erythematosus.

et al. 1994

View full text Add to dashboard Cite

A role for helper T cells in the induction of pathogenic lupus autoantibodies is increasingly supported by data from studies of murine lupus and patients with systemic lupus erythematosus (SLE). However, the poor in vitro function of SLE T cells has hampered the identification and characterization of autoantigen-specific T cells. We used recombinant fusion proteins to study the T cell proliferative response of 31 lupus patients and 27 healthy subjects to a well-characterized SLE autoantigen, the ribosomal P2 protein. Although PBMC from SLE patients showed marked impairment in the proliferative response to the common recall antigen tetanus toxoid when compared with normal subjects, a significantly greater proportion of SLE patients (32%) than normal individuals (0%) showed a T cell response to a recombinant P2 fusion protein. When the SLE patients were subgrouped according to the presence of serum anti-P autoantibody, 7 of 10 anti-P antibody-positive patients, but 0 of 20 anti-P antibody-negative SLE patients, demonstrated > 2,000 cpm [3H]thymidine incorporation and a P2 stimulation index > 5. The specificity of the T cell proliferative response for the P2 protein was confirmed by studies using a second recombinant human P2 fusion protein and by the specific activation of P2-primed T cells by recombinant P2 in secondary cultures. Moreover, the T cell proliferative response to the P2 autoantigen was mediated by CD4-positive T cells and was inhibited by anti-MHC class II antibodies. These data demonstrate the presence of autoantigen-specific T helper cells in patients with SLE and suggest that these T cells drive the production of autoantibodies by B lymphocytes. (J. Clin. Invest. 1994.94:345-352.)

show abstract

Molecular characterization of a somatically mutated anti-DNA antibody bearing two systemic lupus erythematosus-related idiotypes.

Cited by 93 publications

References 38 publications

Generation and analysis of clonal IgM- and IgG-producing human B cell lines expressing an anti-DNA-associated idiotype.

Generation and analysis of clonal IgM- and IgG-producing human B cell lines expressing an anti-DNA-associated idiotype.

Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Autoantigen-specific T cell proliferation induced by the ribosomal P2 protein in patients with systemic lupus erythematosus.

Contact Info

Product

Resources

About