Use of molecular cloning methods to map the distribution of epitopes on topoisomerase I (Scl‐70) recognized by sera of scleroderma patients

D’Arpa, Peter; White-Cooper, Helen; Cleveland, Don W.; Rothfield, Naomi F.; Earnshaw, William C.

doi:10.1002/art.1780331007

Cited by 44 publications

(22 citation statements)

References 42 publications

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“…The location of ER3 was consistent with that of major B cell epitope determined by previous studies (45,46). In this study, we showed that each of four different B cell epitopes was associated with the different HLA-DR genes, suggesting that the specific immune response to each B cell epitope is controlled by different T cell epitopes.…”

Section: Discussionsupporting

confidence: 90%

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The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma).

Kuwana¹,

Kaburaki²,

Okano³

et al. 1993

J. Clin. Invest.

102

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HLA class II alleles were determined using the PCR-RFLP method in Japanese systemic sclerosis (scleroderma) patients with (n = 28) or without (n = 34) anti-topoisomerase I antibodies (anti-topo I). Either the DQB1 *0601 or * 0301 allele was recognized in all anti-topo I positive patients, compared with 44% of anti-topo I negative patients (P < 0.00001, relative risk[RR] > 41) or 58% of Japanese healthy control subjects (P < 0.00001, RR > 24). Tyrosine at position 26 in the second hypervariable region in the ,81 domain of the DQB1 gene is common to these two alleles and is not present in any other known DQB1 alleles. We also examined immunoreactivities of anti-topo I positive sera to four different autoantigenic B cell epitopes of topo I molecule that were expressed as recombinant fusion proteins. One major B cell epitope, located within the region corresponding to amino acid residues 74-248, was perfectly associated with the amino acid sequence FLEDR at positions 67-71 in the j1 domain of the DRB gene. Two other epitopes, corresponding to 316-441 or 658-700, were associated with the serologically defined HLA-DR52 antigen. Patients with both FLEDR and DR52 demonstrated higher antitopo I antibody titers. These results suggest that the HLA-DR and DQ genes together control the autoimmune response to topo I in systemic sclerosis. (J. Clin. Invest. 1993. 92:1296-1301

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Section: Discussionsupporting

confidence: 90%

“…Autoantigenic B cell epitopes on topo I molecule were analyzed by several investigator groups (34,(44)(45)(46)(47). The location of ER3 was consistent with that of major B cell epitope determined by previous studies (45,46).…”

Section: Discussionsupporting

confidence: 68%

The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma).

Kuwana¹,

Kaburaki²,

Okano³

et al. 1993

J. Clin. Invest.

102

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“…47 Scl-70 antibodies bind to the active site of topoisomerase I and inhibit topoisomerase I activity, preventing DNA relaxation. [48][49][50][51] It remains unclear if scl-70 antibodies are pathologic or an epiphenomena. 52 However, antibodies to topoisomerase I (Scl-70) are specific for scleroderma and are associated with a higher risk of diffuse skin disease, pulmonary involvement, and a worse prognosis.…”

Section: Radiation Sensitivity Of Sclerodermamentioning

confidence: 99%

The rationale behind autologous autoimmune hematopoietic stem cell transplant conditioning regimens: concerns over the use of total-body irradiation in systemic sclerosis

Burt

Kallunian

Patel

et al. 2004

Bone Marrow Transplant

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Summary:Hematopoietic stem cell transplantation (HSCT) is becoming an increasingly recognized indication for treatment of autoimmune diseases and severe immunemediated disorders. However, multicenter registry data have demonstrated higher than anticipated early toxicity, approximately 10% for autoimmune diseases in general, and 20-27% for diffuse systemic sclerosis (scleroderma). If uncorrected, this high treatment-related mortality will hinder development of stem cell therapy for immunemediated diseases. In order to develop safer regimens, we address some pitfalls and concepts involved in design and selection of conditioning regimens for autoimmune diseases in general, and because it is associated with the highest regimen-related toxicity, scleroderma in specific.

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“…In contrast to the finding of a single epitope on Topo I, Verheijen et al (13) showed the reactivity of anti-Topo I sera against three different epitope regions toward the C-terminal of Topo I. D'Arpa et al (14) expressed six portions of Topo I and demonstrated that most of anti-Topo I-positive sera recognize multiple epitopes. Kuwana et al (17) detected four epitope regions on Topo I from the N-terminal to C-terminal.…”

Section: Discussionmentioning

confidence: 96%

“…The full-length cDNA sequence of Topo I was subsequently cloned (11). The availability of Topo I cDNA has stimulated a number of investigators to fine-map Ab epitopes on the Topo I molecule (12)(13)(14)(15)(16)(17). Using Western blot with recombinant Topo I fragments as Ags, several anti-Topo I Ab epitopes distributed from the N-terminal to the C-terminal portion of Topo I molecule have been reported (12,17,18).…”

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confidence: 99%

Molecular Recognition Patterns of Serum Anti-DNA Topoisomerase I Antibody in Systemic Sclerosis

Fertig

Medsger

et al. 2004

The Journal of Immunology

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Autoreactive anti-DNA topoisomerase I (anti-Topo I) Abs are commonly detected in sera of systemic sclerosis (SSc) patients. Our studies have established a positive correlation between the levels of serum anti-Topo I Abs and both disease severity and activity of SSc. The molecular targets of anti-Topo I Ab on Topo I domains remain to be further defined. In this report, we studied the molecular recognition pattern of serum anti-Topo I Ab in 52 SSc patients. The highest reactivity of serum anti-Topo I Abs was against the core subdomains I and II (aa 207–441) and, to a lesser extent, against the core subdomain III (aa 433–636) of Topo I. The linker domain (aa 636–712) and the C-terminal domain (aa 713–765) had much less reactivity than the core domain (aa 207–636). Strikingly, very little reactivity was directed against the N-terminal domain (aa 1–213) by serum anti-Topo I Ab. This molecular recognition pattern was consistent among all SSc serum samples studied. Results from patients with serial serum samples indicated that this pattern remained unchanged over time. Interestingly, some naive B cells from healthy controls, upon transformation by EBV, produced IgM Abs against Topo I. These Abs had low affinity for Topo I and reacted equally to all domains of Topo I. The molecular recognition pattern of serum anti-Topo I Ab in SSc suggests the presence of a unique antigenic stimulation in vivo in this disease.

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Use of molecular cloning methods to map the distribution of epitopes on topoisomerase I (Scl‐70) recognized by sera of scleroderma patients

Cited by 44 publications

References 42 publications

The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma).

The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma).

The rationale behind autologous autoimmune hematopoietic stem cell transplant conditioning regimens: concerns over the use of total-body irradiation in systemic sclerosis

Molecular Recognition Patterns of Serum Anti-DNA Topoisomerase I Antibody in Systemic Sclerosis

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