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Molecular Recognition Patterns of Serum Anti-DNA Topoisomerase I Antibody in Systemic Sclerosis¹

Paul Q. Hu^2,*,, Noreen Fertig, Thomas A. Medsger, Jr and Timothy M. Wright^3,*,

Departments of ^* Immunology and Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

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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