Immunization with DNA Topoisomerase I Induces Autoimmune Responses But Not Scleroderma-like Pathologies in Mice

PAUL Q. HU, ARTHUR A. HURWITZ, and JOOST J. OPPENHEIM

ABSTRACT.

Objective. Anti-DNA topoisomerase I (anti-topo-I) antibody is a marker of systemic sclerosis (SSc). Anti-topo-I antibody levels are positively correlated with both disease severity and activity. However, its pathogenic role in SSc remains unclear. We investigated whether induction of an autoreactive antibody response is directly pathogenic in mice.

Methods. Autoimmune responses were induced in mice immunized with human recombinant topo-I (rhutopo-I). Both humoral and T cell-mediated autoimmune responses were assessed. Necropsy analyses were performed to determine pathologic changes in immunized mice.

Results. Autoimmune prone SJL and non-obese diabetic mice developed higher humoral autoreactive responses against mouse topo-I than did BALB/c and C56BL/6 mice. Splenic T cells also showed proliferative responses and interferon-g secretion in response to rhutopo-I. However, serum anti-topo-I antibody levels declined 2 months after the initial immunization. Neither weight loss nor dermal thickening was observed in mice during a followup period of 9 months. Whole-body necropsy analyses, including skin, lung, heart, kidney, gastrointestinal tract, and joints, showed no typical findings of human SSc. Coadministration of anti-CD25 and anti-CTLA-4 antibody with the initial immunization resulted in higher titers of anti-topo-I antibody, but these mice also did not develop SSc-like pathologic features. Development of an anti-topo-I response was not associated with acceleration of the recognized abnormalities in tight-skin mice.

Conclusion. Although tolerance was broken and anti-topo-I antibody was induced by immunization with rhutopo-I in mice, induction of this antibody was not sufficient to induce SSc-like disease. (First Release Oct 15 2007; J Rheumatol 2007;34:2243-52)

Key Indexing Terms:

DNA TOPOISOMERASE I
ANTIBODY
AUTOIMMUNITY
SKIN
SYSTEMIC SCLEROSIS

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From the Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland, USA.

Funded by National Institutes of Health intramural funding support.

P.Q. Hu, PhD, CRTA Fellow; A.A. Hurwitz, PhD, Principal Investigator; J.J. Oppenheim, MD, Laboratory Chief, Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick Cancer Research and Development Center.

Address reprint requests to Dr. J.J. Oppenheim, Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, Building 560, Room 21-89, Frederick, MD 21702-1201, USA.

Accepted for publication July 31, 2007.

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