Immunization with DNA topoisomerase I induces autoimmune responses but not scleroderma-like pathologies in mice.
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-gamma 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.


CONCLUSIONS
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.
Hu
Paul Q
PQ
Laboratory of Molecular Immunoregulation, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, MD 21702, USA.
Hurwitz
Arthur A
AA
Oppenheim
Joost J
JJ
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D004264:DNA Topoisomerases, Type I / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007114:Immunization; D007117:Immunization, Secondary; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D011994:Recombinant Proteins / Q000276:immunology; D012595:Scleroderma, Systemic / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D011994:Recombinant Proteins; D004264:DNA Topoisomerases, Type I