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Abstract

Autoimmunity develops when a lupus-inducing drug is introduced into the thymus of normal mice, but the relevance of this model to the human disorder is unclear in part because it is widely assumed that the thymus is non-functional in the adult. We compared thymus function in 10 patients with symptomatic procainamide-induced lupus to that in 13 asymptomatic patients who only developed drug-induced autoantibodies.T cell output from the thymus was quantified using a competitive polymerase chain reaction that detects T cell receptor DNA excision circles in peripheral blood lymphocytes. Despite the advanced age of the patient population under study, newly generated T cells were detected in all subjects. Although there was no overall quantitative difference between the symptomatic and asymptomatic patients, we found a positive correlation between the level of T cell receptor excision circles in peripheral lymphocytes and serum IgG anti-chromatin antibody activity in patients with drug-induced lupus. The association between autoantibodies and nascent peripheral T cells supports the requirement for T cells in autoantibody production. Our observations are consistent with findings in mice in which autoreactive T cells derived from drug-induced abnormalities in T cell development in the thymus

Keywords

drug-induced lupus T cells thymus autoantibodies

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Goebel C , Vogel C , Wulferink M et al. Procainamide, a drug causing lupus, induces prostaglandin H synthase-2 and formation of T cell-sensitizing drug metabolites in mouse macrophages . Chem Res Toxicol 1999; 12: 488–500 .

Yung RL , Quddus J , Chrisp CE , Johnson KJ , Richardson BC . Mechanisms of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo . J Immunol 1995; 154: 3025–3035 .

Adams LE , Roberts SM , Donovan-Brand R , Zimmer H , Hess EV . Study of procainamide hapten-specific antibodies in rabbits and humans . Int J Immunopharmac 1993; 15: 887–897 .

Kretz-Rommel A , Rubin RL . Persistence of autoreactive T cell drive in required to elicit anti-chromatin antibodies in a murine model of drug-induced lupus . J Immunol 1999; 162: 813–820 .

Kretz-Rommel A , Duncan SR , Rubin RL . Autoimmunity caused by disruption of central T cell tolerance: a murine model of drug-induced lupus . J Clin Invest 1997; 99: 1888–1896 .

Kretz-Rommel A , Rubin RL . Disruption of positive selection of thymocytes causes autoimmunity . Nature Med 2000; 6: 298–305 .

Burlingame RW , Rubin RL . Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin . J Clin Invest 1991; 88: 680–690 .

Rubin RL , Burlingame RW , Arnott JE , Totoritis MC , McNally EM , Johnson AD . IgG but not other classes of anti-[(H2A-H2B)-DNA] is an early sign of procainamide-induced lupus . J Immunol 1995; 154: 2483–2493 .

Douek DC , McFarland RD , Keiser PH et al. Changes in thymic function with age and during the treatment of HIV infection . Nature 1998; 396: 690–695 .

10.

Koop BF , Rowen L , Wang K et al. The human T cell receptor TCRAC/TCRDC (Ca/Cd) region: organization, sequence and evolution of 97.6 kb of DNA . Genomics 1994; 19: 478–493 .

11.

Boysen C , Simon MI , Hood L . Analysis of the 1.1-Mb human alpha/delta T-cell receptor locus with bacterial artificial chromosome clones . Genome Res 1997; 7: 330–338 .

12.

Piatak M , Saag MS , Yang LC et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR . Science 1993; 259: 1749–1754 .

13.

Burlingame RW , Rubin RL . Subnucleosome structures as substrates in enzyme-linked immunosorbent assays . J Immunol Meth 1990; 134: 187–199 .

14.

Haynes BF , Markert ML , Sempowski GD , Patel DD , Hale LP . The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection . A Rev Immunol 2000; 18: 529–560 .

15.

Jamieson BD , Douek DC , Killian S et al. Generation of functional thymocytes in the human adult . Immunity 1999; 10: 569–575 .

16.

Kong F , Chen CIH , Cooper MD . Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation . Immunity 1998; 8: 97–104 .

17.

Lau CC , Du Clos TW . Anti-[(H2A=2B)-DNA] IgG supports the diagnosis of procainamide-induced arthritis or pleuritis . Arthritis Rheum 1999; 42: 1300–1301 .

18.

Schett G , Rubin RL , Steiner G , Hiesberger H , Muller S , Smolen J . The lupus erythematosus cell phenomenon: comparative analysis of antic-hromatin antibody specificity in lupus erythematosus cell-positive and-negative sera . Arthritis Rheum 2000; 43: 420–428 .

19.

Richardson B , Powers D , Hooper F , Yung RL , O'Rourke K . Lymphocyte function-associated antigen 1 overexpression and T cell auto-reactivity . Arthritis Rheum 1994; 9: 1363–1372 .

20.

Prieto J , Takei F , Gendelman R , Christenson B , Biberfeld P , Patarroyo M . MALA-2, mouse homologue of human adhesion molecule ICAM-1 (CD54) . Eur J Immunol 1989; 19: 1551–1557 .

21.

Ernst B , Lee DS , Chang JM , Sprent J , Surh CD . The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery . Immunity 1999; 11: 173–181 .

22.

Adams LE , Balakrishnan K , Roberts SM et al. Genetic, immunologic and biotransformation studies of patients on procainamide . Lupus 1993; 2: 89–98 .

23.

Kretz-Rommel A , Rubin RL . Early cellular events in systemic auto-immunity driven by chromatin-reactive T cells . Cellular Immunol 2001; 208: 125–136 .

Thymus Function in Drug-Induced Lupus

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