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Bovine Thrombin and Systemic Autoimmunity

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Bovine Thrombin and Systemic Autoimmunity
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  Correspondence Bovine Thrombin and Systemic Autoimmunity  To the Editor-in-Chief: In a recent issue of  The American Journal of Pathology  ,Schoenecker and colleagues 1 reported that topical ap-plication of bovine thrombin leads to the development ofan illness resembling systemic lupus erythematosus(SLE) in mice. This observation is surprising. Bovinethrombin has been used in the clinic for hemostasis forover 40 years and there are no reports of the develop-ment of SLE in patients who have received this therapy(see results using the Medline search words “thrombin”and “systemic lupus erythematosus”).However, the central contention of this study, that bo-vine thrombin may induce SLE-like syndrome, has notreally been addressed in the work. Very high doses of asingle, relatively impure preparation of thrombin wereused to induce the autoimmune syndrome. Anotherless impure preparation of thrombin, Thrombin-JMI,was not tested with respect to its capacity to induceautoimmunity in this study. Moreover, since very highdoses of Thrombogen were used, it is unclear whetherthe observations made are relevant to the clinical useof this product.The central hypothesis of the work of Schoenecker etal, 1 that bovine thrombin is responsible for the develop-ment of autoimmunity, is difficult to understand given theantigenic diversity of the antibodies that developed, in-cluding the development of antibodies to unrelated mu-rine clotting factors, which were reported in this study.These findings suggest an alternative hypothesis. Throm-bin is a proteolytic enzyme, which in high concentrationmay act on other substrates including activation of agroup of proteolytically activated receptors (PARs) be-longing to the large family of G protein-coupled receptorsinvolved in the process of inflammation.(cf 2 ) In addi-tion, a variety of other potentially inflammatory proteinsand peptides may be generated during the clottingprocess (including fibrin-derived peptides 3 and kinins).The hypothesis that thrombin’s proteolytic activity, re-gardless of the source, may be responsible for thedevelopment of autoimmunity, suggests that exposureof mice to large quantities of murine thrombin mighthave resulted in a similar pattern of autoimmunity.Thus, a more appropriate test of the hypothesis thatadministration of bovine thrombin induces autoimmu-nity should have included studies of the effects ofmurine and/or recombinant human thrombin.Bruce N. Cronstein New York University School of MedicineNew York, New York  Note: Dr. Cronstein has acted as a consultant to KingPharmaceuticals, which manufactures one of the bovinethrombin preparations. He has also acted as a consultantto or has been supported as a speaker by Merck, Aven-tis, Amgen, Bristol-Myers-Squibb, and Pfizer. References  1. Schoenecker JG, Johnson RK, Lesher AP, Day JD, Love SD, HoffmanMR, Ortel TL, Parker W, Lawson JH: Exposure of mice to topicalbovine thrombin induces systemic autoimmunity. Am J Pathol 2001,159:1957–19692. Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R: Proteinase-activated receptors. Pharmacol Rev 2001, 53:245–2823. Skogen WF, Senior RM, Griffin GL, Wilner GD: Fibrinogen-derivedpeptide Bb1–42 is a multidomained neutrophil chemoattractant.Blood 1988, 71:1475–1479  Authors’ Reply: Thank you for the opportunity to respond to Dr. Cron-stein’s letter regarding our manuscript. When we firstsubmitted our paper, 1 we set forth to study two mecha-nisms that may lead to the autoimmunity observed inmice exposed to bovine thrombin. The first mechanismwas based on “molecular mimicry.” Under this model,exposure to similar, but not homologous, antigens suchas coagulation proteins from another species could leadto the development of autoimmunity by breaking toler-ance. The second mechanism that we began to explorewas that the proteolytic activity of coagulation enzymescould activate protease-activated receptors (PAR) on im-mune cells and lead to a generalized inflammatory andimmune response.At the time of publication, molecular mimicry was anacceptedmechanismcapableofbreakingself-tolerance,leading to autoimmunity. However, the role of PAR in theadaptive immune response had not been demonstrated.Therefore, we deemed it premature to suggest that PARmay play a role in our observations.However, through the use of PAR deficient mice, wehave recently identified a possible mechanism by which American Journal of Pathology, Vol. 162, No. 4, April 2003 Copyright © American Society for Investigative Pathology  1389  coagulation protease(s) may initiate an adaptive immuneresponse by activating dendritic cells. 2 Dendritic cells represent a heterogeneous populationof potent antigen-presenting cells that govern the effectorcell response of the immune system. 3,4 Although it hasbeen suggested that “danger” signals released fromdamaged or necrotic cells induce dendritic cell matura-tion, these signals and their receptors have not been wellcharacterized. 5 Serine proteases are not expressed, orare rapidly inhibited, in the extracellular space of healthytissue. However, during many disease processes theyare released by necrotic cells, secreted by cells of theinnate immune system, and are activated from zymo-gens. 6 In this manner, serine proteases are ideal “dan-ger” signals. We found that developing dendritic cellsexpress PAR-2 and that activation of this receptor in-duces dendritic cell maturation. The ability of proteasesto influence dendritic cell development represents anovel pathway of affecting immune responses. Thus, weconcur with Dr. Cronstein’s comments and thank him forhis insight into our work.Jonathan G. SchoeneckerRyan C. FieldsJeffrey H. Lawson Duke University Medical Center Durham, North Carolina References  1. Schoenecker JG, Johnson RK, Lesher AP, Day JD, Love SD, HoffmanMR, Ortel TL, Parker W, Lawson JH: Exposure of mice to topicalbovine thrombin induces systemic autoimmunity. Am J Pathol 2001,159:1957–19692. Fields RC, Schoenecker JG, Hart JP, Hoffman MR, Pizzo SV, LawsonJH: Protease activated receptor 2 signaling triggers dendritic celldevelopment. Am J Pathol 2003, in press3. Steinman RM: The dendritic cell system and its role in immunogenic-ity. Annu Rev Immunol 1991, 9:271–2964. Banchereau J, Steinman RM: Dendritic cells and the control of immu-nity. Nature 1998, 392:25–525. Matzinger P: An innate sense of danger. Semin Immunol 1998, 10:399–4156. Gallucci S, Lolkema M, Matzinger P: Natural adjuvants: endogenousactivators of dendritic cells. Nat Med 1999, 5:1249–1255 1390 Correspondence AJP April 2003, Vol. 162, No. 4 
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