- Email: [email protected]
Why minocycline can cause systemic lupus – a hypothesis and suggestions for therapeutic interventions based on it
Medical Hypotheses (2004) 63, 31–34
http://intl.elsevierhealth.com/journals/mehy
Why minocycline can cause systemic lupus – a hypothesis and suggestions for therapeutic interventions based on it M.A.M. van Steensel* Department of Dermatology, University Hospital Maastricht, Maastricht, The Netherlands Received 6 November 2003; accepted 3 December 2003
Summary The tetracycline antibiotic minocycline is widely used in dermatology, but can sometimes cause systemic lupus erythematodes, a serious autoimmune disorder. It is not known how it does this. However, recent data suggest that minocycline can protect cells from apoptosis by inhibition of caspase-dependent and independent cell death pathways. Here, it is suggested that this ability of minocycline is responsible for the induction of lupus. This idea is based on the recent insight that incomplete or failed apoptosis of damaged cells, particularly keratinocytes, may be responsible for the development of auto-immunity. The protection against apoptosis as conferred by minocyclin may be incomplete, with failed apoptosis and development of autoimmunity as a result. Experimental confirmation of the theory may be obtained by in vitro experiments using induction of apoptosis in cell types known to be affected by lupus. Next, mice that are sensitive to apoptosis may be used for in vivo experiments. Novel therapeutic approaches to drug-induced lupus may be based on induction of apoptosis; DNA-damaging immunosuppressive agents appear particularly useful. Such treatments can be tested in apoptosis-deficient mice that develop autoimmune disease. c 2004 Elsevier Ltd. All rights reserved.
Introduction The semi-synthetic tetracycline antibiotic minocycline is widely used in dermatology, in particular for the treatment and maintenance therapy of inflammatory disorders such as acne vulgaris [1]. One of the more serious side effects of this widely used drug is the development of systemic lupus erythematodes, an auto-immune disorder characterized a.o. by the presence of anti-nuclear antibodies such as anti-double strand DNA anti*
Tel.: +31-433-877-296. E-mail address: [email protected].
bodies [2,3]. So far, the molecular mechanisms underlying this phenomenon are unclear. Most theories center on genetic predisposition, suggested by an association with some HLA class II haplotypes [4]. As will be discussed below, however, the association may not signify a direct immune mechanism. Direct toxic effects of minocycline metabolites have also been proposed [5,6]. This paper discusses a novel hypothesis that is supported by recent findings in mouse models of Huntington disease and in human forms of hereditary systemic lupus. It may explain why some (genetically susceptible?) individuals develop lupus upon exposure to minocycline.
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2003.12.040
32
Minocycline and apoptosis Apoptosis, or programmed cell death, is a process that is vital for normal embryonic development and, later in life, for clearance of cells with defective genetic material. It is a complex process, with an increasing number of proteins being implicated in its regulation. Broadly speaking, there are two ways in which cells can be induced to apoptose. First, apoptotic signals can be transduced from the cell surface through so-called death receptors, that via adaptor proteins can trigger activation of the caspases that induce cell death. This type of apoptosis is independent of mitochondria. Second, intracellular events may trigger apoptosis which in this case is mitochondria-dependent. In response to DNA damage, p53 can trigger apoptosis via Bid, Bax/Bak, Smac/DIABLO and cytochrome c release from mitochondria [7,8]. Cytochrome c is required for pro-caspase-9 cleavage. Interestingly, caspase-independent apoptosis seems to be required for MHC class II mediated apoptosis of B-lymphocytes [9]. In experimental models of ischemic stroke, Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury, Parkinson’s disease and multiple sclerosis, minocycline has shown remarkably broad neuroprotective properties [10–16]. In a mouse model of ALS, the mechanism seems to be based at least in part on inhibiting the release of cytochrome c from damaged mitochondria [13]. Other effects have been described, such as inhibition of caspase-1, -3 and activation/upregulation of iNOS as well as activation of p38MAPK [15,17–19]. All considered, it seems that minocycline can act as an inhibitor of mitochondria-dependent apoptosis.
Lupus and apoptosis How is this relevant for systemic lupus induced by minocycline? Apoptosis is quite frequent in skin. UV-damage can result in significant DNA damage that can cause the p53-dependent checkpoints to induce apoptosis (which, being caused by an environmental trigger, will be mitochondria-dependent) [20]. A growing body of evidence suggests that systemic lupus (and related diseases) can be the consequence of dysfunctional handling of postapoptosis events [21–23]. One of the causes of familial systemic lupus is deficiency of DNAse I [24,25]. This enzyme is responsible for breaking down the DNA that is released from the nucleus of broken-down apoptotic cells in the so-called nu-
van Steensel cleosomes. Nucleosomal material is highly immunogenic [26]. It is assumed that the DNAseI deficient patients are immunized against their own chromatin and protein because the “waste products” of a normal apoptosis are not properly disposed of [26,27]. Another disorder that can lead to systemic lupus is C1q deficiency [28–30]. This component of the classical component pathway is responsible for the opsonization of cell fragments containing DNA fragments and cytoplasmic remnants that result from apoptosis, marking them for disposal by phagocytes. Deficiency leads to defective opsonization with incomplete phagocytosis of cell debris, again with potential exposure of immunogenic DNA or chromatin to the immune system as a consequence. Similar phenomena are observed in the autoimmune lymphoproliferative syndrome, caused by FasL deficiency [31]. Here, only mitochondriadependent apoptosis functions and is apparently insufficient to prevent unchecked lymphoproliferation and autoimmune disease. The well-known association between psoralen–ultraviolet treatments [32] and systemic lupus also suggests an important role for defective apoptosis.
Hypothesis In a recent PNAS paper, Wang et al. [33] report that minocycline is capable of inhibiting both caspasedependent and -independent mitochondrial cell death pathways. When given for prolonged periods, it is conceivable that minocycline interferes with normal apoptosis in humans. As stated above, apoptosis in skin is a common event in response to environmental stimuli such as exposure to sunlight. The latter is known to aggravate the symptoms of cutaneous lupus. From the Wang paper, it would seem that the protective effect is incomplete, that is, some activation of apoptotic pathways is still observed. Cell death can be prevented even by incomplete inhibition of the mitochondrial-dependent pathways [8]. However, some damage to partially protected cells may still occur. Specifically, breakdown of cytoplasmic proteins can occur as a result of partial activation of the caspase pathways, but nuclear digestion may be incomplete or not happen at all [34–36]. Being deprived of functional cytoplasm, the cell will die anyway, with exposure of its partially digested nuclear material to the environment. Because the apoptotic pathway is not completed, opsonization and subsequent digestion of nuclear material will be insufficient or may not happen at all. In genetically susceptible individuals, exposure of partially di-
Why minocycline can cause systemic lupus gested nuclear material that results from the incomplete apoptosis that may occur in the presence of minocycline, may result in immunization to nucleosomal material. The above chain of events affects caspasedependent apoptosis in skin. Because minocyclin can also inhibit the caspase-independent pathways, immune regulation may also be affected as a consequence of insufficient “pruning” of potentially autoreactive B-cells [9]. It is conceivable that this mechanism might contribute to the induction of lupus. Moreover, it may also explain the association of particular HLA class II haplotypes with minocycline-induced lupus (see above). Theoretically, prolonged administration of minocycline in susceptible individuals may lead to the development of (B-cell) lymphomas as well. Indeed, there is a report of Sezary-like cells being found in a minocyclin-induced adverse drug reaction [37]. However, no reports exist of B-cell lymphomas being induced by minocycline. This hypothesis does not directly explain the specific association with lupus. Why do other autoimmune diseases not occur upon use of minocycline? A possible explanation might be that nucleosomal material is more immunogenic than cytoplasmic components such as centrioles. Alternatively, since the protective effect of minocycline seems to be incomplete, the timing of events during apoptosis may influence the availability of intracellular antigens. As stated above, digestion of the cytoplasm may be complete while digestion of the nucleus is not. The cell dies, exposing chromatin and naked DNA to the immune system, whereas the completely digested cytoplasm poses no problems. Also, the immune response to non-histone proteins seems to be organ-specific [38]. Hence another prediction of the theory presented here is that disorders caused by immune responses against cytoplasmic components will be far less frequently found to be associated with drugs and will also less frequently (or perhaps not at all) be found to be associated with defective apoptosis. It would be of considerable interest to examine whether other drugs that can induce systemic lupus can protect cells from apoptosis. If they do, chemical structure may not be as relevant as stated elsewhere. In vitro experiments using cells from tissues known to be involved in druginduced lupus such as keratinocytes could be used to address this notion. Minocycline might be added to cultures of keratinocytes that are induced to apoptose using pro-apoptotic agents such as TRAIL. Apoptosis can be readily demonstrated by means of TUNEL and annexin-V staining. If the hypothesis holds true, agarose gel electrophoresis
33 of the cells’ DNA should show incompletely digested DNA. In vivo demonstration of a protective effect may be achieved using any of several mouse models that show increased sensitivity to apoptosis, such as Bax deficient mice [39]. Finally, an important consequence of the theory is that minocycline-induced lupus, and perhaps other forms of systemic lupus as well, may potentially be treated with apoptosis-inducing agents. Because an immunosuppressive effect would be rather convenient in the treatment of lupus, DNA damaging agents such as etoposide may be considered [40]. This idea may be tested in animal models of systemic lupus and drug-induced systemic lupus such as the Tnfrsf6lpr mouse that has a mutation in the FAS protein, which renders it incapable of stimulating apoptosis [41].
References [1] Rossman RE. Minocycline treatment of tetracycline-resistant and tetracycline-responsive acne vulgaris. Cutis 1981; 27:196–7, 201, 207. [2] Tubach F, Kaplan G, Berenbaum F. Highly positive dsDNA antibodies in minocycline-induced lupus. Clin Exp Rheumatol 1999;17:124–5. [3] Schlienger RG, Bircher AJ, Meier CR. Minocycline-induced lupus. A systematic review. Dermatology 2000;200: 223–31. [4] Dunphy J, Oliver M, Rands AL, Lovell CR, McHugh NJ. Antineutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome. Br J Dermatol 2000;142:461–7. [5] Adhami E. A predictive equation for drug-induced lupus. Med Hypotheses 2003;61:473–6. [6] Knowles SR, Shapiro LE, Shear NH. Reactive metabolites and adverse drug reactions: clinical considerations. Clin Rev Allergy Immunol 2003;24:229–38. [7] Schuler M, Green DR. Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 2001;29:684–8. [8] Henry H, Thomas A, Shen Y, White E. Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. Oncogene 2002;21:748–60. [9] Drenou B, Blancheteau V, Burgess DH, Fauchet R, Charron DJ, Mooney NA. A caspase-independent pathway of MHC class II antigen-mediated apoptosis of human B lymphocytes. J Immunol 1999;163:4115–24. [10] Wells JE, Hurlbert RJ, Fehlings MG, Yong VW. Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 2003;126:1628–37. [11] Thomas M, Le WD, Jankovic J. Minocycline and other tetracycline derivatives: a neuroprotective strategy in Parkinson’s disease and Huntington’s disease. Clin Neuropharmacol 2003;26:18–23. [12] Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM. Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 2002;52:54–61. [13] van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport 2002;13:1067–70.
34 [14] Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 2002;51:215–23. [15] Du Y, Ma Z, Lin S, et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA 2001;98: 14669–74. [16] Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998;95:15769–74. [17] Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000;6: 797–801. [18] Lin S, Zhang Y, Dodel R, Farlow MR, Paul SM, Du Y. Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons. Neurosci Lett 2001;315:61–4. [19] Wu DC, Jackson-Lewis V, Vila M, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002;22:1763–71. [20] Cleaver JE, Crowley E. UV damage, DNA repair and skin carcinogenesis. Front Biosci 2002;7:d1024–43. [21] White S, Rosen A. Apoptosis in systemic lupus erythematosus. Curr Opin Rheumatol 2003;15:557–62. [22] Cohen PL, Caricchio R, Abraham V, et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 2002;196: 135–40. [23] Bijl M, Limburg PC, Kallenberg CG. New insights into the pathogenesis of systemic lupus erythematosus (SLE): the role of apoptosis. Neth J Med 2001;59:66–75. [24] Yasutomo K, Horiuchi T, Kagami S, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 2001;28:313–4. [25] Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 2000;25:177–81. [26] Dieker JW, van der Vlag J, Berden JH. Triggers for antichromatin autoantibody production in SLE. Lupus 2002;11: 856–64. [27] Walport MJ. Lupus, DNase and defective disposal of cellular debris. Nat Genet 2000;25:135–6.
van Steensel [28] Botto M, Dell’Agnola C, Bygrave AE, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998;19:56–9. [29] Botto M, Walport MJ. C1q, autoimmunity and apoptosis. Immunobiology 2002;205:395–406. [30] Trendelenburg M, Schifferli JA. Apoptosis and C1q: possible explanations for the pathogenesis of systemic lupus erythematosus. Z Rheumatol 2000;59:172–5. [31] Jackson CE, Puck JM. Autoimmune lymphoproliferative syndrome, a disorder of apoptosis. Curr Opin Pediatr 1999; 11:521–7. [32] Eyanson S, Greist MC, Brandt KD, Skinner B. Systemic lupus erythematosus: association with psoralen–ultraviolet. A treatment of psoriasis. Arch Dermatol 1979;115:54–6. [33] Wang X, Zhu S, Drozda M, et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA 2003;100:10483–7. [34] Sordet O, Rebe C, Plenchette S, et al. Specific involvement of caspases in the differentiation of monocytes into macrophages. Blood 2002;100:4446–44453. [35] Deng Y, Lin Y, Wu X. TRAIL-induced apoptosis requires Baxdependent mitochondrial release of Smac/DIABLO. Genes Dev 2002;16:33–45. [36] Lavie G, Kaplinsky C, Toren A, et al. A photodynamic pathway to apoptosis and necrosis induced by dimethyl tetrahydroxyhelianthrone and hypericin in leukaemic cells: possible relevance to photodynamic therapy. Br J Cancer 1999;79:423–32. [37] Kettaneh A, Fain O, Ziol M, et al. Minocycline-induced systemic adverse reaction with liver and bone marrow granulomas and Sezary-like cells. Am J Med 2000;108:353–4. [38] Dewair MA, Matthaei H. Tissue specificity of nonhistone proteins from human chromatin. Mol Gen Genet 1976;146: 309–12. [39] Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 1995;270:96–9. [40] Pedersen RS, Bistrup C. Etoposide: more effective and less bone-marrow toxic than standard immunosuppressive therapy in systemic vasculitis? Nephrol Dial Transplant 1996;11: 1121–3. [41] Takahashi T, Tanaka M, Brannan CI, et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 1994;76:969–76.
http://intl.elsevierhealth.com/journals/mehy
Why minocycline can cause systemic lupus – a hypothesis and suggestions for therapeutic interventions based on it M.A.M. van Steensel* Department of Dermatology, University Hospital Maastricht, Maastricht, The Netherlands Received 6 November 2003; accepted 3 December 2003
Summary The tetracycline antibiotic minocycline is widely used in dermatology, but can sometimes cause systemic lupus erythematodes, a serious autoimmune disorder. It is not known how it does this. However, recent data suggest that minocycline can protect cells from apoptosis by inhibition of caspase-dependent and independent cell death pathways. Here, it is suggested that this ability of minocycline is responsible for the induction of lupus. This idea is based on the recent insight that incomplete or failed apoptosis of damaged cells, particularly keratinocytes, may be responsible for the development of auto-immunity. The protection against apoptosis as conferred by minocyclin may be incomplete, with failed apoptosis and development of autoimmunity as a result. Experimental confirmation of the theory may be obtained by in vitro experiments using induction of apoptosis in cell types known to be affected by lupus. Next, mice that are sensitive to apoptosis may be used for in vivo experiments. Novel therapeutic approaches to drug-induced lupus may be based on induction of apoptosis; DNA-damaging immunosuppressive agents appear particularly useful. Such treatments can be tested in apoptosis-deficient mice that develop autoimmune disease. c 2004 Elsevier Ltd. All rights reserved.
Introduction The semi-synthetic tetracycline antibiotic minocycline is widely used in dermatology, in particular for the treatment and maintenance therapy of inflammatory disorders such as acne vulgaris [1]. One of the more serious side effects of this widely used drug is the development of systemic lupus erythematodes, an auto-immune disorder characterized a.o. by the presence of anti-nuclear antibodies such as anti-double strand DNA anti*
Tel.: +31-433-877-296. E-mail address: [email protected].
bodies [2,3]. So far, the molecular mechanisms underlying this phenomenon are unclear. Most theories center on genetic predisposition, suggested by an association with some HLA class II haplotypes [4]. As will be discussed below, however, the association may not signify a direct immune mechanism. Direct toxic effects of minocycline metabolites have also been proposed [5,6]. This paper discusses a novel hypothesis that is supported by recent findings in mouse models of Huntington disease and in human forms of hereditary systemic lupus. It may explain why some (genetically susceptible?) individuals develop lupus upon exposure to minocycline.
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2003.12.040
32
Minocycline and apoptosis Apoptosis, or programmed cell death, is a process that is vital for normal embryonic development and, later in life, for clearance of cells with defective genetic material. It is a complex process, with an increasing number of proteins being implicated in its regulation. Broadly speaking, there are two ways in which cells can be induced to apoptose. First, apoptotic signals can be transduced from the cell surface through so-called death receptors, that via adaptor proteins can trigger activation of the caspases that induce cell death. This type of apoptosis is independent of mitochondria. Second, intracellular events may trigger apoptosis which in this case is mitochondria-dependent. In response to DNA damage, p53 can trigger apoptosis via Bid, Bax/Bak, Smac/DIABLO and cytochrome c release from mitochondria [7,8]. Cytochrome c is required for pro-caspase-9 cleavage. Interestingly, caspase-independent apoptosis seems to be required for MHC class II mediated apoptosis of B-lymphocytes [9]. In experimental models of ischemic stroke, Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury, Parkinson’s disease and multiple sclerosis, minocycline has shown remarkably broad neuroprotective properties [10–16]. In a mouse model of ALS, the mechanism seems to be based at least in part on inhibiting the release of cytochrome c from damaged mitochondria [13]. Other effects have been described, such as inhibition of caspase-1, -3 and activation/upregulation of iNOS as well as activation of p38MAPK [15,17–19]. All considered, it seems that minocycline can act as an inhibitor of mitochondria-dependent apoptosis.
Lupus and apoptosis How is this relevant for systemic lupus induced by minocycline? Apoptosis is quite frequent in skin. UV-damage can result in significant DNA damage that can cause the p53-dependent checkpoints to induce apoptosis (which, being caused by an environmental trigger, will be mitochondria-dependent) [20]. A growing body of evidence suggests that systemic lupus (and related diseases) can be the consequence of dysfunctional handling of postapoptosis events [21–23]. One of the causes of familial systemic lupus is deficiency of DNAse I [24,25]. This enzyme is responsible for breaking down the DNA that is released from the nucleus of broken-down apoptotic cells in the so-called nu-
van Steensel cleosomes. Nucleosomal material is highly immunogenic [26]. It is assumed that the DNAseI deficient patients are immunized against their own chromatin and protein because the “waste products” of a normal apoptosis are not properly disposed of [26,27]. Another disorder that can lead to systemic lupus is C1q deficiency [28–30]. This component of the classical component pathway is responsible for the opsonization of cell fragments containing DNA fragments and cytoplasmic remnants that result from apoptosis, marking them for disposal by phagocytes. Deficiency leads to defective opsonization with incomplete phagocytosis of cell debris, again with potential exposure of immunogenic DNA or chromatin to the immune system as a consequence. Similar phenomena are observed in the autoimmune lymphoproliferative syndrome, caused by FasL deficiency [31]. Here, only mitochondriadependent apoptosis functions and is apparently insufficient to prevent unchecked lymphoproliferation and autoimmune disease. The well-known association between psoralen–ultraviolet treatments [32] and systemic lupus also suggests an important role for defective apoptosis.
Hypothesis In a recent PNAS paper, Wang et al. [33] report that minocycline is capable of inhibiting both caspasedependent and -independent mitochondrial cell death pathways. When given for prolonged periods, it is conceivable that minocycline interferes with normal apoptosis in humans. As stated above, apoptosis in skin is a common event in response to environmental stimuli such as exposure to sunlight. The latter is known to aggravate the symptoms of cutaneous lupus. From the Wang paper, it would seem that the protective effect is incomplete, that is, some activation of apoptotic pathways is still observed. Cell death can be prevented even by incomplete inhibition of the mitochondrial-dependent pathways [8]. However, some damage to partially protected cells may still occur. Specifically, breakdown of cytoplasmic proteins can occur as a result of partial activation of the caspase pathways, but nuclear digestion may be incomplete or not happen at all [34–36]. Being deprived of functional cytoplasm, the cell will die anyway, with exposure of its partially digested nuclear material to the environment. Because the apoptotic pathway is not completed, opsonization and subsequent digestion of nuclear material will be insufficient or may not happen at all. In genetically susceptible individuals, exposure of partially di-
Why minocycline can cause systemic lupus gested nuclear material that results from the incomplete apoptosis that may occur in the presence of minocycline, may result in immunization to nucleosomal material. The above chain of events affects caspasedependent apoptosis in skin. Because minocyclin can also inhibit the caspase-independent pathways, immune regulation may also be affected as a consequence of insufficient “pruning” of potentially autoreactive B-cells [9]. It is conceivable that this mechanism might contribute to the induction of lupus. Moreover, it may also explain the association of particular HLA class II haplotypes with minocycline-induced lupus (see above). Theoretically, prolonged administration of minocycline in susceptible individuals may lead to the development of (B-cell) lymphomas as well. Indeed, there is a report of Sezary-like cells being found in a minocyclin-induced adverse drug reaction [37]. However, no reports exist of B-cell lymphomas being induced by minocycline. This hypothesis does not directly explain the specific association with lupus. Why do other autoimmune diseases not occur upon use of minocycline? A possible explanation might be that nucleosomal material is more immunogenic than cytoplasmic components such as centrioles. Alternatively, since the protective effect of minocycline seems to be incomplete, the timing of events during apoptosis may influence the availability of intracellular antigens. As stated above, digestion of the cytoplasm may be complete while digestion of the nucleus is not. The cell dies, exposing chromatin and naked DNA to the immune system, whereas the completely digested cytoplasm poses no problems. Also, the immune response to non-histone proteins seems to be organ-specific [38]. Hence another prediction of the theory presented here is that disorders caused by immune responses against cytoplasmic components will be far less frequently found to be associated with drugs and will also less frequently (or perhaps not at all) be found to be associated with defective apoptosis. It would be of considerable interest to examine whether other drugs that can induce systemic lupus can protect cells from apoptosis. If they do, chemical structure may not be as relevant as stated elsewhere. In vitro experiments using cells from tissues known to be involved in druginduced lupus such as keratinocytes could be used to address this notion. Minocycline might be added to cultures of keratinocytes that are induced to apoptose using pro-apoptotic agents such as TRAIL. Apoptosis can be readily demonstrated by means of TUNEL and annexin-V staining. If the hypothesis holds true, agarose gel electrophoresis
33 of the cells’ DNA should show incompletely digested DNA. In vivo demonstration of a protective effect may be achieved using any of several mouse models that show increased sensitivity to apoptosis, such as Bax deficient mice [39]. Finally, an important consequence of the theory is that minocycline-induced lupus, and perhaps other forms of systemic lupus as well, may potentially be treated with apoptosis-inducing agents. Because an immunosuppressive effect would be rather convenient in the treatment of lupus, DNA damaging agents such as etoposide may be considered [40]. This idea may be tested in animal models of systemic lupus and drug-induced systemic lupus such as the Tnfrsf6lpr mouse that has a mutation in the FAS protein, which renders it incapable of stimulating apoptosis [41].
References [1] Rossman RE. Minocycline treatment of tetracycline-resistant and tetracycline-responsive acne vulgaris. Cutis 1981; 27:196–7, 201, 207. [2] Tubach F, Kaplan G, Berenbaum F. Highly positive dsDNA antibodies in minocycline-induced lupus. Clin Exp Rheumatol 1999;17:124–5. [3] Schlienger RG, Bircher AJ, Meier CR. Minocycline-induced lupus. A systematic review. Dermatology 2000;200: 223–31. [4] Dunphy J, Oliver M, Rands AL, Lovell CR, McHugh NJ. Antineutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome. Br J Dermatol 2000;142:461–7. [5] Adhami E. A predictive equation for drug-induced lupus. Med Hypotheses 2003;61:473–6. [6] Knowles SR, Shapiro LE, Shear NH. Reactive metabolites and adverse drug reactions: clinical considerations. Clin Rev Allergy Immunol 2003;24:229–38. [7] Schuler M, Green DR. Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 2001;29:684–8. [8] Henry H, Thomas A, Shen Y, White E. Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. Oncogene 2002;21:748–60. [9] Drenou B, Blancheteau V, Burgess DH, Fauchet R, Charron DJ, Mooney NA. A caspase-independent pathway of MHC class II antigen-mediated apoptosis of human B lymphocytes. J Immunol 1999;163:4115–24. [10] Wells JE, Hurlbert RJ, Fehlings MG, Yong VW. Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 2003;126:1628–37. [11] Thomas M, Le WD, Jankovic J. Minocycline and other tetracycline derivatives: a neuroprotective strategy in Parkinson’s disease and Huntington’s disease. Clin Neuropharmacol 2003;26:18–23. [12] Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM. Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 2002;52:54–61. [13] van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport 2002;13:1067–70.
34 [14] Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 2002;51:215–23. [15] Du Y, Ma Z, Lin S, et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA 2001;98: 14669–74. [16] Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998;95:15769–74. [17] Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000;6: 797–801. [18] Lin S, Zhang Y, Dodel R, Farlow MR, Paul SM, Du Y. Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons. Neurosci Lett 2001;315:61–4. [19] Wu DC, Jackson-Lewis V, Vila M, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002;22:1763–71. [20] Cleaver JE, Crowley E. UV damage, DNA repair and skin carcinogenesis. Front Biosci 2002;7:d1024–43. [21] White S, Rosen A. Apoptosis in systemic lupus erythematosus. Curr Opin Rheumatol 2003;15:557–62. [22] Cohen PL, Caricchio R, Abraham V, et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 2002;196: 135–40. [23] Bijl M, Limburg PC, Kallenberg CG. New insights into the pathogenesis of systemic lupus erythematosus (SLE): the role of apoptosis. Neth J Med 2001;59:66–75. [24] Yasutomo K, Horiuchi T, Kagami S, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 2001;28:313–4. [25] Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 2000;25:177–81. [26] Dieker JW, van der Vlag J, Berden JH. Triggers for antichromatin autoantibody production in SLE. Lupus 2002;11: 856–64. [27] Walport MJ. Lupus, DNase and defective disposal of cellular debris. Nat Genet 2000;25:135–6.
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