Drug-induced lupus (DIL) refers to a syndrome resembling the idiopathic autoimmune disease systemic lupus erythematosus, but is a deleterious consequence ...
Biochemical Mechanisms in Autoimmunity Biochemical Immunology Group/British Society for Immunology Joint Colloquium Organized and Edited by E. Sim (Oxford) at the 636th Meeting, held at Trinity College, Dublin, 4-7 September 1990, Sponsored by Grant Instruments, Millipore (U.K.) Ltd and Purite Ltd
Drug-induced autoimmunity: a disorder at the interface between metabolism and immunity Robert L. Rubin and Rufus W. Burlingame W. M. Keck Autoimmune Disease Center, Scripps Clinic & Research Foundation, 10666 N. Torrey Pines Road, La Jolla,CA 92037 U.S.A. Drug-induced lupus (DIL) refers to a syndrome resembling the idiopathic autoimmune disease systemic lupus erythematosus, but is a deleterious consequence of therapy with certain drugs [ 1-31. Typically, DIL occurs after several months or years of therapy with the offending agent, and onset of symptoms is often insidious, developing in intensity over 1-2 months before diagnosis can be made. Joint pain is the most common complaint, occasionally evolving to frank arthritis. Lung involvement, particularly pleuritic chest pain and effusions, is also common as are constitutional symptoms of fever, weight loss and fatigue. In addition, many patients treated with lupus-inducing drugs develop serological abnormalities without symptoms of disease. Antinuclear antibodies in these asymptomatic patients are clearly drug-induced and, as with the lupus-like symptoms, gradually subside after discontinuation of therapy. Drug-induced autoimmuity with or without associated lupus-like symptoms cannot be readily explained by any known pharmacological action of or immunological reaction to the offending drugs and raises fundamental questions regarding maintenance of normal immunological self-tolerance. There are at least three features of druginduced autoimmunity which have to be considered in any mechanism proposed to explain this phenomenon.
agent before signs and/or symptoms become manifested is not typical of a toxic drug reaction or classical drug allergy. Drug-induced autoimmunity is clearly a systemic disease, and there is no evidence of an immediate or delayed type hypersensitivity reaction to the drug itself. (2) Chemical heterogeneity of Offending agents
There appears to be no common denominator of a pharmacological, therapeutic or chemical nature which links drugs with the capacity to induce lupuslike disease. These drugs include antibiotics (isoniazid, griseofulvin, streptomycin, tetracycline, sulphonamides, nitrofurantoin), anti-inflammatory agents (o-penicillamine, gold salts) and psychotropic drugs (chlorpromazine, lithium). The largest general pharmacological category of drugs associated with DIL is related to treatment of cardiovascular diseases, but this is also a heterogeneous group and consists of anti-arrhythymics (procainamide, quinidine, acebutalol, practalol) and antihypertensives (hydralazine, methyldopa, some /?blockers). Most of these drugs have one or two aromatic rings, but are otherwise chemically dissimilar. The amino group on procainamide is required for induction of autoimmunity, and other important functional groups are the hydrazide group) on hydralazine and isoniazid and the sulphhydryl group on propylthiouracil. However, these reactive moieties are not components of other lupus-inducing drugs.
( I ) Very slow kinetics The requirement of many months and often years of continuous exposure to the pharmacological
(3) Specificity of autoimmune reaction The autoimmune response to drugs is largely restricted to anti-histone and anti-denatured DNA
Abbreviations used: ANA, antinuclear antibody; DIL, drug-induced lupus; MPO. myeloperoxidase; SOD, superoxide dismutase.
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antibodies, which account for the antinuclear antibody (ANA) activity of the sera. Other autoantibodies or antibodies to exogenous agents (or to the drug itself) are not elicited, suggesting a specific immune response to nucleohistone in the absence of global POIYCIOMI activation. Symptomatic and asymptomatic drug-induced autoimmunity are associated with different types of anti-histone antibodies, but the predominant autoantibody in symptomatic drug-induced lupus is of highly restricted specificity (see below), and the drug is not a component nor effects the structure of the target antigen.
Fig. I
Prevalence of IgG antibodies to the H2A-H2B complex in patients treated with procainamide Triangles indicate serum samples with anti-(HZA-HZB) that decrease at least 2-fold when tested against H2A-H2B complex denatured in SDS. Circles represent sera with similar activity on the native H2A-H2B complex and the denatured antigen. The broken line at 1.4 optical density units defines an arbitrary cut-off value for a positive reaction characteristic of serum from patients with symptomatic procainamide-induced lupus. Reproduced from N.Engl. ]. Med. [9],with permission. lor
Autoantibodies to subnucleosome structures Various reports using Western blot analysis demonstrated antibody in DIL to individual histones, but the significance of these observations is unclear because there is little agreement in the predominant antigenic targets [4-71, and little diagnostic utility or insight into the nature of the putative immunogen underlying autoantibody elicitation has been derived. The natural form of histones is a highly organized intermolecular complex called the nucleosome, the fundamental unit of chromatin structure. The core of the nucleosome consists of three subunits, two H2A-HZB dimers flanking an H3-H4 tetramer [8]. This histone octamer is surrounded by approximately two turns (146 base pairs) of DNA, and a linear array of these core particles held together by a short piece of linker DNA along with bound H1 generates the 100 A diameter primary polynucleosome fibre. If chromatin or its subunits are driving the autoimmune response in drug-induced autoimmunity, the specificity of the induced anti-histone antibodies should reflect this natural organization of histones in chromatin. The importance of H2A-HZB interactions in binding of anti-histone antibodies is suggested by the data in Fig. 1. All patients with procainamideinduced lupus displayed anti-(HZA-H2B) levels at least 5 S.D. above normal serum binding. Heat denaturation of the H2A-HZB dimer in the presence of SDS substantially lowered antibody binding, and these sera showed negligible reactivity with component histones H2A and H2B [9]. In contrast only 6 of 3 1 asymptomatic procainamidetreated patients (average duration of therapy being 3 1 months) had elevated reactivity to the H2A-H2B dimer, but four of these samples also reacted with the component histones H2A and/or H2B. These data suggest that the interaction between HZA and H2B generates or stabilizes an epitope recognized
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8t
A A A
LYl
0
Symptomatic (20)
Asymptomatic
Normal
(31)
(31)
by patients with symptomatic procainamideinduced lupus. As previously explained, the HZA-H2B dimer is normally associated with DNA in the core particle of the nucleosome, so it was of interest to test the effect of DNA on the antigenicity of the H2A-H2B dimer. As shown in Table 1, DNA enhanced 2-10-fold the antigenicity of the H2A-HZB dimer for all sera from patients with procainamide-induced lupus. Increased binding to the (H2A-H2B)-DNA complex was not due to a separate population of antibodies to DNA as the sera did not react with DNA bound to solid-phase methylated albumin. Of particular interest was the finding that sera from patients with lupus induced by other drugs also had pronounced reactivity with the (HZA-HZB)-DNA complex (Table 1). Two patients with lupus induced by quinidine and single patients with lupus induced by penicillamine and isoniazid had pronounced reactivity with the dimer-DNA complex. Interestingly, four of the eight sera shown in Table 1 displayed negligible binding to the H2A-HZB dimer in the absence of DNA. None of these sera reacted with DNA by itself and negligible activity with the component
Autoimmunity
Table I
Antibody to (H2A-H2B)-DNA-containing antigens in DIL
IgG antibody (in enzyme immunoassay) Lupus-inducing drug
Patient
H2A
I55
H2B
H2A-H2B
(H2A-H2B)-DNA
DNA
0.30 0.05 0.08 0.05 0.1 I 0.00 0.05 0.65 0.04 f 0.0 I
3.13 2.85 0.6 I 0. I 2 0. I5 0.02 0.05 ’0.77 0.03 f0.0 I
8.48 8.03 4.57 3.4 I 4.98 I .62 6.95 8.17 0.07 f0.04
0.09 0.0I 0.06 0.03 0.05 0.0I 0.15 0.2 I 0.03 f0.0 I
~
Procainamide Procainamide Procainamide Procainamide Quinidine Quinidine Penicillamine lsoniazid Mean f S.D. of six normal sera
I 2 3 4 5 6 7 8
0.19 0.03 0.14 0.06 0.08 0.0 I 0.04 0.2 I 0.05 f 0.02
histones H2A and H2B was observed. This similarity in antibody specificity to the (H2A-H2B)DNA complex implies a common mechanism for induction of anti-histone antibodies by chemically dissimilar drugs. The (H2A-H2B)-DNA epitope is contained within a natural subunit of chromatin, suggesting that some form of chromatin may drive the autoimmune response in drug-induced lupus. However, numerous attempts to elicit autoantibodies by various immunization protocols have generally been unsuccessful. Immune responses are usually not observed unless the autoantigen is modified from its native structure by either deliberate or unavoidable denaturation. Monoclonal and polyclonal antibodies elicited by immunization of mice with target antigens in systemic lupus erythematosus, namely DNA [lo, 111, thyroglobulin [12], proliferating cell nuclear antigen [ 131, Sjogrens syndrome B antigen [14, 151, Sjogrens syndrome A antigen [ 15, 161, tubulin [ 171 or Smith antigen [ 181 reacted with certain forms of the eliciting agent, but generally displayed binding characteristics different from those of naturally occurring autoantibodies Chromatin is also a poor immunogen (R. L. Rubin, unpublished work), but we were able to elicit a robust anti-histone response in B6D2 F1 mice by immunization with total histones adsorbed to latex beads [ 191. However, although these antibodies bound to the H2A-H2B dimer, they did not react with dimer-DNA, chromatin or nuclei, indicating that true autoantibodies were not induced. Therefore, drug induction of antibodies to chromatin components cannot be readily explained by a process akin to experimental immunization. Furthermore, patients with drug-induced lupus rarely have
antibodies to other components of chromatin such as the H3-H4 tetramer, tetramer-DNA complex or native DNA (although anti-H1 activity is frequently observed) [20]. An immunogen derived from chromatin consisting of (HZA-HZB)-DNA without the H3-H4 tetramer is unlikely to occur because tetramer-DNA associations are much more stable than dimer-DNA interactions in chromatin [21, 221. Collectively,these observations appear to fail to provide a satisfactory explanation for induction of anti-histone antibodies by lupus-inducing drugs. In experimental immunization protocols it is well known that immune responses to xenogenic or allogenic antigens can be suppressed by monomeric forms of the immunogen. In fact, a recent study with mice transgenic for the hen-egg lysozyme gene demonstrated that capacity to elicit an ‘autoimmune’ response to lysozyme was inversely dependent upon the amount of soluble lysozyme secreted in vivo through a process involving downregulation of surface IgM on lysozyme-reactive B-cells [23]. In a similar way the extensive cell turnover and concomitant release of catabolized selfmaterial may generate in vivo low molecular mass antigens which inhibit autoreactive B-cells. One might speculate, therefore, that the key to understanding drug elicitation of autoantibodies may not only have to address the form of the putative immunogen but also the structure of non-immunogenic, low molecular mass self-antigens which may modulate autoimmune responses. Lupus-inducing drugs may interfere with the normal processes responsible for catabolism, clearing and/or processing cell debris, resulting in de-control of autoimmune tolerance to specific components of chromatin.
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Drug metabolism by neutrophils
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The aromatic amino group on procainamide and the hydrazine group on hydralazine and isoniazid can be acetylated by hepatic acetyltransferases. People with genetically-determined high levels of acetyltransferase require a longer duration of therapy than slow acetylators before antinuclear antibodies and DIL develop [24]. These observations, together with the demonstration that Nacetylprocainamide did not induce lupus symptoms [24], ANA (anti-nuclear antibodies) or anti-denatured DNA [25, 261, indicate that the free amino group is necessary for the pathogenic effects of procainamide. However, the parent compound is largely immunologically inert, suggesting that metabolism at the amino/hydrazino group (which would be blocked by acetylation) is required for generation of the autoimmunity-inducing compound. Oxidative metabolism of procainamide by the hepatic microsomal mono-oxygenase system has been demonstrated in vitro [27,28], and experimental studies in vivo suggest that hydralazine and isoniazid may also undergo first-pass oxidative metabolism in the liver [29]. Procainamidehydroxylamine is the immediate product of procainamide oxidation [301. This unstable metabolite will non-enzymically oxidize to nitrosoprocainamide, mediated by dissolved molecular oxygen, and will undergo redox cycling with haemoglobin in red blood cells [31] and with other intracellular reducing agents [32, 331. Procainamide-hydroxylamine/nitroso is highly cytotoxic, killing continuously dividing cells -in tissue culture and activated lymphocytes within minutes at micromolar concentrations [321. Immunoglobulin synof whole blood with 0.4-4 pM-procainamidehydroxylamine [34], suggesting that subtoxic concentrations of this reactive metabolite may be immunostimulatory. Whatever the crucial target in vivo or the ultimate mechanism, studies with these
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able reservoir of oxidative potential. When the Fc or complement receptors of neutrophils are engaged by opsonized particles, a respiratory burst response is initiated. The ectoenzyme NADPH oxidase is activated, resulting in reduction of molecular oxygen by NADPH to produce superoxide anion (0;).This 0 ; ion accumulates in the extracellular environment and rapidly undergoes an oxidation/ reduction reaction [that can be accelerated by superoxide dismutase (SOD)] to form H,O,. Usually accompanying the respiratory burst (depending on the stimulus) is neutrophil degranulation, in which a portion of the contents of specific and azurophil granules is also released into the extracellular environment. Myeloperoxidase (MPO) is the predominant enzyme in azurophil granules and catalyses the peroxidation of chloride ions (CI-) to produce hypochlorite ions (OCI- ). In vitro, these processes are largely complete 5- 10 min after stimulation [35]. Fig. 2 Production of cytotoxic procainamide by activated neutrophils Mixtures of I X IO5 GM4627B target cells per ml, 3 X I O5 neutrophils per ml and increasing concentrations of procainamide ( 0 ) or N-acetylprocainamide (0)were activated with I mg opsonized zymosan/ml. After overnight incubation at 3PC in the presence of [3H]thymidine, target cell viability was measured by scintillation counting. Viability in the absence of neutrophils with (0) or without (A)opsonized zymosan is also shown. Error bars are fs.0. Reproduced from J. Clin. Invest. 1361. with permission.
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-
I
9..\
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A bioassay was devised to detect short-lived, reactive drug metabolites generated in the extracellular medium by neutrophils activated with various agents. If the drug metabolite is cytotoxic, the capacity of a co-present cell line to continue dividing is blocked as measured by ["]-thymidine incorporation into DNA. As shown in Fig. 2, when procainamide was added, a dose-dependent decrease in viability of the target cells was observed only if activated neutrophils were present. N-acetylprocainamide did not support toxic product development, indicating that the aromatic amino group of procainamide was the site of its transformation. This bioassay is highly versatile. In addition to altering the concentration of drug and of neutrophils, the activating agent is an important variable and the cytotoxic potency of the metabolites depends upon the target cell [321. Furthermore, the mechanism underlying this phenomenon can be readily explored. For example, as shown in Fig. 3, addition of catalase (which hydrolyses H,O,) but not of denatured catalase completely blocked generation of cytotoxic products, but SOD, which removes O;, had no effect on cytotoxicity. These and other studies (more fully described in [ 3 6 ] ) allowed deduction of the mechanism for biotransformation of procainamide as depicted in Fig. 4. The H,O, produced by the dismutation of 0; serves as the primary substrate for MPO-mediated co-oxidation of procainamide to the hydroxylamine. This 0; is derived from the respiratory burst and MPO is released into the medium during subsequent degranulation which is triggered when neutrophils are activated with particles such as opsonized zymosan. Application of other lupus-inducing drugs to the bioassay gave variable results. Propylthiouracil produced a cytotoxicity stoichiometry related to neutrophil concentration which was essentially indistinguishable from that produced by procainamide. Hydralazine and quinidine also generated cytotoxic products but higher neutrophil concentrations were required. Neutrophil-mediated cytotoxicity of hydralazine was apparently due to the hydrazine group because pthalazine, an analogue of hydralazine lacking this group, did not support cytotoxic product development. These data suggest that the capacity to be metabolized by activated neutrophils may be a common feature of autoimmunity-inducing drugs and may explain why, although the parent compounds are chemically and pharmacologically very dissimilar, the transformed products may all be highly reactive. Of greatest importance is whether
Fig. 3
Component
requirements for procainamide metabolism by neutrophils
Target cell viability was measured as described in Fig. 2 using 0.03 mn-procainamide. The production of 0; was measured by cytochrome c reduction on 3 X I O6 neutrophildml. Further details in [36]. Op.Zy, opsonized zymosan; PA, procainamide; den. cat, denatured catalase: PMA, phorbol 12-myristate 13-acetate. Target cell viability (c.p.rn.+ s I) Adbtions to Nwtrophils None O P ZY PA+OpZy camlase + PA + O p Zy den cat +PA + O p Zy SOD +PA +Op Zy den SOD +PA + Op Zy
* '
'
io
40
X
10- ')
2o
24
None 0P.ZY PMA SOD + PMA den.SOD + PMA
0
I0
30
50
0; Production (nrnol f s.i)./15 rnin per 3 x 10' neutrophil)
Fig. 4
Proposed scheme for oxidation of procainamide to the hydroxylamine by activated neutrophils The H202produced by the dismutation of 0;serves as the primary substrate for MPO-mediated co-oxidation of the procainamide (R-#-NH,) to the hydroxylamine (R#-NHOH). Reproduced from J. Clin. Invest. [36], with permission. PMN, polymorphonucleocyte.
NAOPH
R-Q-NHz MPO
activated neutrophils may mediate oxidative metabolism of drugs in viva This could come about as a result of endogenous neutrophil activation accompanying chronic inflammatory conditions such as those associated with ageing, underlying rheumatic symptoms or a concomitant infection. The low probability that a patient treated with a lupus-inducing drug will develop an infection at a site that could generate drug metabolites accessible to a lymphoid compartment may explain the long
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lag time between administration of drug and development of autoimmunity. Although this notion is difficult to test, recent studies demonstrating that mice injected with gold sodium thiomalate (I) do not respond to gold of the 1 + oxidation state but are hyper-responsive to gold (111), as measured by popliteal lymph node enlargement, suggests that gold (I) had undergone an oxidative reaction to gold (111) in vivo [37], possibly mediated by activated neutrophils. Identification of lymphocyte-reactive metabolites may be aided by in Vitro studies involving stimulation of human peripheral blood lymphocytes from drug-treated patients or splenocytes from experimental animals with candidate drug metabolites or their conjugates.
Working model Fig. 5 is a working model for a possible approach to understanding drug-induced autoimmunity. The first, relatively rare event may be a localized inflammatory reaction within a lymphoid compartment in an individual being treated with the offending agent. Neutrophils, because of their abundance, their capacity to accumulate almost anywhere, and their reservoir of oxidative potential, would appear to be prime candidates for transforming drugs to reactive forms. Drug oxidation, which for some drugs is blocked by acetylation, is a promiscuous property of MPO released from activated neutrophils. We suspect that low concentrations of reactive drug metabolites may cause a general, non-specific immune dysregulation resulting in lymphokine production. Cytotoxicity may also play a role in induction of autoantibodies by disrupting normal Fig. 5 Working model for drug-induced autoimmunity
DRUG oxidative m;tabolism by activated phagocytes rapid acetylation +
,
DRUG’
1
specific autoantibodies
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physiological cell death pathways. Aberrant, potentially immunogenic self-materials may form, and the exquisite specificity of the autoantibodies which characterize drug-induced lupus may be the result of disruption of an antigen-mediated process for maintaining autoimmune tolerance. We thank Judy Zubar and Janice Arnott for expert technical assistance and Caryl Kane for invaluable help in the preparation of the manuscript. This work was supported in part by NIH grant AK34358 and I’HS grant KKOO833.
1. Lee, S. I,. & Chase, 1’. H. (1975) Semin. Arthritis Kheum. 5.83-103 2. Weinstein, A. ( 1 980) hog. Clin. Immunol. 4, 1-2 1 3. Kubin, K. I,. (1989) in Autoimmunity and Toxicology: Immune Disregulation Induced by Drugs and Chemicals (Kammuller, M., Bloksma. M. & Seinen. W., eds.), pp. 1 19- 150, Elsevier, Amsterdam 4. Gohill, J., Cary, P. D.,Couppez, M. & Fritzler, M. J. (1985) J. Imrnunol. 135,3116-3121 5. Portanova. J. P., Arndt, K. E., Tan, E. M. & Kotzin. H. L. (1987)J. Immunol. 138.446-45 1 6. Bernstein, K. M., Hobbs, K.N., Lea, D. J., Ward. D. J. & Hughes, G. K. V. (1985) Arthritis Kheum. 28, 285-293 7. Craft, J. E.. Kadding. J. A.. Harding, M. W., Hernstein. K. M. & Hardin, J. A. (1987) Arthritis Kheum. 30, 689-694 8. Hurlingame, K. W., Love, W. E., Wang. H.-C., Hamlin. K., Xuong, N.-H. & Moudrianakis. E. N. (1985) Science 228,546-553 9. Totoritis. M. C., Tan, E. M., McNally, E. M. & Kubin, K. 1,. (1988) N. Engl. J. Med. 318. 1431-1430 10. Madaio. M. P., Hodder, S., Schwartz, K.S. & Stollar, B. L). (1984)J. Irnrnunol. 132,872-876 1 1 . Schwartz, K. S. & Stollar, H. D. (1985) J. Clin. Invest. 75,321-327 12. Kuf, J., Canyon. P.. Sarles-Philip. N.. Kourilsky, F.& Lissitzky, S. (1983) EMBO J. 2, 1821-1826 13. Ogata, K., Ogata, Y., Takasaki. Y. & Tan. E. M. (1987) J. Immunol. 139,2942-2946 14. Chan, E.K. L. & Tan, E. M. (1987)J. Exp. Med. 166, 1627- 1640 15. Bachmann, M., Mayet. W. J., Schroder, H. C.. I’feifer, K., Meyer zum Buschenfelde, K.-H. & Muller, W. E. G. (1986) Proc. Natl. Acad. Sci. USA. 83,7770-7774 16. Kosario. M. 0..Fox, 0. F..Koren, E. & Harley, J. H. (1988) Arthritis Kheum. 31,227-237 17. Matthes, T., Wolff, A., Soubiran, l’.$ Gros, F. & IXghiero, G.(1988)J. Immunol. 141, 3135-3141 18. Shores, E. W., Pisetsky. Ll. S., Grudier. J., Eisenberg, K. A. & Cohen, 1’. I,. (1988) Immunology 65. 473-478 19. Kubin, K. I,., Tang, F.-I,.. Tsay, G. & I’ollard. K. M. (1990) Clin. Immunol. Immunopathol. 54, 320-332 20. Hurlingame, K. W. & Kubin, K. I,. (1989) Arthritis Kheum. 32,522 (Abstract)
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21. Nelson, 11. A., Mencke, A. J., Chambers. S. A.. Oosterhof, 1). K. & Kill. R.I,. (1982) Biochemistry 21, 4350-4362 22. Oohara, 1. & Wada, A. (1987) J. Mol. Hiol. 196, 399-41 I 23. Goodnow, C. C., Crosbie, J.$Jorgensen, H., Brink. H. A. 8i Hasten. A. (1989) Nature (London) 342. 385-391 24. Woosley. K. I,., Ilrayer, L). E., Keidenberg. M. M., Nies. A. S.. Carr. K. & Oates, J. A. (1978) N. Engl. J. Med. 298, 1 157- 1 159 25. Koden. L). M., Reek, S. H., Higgins. S. H.. Wilkinson, G. K.. Smith, K. F.. Oates. J. A. & Woosley, K. I,. ( 1980) Am. J. Cardiol. 46.463-468 26. Lahita. K., Kluger, J.$ Drayer, L). E., Koffler, I). & Keidenberg, M. M. (1979) N. Engl. J. Med. 301. 1382- 1385 27. lktrecht, J. I>., Sweetman, 13. J., Woosley, K. I,. & Oates. J. A. (1984) 1)rug Metab. Dispos. 1 2 , 7 7 4 1 28. Hudinsky, K.A.. Roberts, S. M.. Coats, E. A., Adams. 1,. 8i [less, E. V. (1987) Drug Metab. Ilispos. 15, 37-43 .?). Hein. 1). w. & Weber, w. w. (1989) in Autoimmunity and Toxicology (Kamrnueller. M. E.,
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Received 20 August 1990
Antibodies to intracellular antigens in systemic autoimmune disease Robert M. Bernstein Rheumatology Department, Manchester Royal Infirmary, University of Manchester, Oxford Road, Manchester M I3 9WL, U.K.
W e all harbour the ability to make autoantibodies against certain components of our cells and plasma. Low levels may serve to accelerate the removal of cellular debris by the reticuloendothelial system 11 1, while autoantibodies to histones, mitochondria and smooth muscle can reach high titre during exposure to certain drugs, bacteria and viruses. Heat-shock proteins are dominant antigens in the immune response to bacteria and protozoa, and some antiDNA antibodies have close structural similarities to antibodies to bacterial proteins 121. It seems that autoimmunity and protective immunity are two sides of a coin. In the systemic autoimmune diseases, the checks and balances are disturbed, and autoantibodies reach high titres. Yet, as indicated in Table 1. this is no release of the floodgates. Just a few autoantibodies are synthesized in abundance in each disease, and less than 0.1% of cellular macromolecules are targets for autoimmunity. This selectivity makes it improbable that these are random Abbreviation used: I’CNA. proliferating cell nuclear antigen.
responses to tissue damage. It seems rather that iutoantibodies offer a clue to aetiology. They may be reporters of past events, such as the hijack of cells by a pathogenic virus. Some autoantibodies do enter into the pathological process, binding to cell membranes or forming immune complexes which deposit in tissues and promote inflammation, but others play no obvious part in the accompanying disease. To the clinician autoantibodies are useful extra pieces in the jigsaw of signs and symptoms leading to diagnosis, while to the biochemist they can be interesting probes of molecular function.
Historical In the 1940s the first autoantibody phenomena to be noted were the false-positive test for syphilis, the Lupus Erythematosus cell phenomenon (phagocytosis of nuclear material by polymorphs) and rheumatoid factor. Recognition of the LE cell phenomenon as an opsonin reaction involving antibody to nucleoprotein led to the immunofluorescence technique for antinuclear antibody [31, with its various patterns [4],the detection of pre-
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