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A tribute to an outstanding immunologist – Ian Reay Mackay
Journal of Autoimmunity 31 (2008) 197–200
Contents lists available at ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
A tribute to an outstanding immunologist – Ian Reay Mackay Senga Whittingham*, Merrill J. Rowley, M. Eric Gershwin Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
a b s t r a c t Keywords: Autoimmunity Primary biliary cirrhosis Ian Mackay Diagnostic autoimmunity
The 11th Australasian Autoimmunity Workshop was held in Melbourne, Australia from July 6–8, 2007 organized by the Monash University Autoimmunity Network. The workshops, founded by the late Kevin Lafferty, are a chance for Australasians interested in research into autoimmune disease to present and discuss their work. This workshop also was a chance to acknowledge Ian Mackay, a pioneer clinicianscientist who has made major contributions to our understanding of autoimmune diseases. Friends, colleagues and former students attended the Workshop and acknowledged Ian’s expertise and mentorship. This edition of the Journal of Autoimmunity pays tribute to Ian Mackay. It features articles from attendees at the workshop, and contributions from some of Ian’s past students and past and current collaborators. Ó 2008 Elsevier Ltd. All rights reserved.
Introducing Ian Mackay and explaining his contributions to human immunology in this short introduction is much like trying to summarize War and Peace for a high school primer. Ian Mackay is one of the pioneers in the development of the concept of autoimmunity as a cause of defined and treatable human chronic disease from an unpopular theory to one that is now accepted universally. His career has been a long and stellar one in clinical research. In the 1950s in London under the tutelage of Sheila Sherlock (later Dame Sheila Sherlock), Ian developed an interest in hepatology when it was still a fledgling clinical specialty. The sound knowledge of diseases of the liver gained during that period stood him in good stead when, in 1956, he joined the Clinical Research Unit (CRU) of the Walter and Eliza Hall Institute (WEHI) and The Royal Melbourne Hospital. Here the hospital ward-research institute milieu was ideally suited to the pursuit of clinical research. A 27 bed ward of patients was linked by a door to laboratories that were wholly dedicated to clinical research and these laboratories were part of * Corresponding author. Tel.: þ61 3 9905 1438; fax: þ61 3 9905 3726. E-mail address: [email protected] (S. Whittingham). 0896-8411/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2008.04.004
WEHI then under the directorship of Macfarlane Burnet (later Nobel Laureate). The hepatitis viruses had not been discovered and adult patients with chronic liver disease not due to alcohol or drugs, were a heterogeneous group. In the CRU a group of patients had been observed to have chronic relapsing hepatocyte damage that had been nominated ‘active chronic hepatitis’, and in this group there was a preponderance of female patients with hyperglobulinemia whose blood tested positive for lupus erythematosus (LE) cells. Ian gave their hepatitis the descriptive name ‘lupoid hepatitis’ [1] because of the LE association although later, when the nature of the illness was unveiled as autoimmune, he revised the name to autoimmune hepatitis (AIH) [2]. Apart from the LE association these patients also demonstrated serologic reactivity with fractions of cytoplasm from liver tissue by a complement fixation test that a visiting scientist to WEHI, Carlton Gajdusek (later Nobel Laureate), was investigating as a possible test for hepatitis virus. Further studies showed that this test was not a test for hepatitis virus and although it demonstrated auto-reactivity and became known as the autoimmune complement fixation (AICF) test, it was not specific for lupoid hepatitis. High titers of auto-reactivity by the AICF test were reported by Ian in primary biliary cirrhosis [3] and historically, that was an important finding because it was the first demonstration of antimitochondrial antibody (AMA) in PBC. Apart from AIH, PBC became one of Ian’s major interests, particularly when techniques for cloning autoantigens became available. However, it was some 30 years later before Eric Gershwin came to the CRU as a visiting professor and successfully cloned the mitochondrial autoantigen [3], and Eric and Ian opened up an exciting new field of research in PBC. Ian’s contribution to the characterization of the autoimmune hepatic diseases, AIH and PBC,
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is immeasurable. He quite courageously, gave immunosuppressive treatment to young women with AIH when immunosuppressive drugs were still crude preparations and for this, his reward was not only dramatic improvement in the health of these women but also their greatly prolonged survival. He developed reliable diagnostic serology for AIH that led to elegant studies on F actin with his former registrar, Ban Hock Toh, and more recently Cris dos Remedios, and he demonstrated the strong association of AIH with HLA-B8-DR3. As the group of patients with AIH expanded it became clear to Ian that these and patients with other autoimmune diseases (AID) fulfilled a set of diagnostic criteria. These criteria were: preponderance in women, presence of autoantibodies in serum, a raised level of serum globulin, histological evidence of chronic inflammation in the target organ, a response to corticosteroid drugs, and the presence of other autoimmune diseases in the same subject or a family member. By 1963 Ian had amassed sufficient clinical and laboratory evidence to publish a book that he coauthored with Macfarlane Burnet [4]. In their book that was first devoted to AID, they nominated chronic diseases that they believed, in time, would be proven to be autoimmune. Their predictions were not far off the mark and there were few omissions. While Ian was gathering proof for autoimmunity in liver disease, some stunning experiments were being undertaken in the USA. There was little support for the concept of autoimmunity in the USA in the early 1950s, so when Noel Rose a student of Ernst Witebsky, obtained evidence for an experimental animal model of autoimmune thyroiditis, Witebsky, a revered immunologist of ‘the old school’, had some difficulty accepting his student’s results. Although Noel had a sisyphean struggle to provide incontrovertible proof for his finding, the evidence was unshakeable and the model was faithful to human thyroiditis described by Ivan Roitt and Deborah Doniach in London. The trajectory for future research on autoimmunity in clinical and experimental medicine was largely determined by these studies from Australia, USA and the UK. Staunch non-believers became converts to autoimmunity and the field of autoimmunity became richer for the warm friendship that developed between Ian Mackay and Noel Rose. They not only co-edited a book that became the definitive reference book on autoimmunity and is now in the 4th edition [5], but they have been active in establishing interest groups and promoting training programs in clinical immunology and autoimmunity in their respective countries. When Ian Mackay succeeded Ian Wood as head of the CRU he assembled a team of young enthusiastic scientists and clinicians to undertake research in autoimmunity and care for patients with autoimmune disease. One of the strengths of the CRU was the team spirit. Each member, whatever position they held, was encouraged to actively participate in discussion ranging from interpretation of results of laboratory experiments and clinical findings to theories on the concept of autoimmunity. Socially, Ian was a generous host. Medical students and members of the CRU will remember many a party held around and sometimes in the swimming pool at Ian’s home where his partner Pat, a distinguished anesthetist, as a gracious hostess supervised the serving of food and drinks by the Mackay children. As the CRU was part of WEHI and this same family spirit was fostered by Macfarlane Burnet and then by Gustav Nossal (later Sir Gustav Nossal) when he became director, there was ample opportunity for collaboration with those undertaking research in basic immunology. Indeed, the tearoom was as important as the seminar room for the exchange of ideas and active and often spirited discussion. There were many highlights to research in the CRU during Ian’s watch, spanning the years 1963–1987. Ian always encouraged the pursuit of work at the cutting edge of research and for some projects was ‘a man before his time’. An example of the latter was an attempt
to develop a computer-based medical record in the late 1960s. The system devised by two PhD students, Vance Gledhill and Alex McPherson, worked well as a pilot scheme, but at that time the computer hardware was inadequate and the minds of clinicians unprepared for application of such a system to a large general hospital. Ian’s search for sensitive diagnostic markers of autoimmunity was ongoing as were his attempts to develop simple tests for the measurement of immune function. This led to numerous studies on normal subjects including those on a rural population of some 7500 subjects in Busselton, Western Australia to establish the prevalence of autoimmunity and its effect on the community. The results not only clearly demonstrated the influence of gender, age, and inheritance on the development of autoantibodies but also the role autoantibodies have in predicting the development of AID and, in subjects with no overt signs of AID, the risk of morbidity and premature death from cardiovascular disease. Never far from Ian’s thoughts was the part played by the thymus gland in autoimmunity. In the 1960s he pondered on the presence of lymphoid follicles with germinal centers and plasma cells in the medulla of older NZB mice with autoimmune hemolytic anemia (AHA) and reports of a beneficial effect of thymectomy in children with intractable, life-threatening AHA. With his radiologist colleague, Bill Hare, he showed that the shape and size of the human thymus could be measured accurately on the shadow obtained by pneumomediastinography. Thymectomy performed in patients with systemic lupus erythematosus had little, if any, beneficial effect but notable success, even cure, was observed long-term in subjects with myasthenis gravis. The experimental work in the CRU and ideas on the role of the thymus in autoimmunity have been described in a book Ian co-authored with Gideon Goldstein [6]. Ian’s long-term interest in experimental allergic encephalomyelitis (EAE) as a model of multiple sclerosis began when his biochemist colleague, Pat Carnegie, characterized encephalitogenic peptides that were used as autoantigens to set up various experimental models of EAE. Soon joined by Claude Bernard who came to the CRU as a post-doctoral fellow, the trio continued the collaboration for many years. The two PhD students in this research program went on to carve out illustrious careers elsewhere, one in medicine and politics in Alberta, Canada and the other in neuroimmunology at the Salk Institute and Mayo Clinic, USA. The simple classification of AIDs proposed by Ian in 1969 grouped them in two clusters, the multisystem and thyrogastric clusters [7]. There was some disease overlap but, in the main, the association of AIDs in individual subjects and their families was unique to the cluster. ‘Guilt by association’ was a term favored by Ian when he suspected a disease might be autoimmune because of the company it kept. It was long suspected from various studies in the CRU that diabetes mellitus was an AID and a member of the thyrogastric cluster but an autoantibody specific for diabetes eluded detection until Bottazzo, in London, discovered the pancreatic islet cell autoantibody. In 1949 Ian Wood designed a flexible gastric biopsy tube that for the first time enabled the study of multiple samples of gastric mucosa from living subjects. Meticulous in his research Ian Wood had in one publication alone reported his experience of gastric biopsy in over 1000 subjects. When Ian Mackay joined the CRU in 1956 he was exposed to this research and when he became head in 1963 he inherited this wealth of experience in gastric histopathology. Gastric atropy was known to be associated with pernicious anemia (PA) but why it was associated was unknown and the majority of patients with chronic gastritis comprised a heterogeneous group in whom the cause was unknown. When gastric parietal cell and intrinsic factor autoantibodies were discovered in patients with PA markers became available for studying chronic gastritis due to autoimmunity at its various stages of evolution. In 1973, in a landmark study [8], Ian with Reg Strickland proposed
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a classification for chronic gastritis: Type A gastritis was autoimmune and confined to the body of the stomach and Type B gastritis was mainly antral. Infection was presumed to be the cause of Type B gastritis but proof of that did not come until a decade later when Helicobacter pylori was discovered to be the causative organism. When Ian retired from the CRU in 1987 he allowed no time to reflect on any void that might be created by the cessation of a busy and challenging life spent on clinical duties and research. Due to his interest in the role of mitochondria in the immune response in PBC, he had, prior to retirement, set up collaborative studies with Tony Linnane, an expert in mitochondria at Monash University. This resulted in an invitation from Tony Linnane to establish an Autoimmunity Laboratory in his department to expand the existing research on autoimmunity and mitochondria. Ian sought competitive research funding for this new venture and was soon joined by the first PhD student he had supervised when he became head of the CRU, Merrill Rowley, who brought with her the laboratory expertise and experience in research required for the establishment of such a laboratory. This was the start of a productive period of research, focusing mainly on PBC initially but soon also on type 1 diabetes and rheumatoid arthritis. The main thrust of the research has been the study of epitopes on molecules that behave as autoantigens in these diseases and for this work experience in a variety of techniques has been developed. These techniques included immunoassays for the detection of autoantibodies, enzyme inhibition assays to measure functional impairment due to autoantibody, phage display to identify conformational epitopes, and Fourier transform infrared microscopy to correlate changes in chemical composition of tissues produced by autoantibody with the structural changes observed by light microscopy. Ian has continued his collaborative studies on PBC with Eric Gershwin and various Japanese colleagues. He has also worked closely with Paul Zimmet on epidemiologic studies on type 1 diabetes, particularly on autoantibodies to glutamic acid decarboxylase (GAD). It was in such studies that apparently healthy adults were observed to have anti-GAD demonstrable for up to 10 years before expression of disease and anti-GAD were also present in a subset of people with type 2 diabetes who subsequently required insulin for treatment. This led Ian to coin the term LADA (Latent Autoimmune Diabetes of Adults) to describe their form of type 1 diabetes. The study of the two isoforms of GAD, GAD65 and GAD67 has been a major part of the research in the laboratory and the highlight for 2007 was the solution of the crystal structures of these two isoforms. Over the years Ian has spent countless hours at his desk in his study at home. He enjoys writing. Indeed, writing has been a necessary part of life for him, and his study has always been a special place. The entire wall of a former study featured the spectacular night skyline of New York but now in his new home the scene is more subdued. His desk overlooks a peaceful, attractive garden lovingly tended by Pat. Ian has authored over 700 full-length articles on clinical and experimental research on autoimmunity in respected journals, as well as in many books. He has always been generous with the time he has given to committee work, editorial boards, reviewing grants, theses, reports and articles in journals, and the endless requests for help with tasks related to research. He is a Member of the Order of Australia and a Fellow of the Australian Academy of Science, and in his wardrobe of honors and awards he has many caps. There are many who have worked or collaborated with Ian in research who have not been named in this tribute. Ian will remember you with affection and would wish to acknowledge your contribution in introducing the concept of autoimmunity to the world of clinical medicine and for providing the intellectual sustenance for him to ponder on yet ‘unfinished business’ in autoimmunity [9].
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The 8th Australasian Autoimmunity Workshop marked his 80th birthday, and there was a dinner attended by many of his friends and past students, who provided vignettes from their memories of their time with Ian. We note some interesting comments from Dr. Brian Youl, a former clinical Registrar. ‘‘Dr IR Mackay caught me on the rebound from a disastrous first attempt at the Australasian Fellowship examinations – I had confidently diagnosed cystic fibrosis in an elderly chap with chronic lung disease in the long case. I went on to spend a year as his senior registrar in the Clinical Research Unit. Bizarrely, the highly talented Elsdon Storey was our junior registrar. Sandwiched between these marvelous intellects I couldn’t help but improve. The Problem Oriented approach to medical clerking, while irritating in its rigor, seemed to clarify my analysis of cases, and Ian’s ward rounds were undoubtedly more frightening than anything I was to encounter on my second, successful attempt at the ‘‘Part II’’. I hope I will never forget the time on Ward 3 East when, horrified at being asked the mechanism of action of digoxin on a ward round attended by, among others, two of the then authors of ‘‘Harrison’s Textbook of Medicine’’, I instantly dropped to the floor and underwent a grand mal convulsion. Ian, the consumate diagnostician, having quite correctly recognized this to be a pseudoseizure, immediately turned to Storey and grilled him about the early works of Ovid. They went on to argue about the relative merits of his ‘Tristia’ and ‘Epistulae ex Ponto’. At the next bed I chipped in with ‘‘What about Patterson, Dr Mackay? You know, ‘There was movement at the station, and the word had passed around’’’. Ian glared at me and retorted, ‘‘The word had GOT around, Youl. We’ll move on!’’ In addition, from Len Harrison, current Head of the Clinical Research Unit at WEHI, and collected by another clinical Registrar of Ian Mackay, Dr. Alan Ebringer, come under the following 10 aphorisms of Ian Mackay: 1. If you have done only 10 drafts of your paper, then you have not really read it. 2. Once you have done 20 drafts, your paper is approaching the publishable ideal. (My paper on ‘‘chloroquine neuromyopathy’’ went through 22 drafts.) 3. Do not quote a paper in your references that you have not read; sooner or later you will be found out. 4. Every chronic disease is autoimmune unless proved otherwise. 5. An alcoholic patient is usually dominated by a strong willed mother or wife, and sometimes both. 6. When giving a research talk, remember there are only two or three people in the audience to whom your presentation is addressed; the others don’t count. 7. There is no such thing as a ‘‘slough’’ or routine case in your ward; every patient can teach you good medicine. 8. You have no right to play ‘‘god’’ with incurable diseases; you must do your best till the end. 9. The concept of ‘‘euthanasia’’ interferes with clear medical thinking and has been banished. 10. Mouse immunologists usually have a poor grasp of medicine and inevitably will make fools of themselves during ward rounds. Although Ian retired from the Hall Institute in 1987, his work has continued virtually unabated and since 1987, Mackay and Gershwin have co-authored 39 papers [10–48]. At the 8th Australasian Autoimmunity Workshop Ian’s work was noted as follows. ‘‘Ian was at WEHI for 32 years, 24 years as Head of the Clinical Research Unit (1963–1987). During that time he laid the foundations for the modern understanding of autoimmune diseases. His interest in this area dated from the 1950s when, with Carlton Gajdusek (who later received the Nobel Prize for his work on kuru), he recognized that a laboratory test developed by Gajdusek to demonstrate hepatitis A
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virus was actually detecting an autoimmune reaction between human serum and liver. The autoimmune complement fixation test developed by Ian and Gajdusek was the first to demonstrate autoantibodies in liver disease. This led him to describe autoimmune chronic active hepatitis, a paradigm for other autoimmune diseases. His subsequent description in 1957 of autoimmune primary biliary cirrhosis was capped 30 years later by the cloning of the gene for the M2 mitochondrial autoantigen of this disease, in a collaborative study with Eric Gershwin’’. It is fitting to update our tribute to Ian on the occasion of his 85th birthday.
References [1] Cowling DC, Mackay IR, Taft LI. Lupoid hepatitis. Lancet 1956;271:1323–6. [2] Mackay IR, Weiden S, Hasker J. Autoimmune hepatitis. Ann N Y Acad Sci 1965; 124:767–80. [3] Mackay IR. Primary biliary cirrhosis showing a high titer of autoantibody; report of a case. N Engl J Med 1958;258:185–8. [4] Mackay I, Burnet F. Autoimmune diseases, pathogenesis, chemistry and therapy. Springfield: Thomas; 1963. [5] Rose N, Mackay I. Amsterdam: Elsevier; 2006. [6] Goldstein G, Mackay I. The human thymus. London: William Heinemann; 1969. [7] Mackay IR. Autoimmune disease. Med J Aust 1969;1:696–9. [8] Strickland RG, Mackay IR. A reappraisal of the nature and significance of chronic atrophic gastritis. Am J Dig Dis 1973;18:426–40. [9] Mackay IR. Autoimmune diseases of the liver, autoimmune hepatitis and primary biliary cirrhosis: unfinished business. Hepatol Res 2007;37(Suppl. 3): S357–64. [10] Aoki CA, Roifman CM, Lian ZX, Bowlus CL, Norman GL, Shoenfeld Y, et al. IL-2 receptor alpha deficiency and features of primary biliary cirrhosis. J Autoimmun 2006;27:50–3. [11] Gershwin ME, Ansari AA, Mackay IR, Nakanuma Y, Nishio A, Rowley MJ, et al. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells. Immunol Rev 2000;174:210–25. [12] Gershwin ME, Coppel RL, Bearer E, Peterson MG, Sturgess A, Mackay IR. Molecular cloning of the liver-specific rat F antigen. J Immunol 1987;139:3828–33. [13] Gershwin ME, Coppel RL, Mackay IR. Primary biliary cirrhosis and mitochondrial autoantigens–insights from molecular biology. Hepatology 1988;8:147–51. [14] Gershwin ME, Mackay IR. Primary biliary cirrhosis: paradigm or paradox for autoimmunity. Gastroenterology 1991;100:822–33. [15] Gershwin ME, Mackay IR. New knowledge in primary biliary cirrhosis. Hosp Pract (Minneap) 1995;30:29–36. [16] Gershwin ME, Mackay IR. The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 2008;47:737–45. [17] Gershwin ME, Mackay IR, Sturgess A, Coppel RL. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 1987;138:3525–31. [18] Gershwin ME, Rowley M, Davis PA, Leung P, Coppel R, Mackay IR. Molecular biology of the 2-oxo-acid dehydrogenase complexes and anti-mitochondrial antibodies. Prog Liver Dis 1992;10:47–61. [19] Invernizzi P, Selmi C, Mackay IR, Podda M, Gershwin ME. From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2005;3:401–10. [20] Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R, et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006; 203:1209–19. [21] Iwayama T, Leung PS, Rowley M, Munoz S, Nishioka M, Nakagawa T, et al. Comparative immunoreactive profiles of Japanese and American patients with primary biliary cirrhosis against mitochondrial autoantigens. Int Arch Allergy Immunol 1992;99:28–33. [22] Kinoshita H, Omagari K, Whittingham S, Kato Y, Ishibashi H, Sugi K, et al. Autoimmune cholangitis and primary biliary cirrhosis–an autoimmune enigma. Liver 1999;19:122–8. [23] Kita H, Mackay IR, Van De Water J, Gershwin ME. The lymphoid liver: considerations on pathways to autoimmune injury. Gastroenterology 2001;120: 1485–501.
[24] Lan RY, Mackay IR, Gershwin ME. Regulatory T cells in the prevention of mucosal inflammatory diseases: patrolling the border. J Autoimmun 2007;29: 272–80. [25] Lleo A, Invernizzi P, Selmi C, Coppel RL, Alpini G, Podda M, et al. Autophagy: highlighting a novel player in the autoimmunity scenario. J Autoimmun 2007; 29:61–8. [26] Mackay IR, Gershwin ME. Molecular basis of mitochondrial autoreactivity in primary biliary cirrhosis. Immunol Today 1989;10:315–8. [27] Mackay IR, Gershwin ME. Primary biliary cirrhosis: current knowledge, perspectives, and future directions. Semin Liver Dis 1989;9:149–57. [28] Mackay IR, Gershwin ME. Primary biliary cirrhosis: considerations on pathogenesis based on identification of the M2 autoantigens. Springer Semin Immunopathol 1990;12:101–19. [29] Mackay IR, Gershwin ME. The nature of autoimmune disease. Semin Liver Dis 1997;17:3–11. [30] Mackay IR, Van de Water J, Gershwin ME. Autoimmunity. Thoughts for the millennium. Clin Rev Allergy Immunol 2000;18:87–117. [31] Mackay IR, Whittingham S, Fida S, Myers M, Ikuno N, Gershwin ME, et al. The peculiar autoimmunity of primary biliary cirrhosis. Immunol Rev 2000;174: 226–37. [32] Moehario LH, Smooker PM, Devenish RJ, Mackay IR, Gershwin ME, Marzuki S. Nucleotide sequence of a cDNA encoding the lipoate acetyl transferase (E2) of human heart pyruvate dehydrogenase complex differs from that of human placenta. Biochem Int 1990;20:417–22. [33] Moritoki Y, Lian ZX, Wulff H, Yang GX, Chuang YH, Lan RY, et al. AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers. Hepatology 2007;45:314–22. [34] Mu FT, Alderuccio F, Toh BH, Gershwin ME, Coppel R, Mackay IR. Murine monoclonal antibody to mitochondria reacts with the 72 kD antigen of primary biliary cirrhosis. Clin Exp Immunol 1988;71:100–6. [35] Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, et al. Antimitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 2006;177:1655–60. [36] Parikh-Patel A, Gold E, Mackay IR, Gershwin ME. The geoepidemiology of primary biliary cirrhosis: contrasts and comparisons with the spectrum of autoimmune diseases. Clin Immunol 1999;91:206–18. [37] Reynoso-Paz S, Coppel RL, Mackay IR, Bass NM, Ansari AA, Gershwin ME. The immunobiology of bile and biliary epithelium. Hepatology 1999;30:351–7. [38] Rieger R, Leung PS, Jeddeloh MR, Kurth MJ, Nantz MH, Lam KS, et al. Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun 2006;27:7–16. [39] Rowley MJ, Cook AD, Mackay IR, Teuber SS, Gershwin ME. Comparative epitope mapping of antibodies to collagen in women with silicone breast implants, systemic lupus erythematosus and rheumatoid arthritis. Curr Top Microbiol Immunol 1996;210:307–16. [40] Rowley MJ, Gershwin ME, Mackay IR. Collagen antibodies in juvenile arthritis and adult rheumatoid arthritis: differences in levels and type-specificity. J Rheumatol 1988;15:289–94. [41] Selmi C, Mackay IR, Gershwin ME. The immunological milieu of the liver. Semin Liver Dis 2007;27:129–39. [42] Shoenfeld Y, Blank M, Abu-Shakra M, Amital H, Barzilai O, Berkun Y, et al. The mosaic of autoimmunity: prediction, autoantibodies, and therapy in autoimmune diseases–2008. Isr Med Assoc J 2008;10:13–9. [43] Surh CD, Danner DJ, Ahmed A, Coppel RL, Mackay IR, Dickson ER, et al. Reactivity of primary biliary cirrhosis sera with a human fetal liver cDNA clone of branched-chain alpha-keto acid dehydrogenase dihydrolipoamide acyltransferase, the 52 kD mitochondrial autoantigen. Hepatology 1989;9:63–8. [44] Teoh KL, Rowley MJ, Zafirakis H, Dickson ER, Wiesner RH, Gershwin ME, et al. Enzyme inhibitory autoantibodies to pyruvate dehydrogenase complex in primary biliary cirrhosis: applications of a semiautomated assay. Hepatology 1994;20:1220–4. [45] Teuber SS, Coppel RL, Ansari AA, Leung PS, Neve R, Mackay IR, et al. The identification and cloning of the murine genes encoding the liver specific F alloantigens. J Autoimmun 1991;4:857–70. [46] Tsuneyama K, Harada K, Yasoshima M, Hiramatsu K, Mackay CR, Mackay IR, et al. Monocyte chemotactic protein-1, -2, and -3 are distinctively expressed in portal tracts and granulomata in primary biliary cirrhosis: implications for pathogenesis. J Pathol 2001;193:102–9. [47] Van de Water J, Surh CD, Leung PS, Krams SM, Fregeau D, Davis P, et al. Molecular definitions, autoepitopes, and enzymatic activities of the mitochondrial autoantigens of primary biliary cirrhosis. Semin Liver Dis 1989;9:132–7. [48] Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH, et al. IL2 receptor alpha(/) mice and the development of primary biliary cirrhosis. Hepatology 2006;44:1240–9.
Contents lists available at ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
A tribute to an outstanding immunologist – Ian Reay Mackay Senga Whittingham*, Merrill J. Rowley, M. Eric Gershwin Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
a b s t r a c t Keywords: Autoimmunity Primary biliary cirrhosis Ian Mackay Diagnostic autoimmunity
The 11th Australasian Autoimmunity Workshop was held in Melbourne, Australia from July 6–8, 2007 organized by the Monash University Autoimmunity Network. The workshops, founded by the late Kevin Lafferty, are a chance for Australasians interested in research into autoimmune disease to present and discuss their work. This workshop also was a chance to acknowledge Ian Mackay, a pioneer clinicianscientist who has made major contributions to our understanding of autoimmune diseases. Friends, colleagues and former students attended the Workshop and acknowledged Ian’s expertise and mentorship. This edition of the Journal of Autoimmunity pays tribute to Ian Mackay. It features articles from attendees at the workshop, and contributions from some of Ian’s past students and past and current collaborators. Ó 2008 Elsevier Ltd. All rights reserved.
Introducing Ian Mackay and explaining his contributions to human immunology in this short introduction is much like trying to summarize War and Peace for a high school primer. Ian Mackay is one of the pioneers in the development of the concept of autoimmunity as a cause of defined and treatable human chronic disease from an unpopular theory to one that is now accepted universally. His career has been a long and stellar one in clinical research. In the 1950s in London under the tutelage of Sheila Sherlock (later Dame Sheila Sherlock), Ian developed an interest in hepatology when it was still a fledgling clinical specialty. The sound knowledge of diseases of the liver gained during that period stood him in good stead when, in 1956, he joined the Clinical Research Unit (CRU) of the Walter and Eliza Hall Institute (WEHI) and The Royal Melbourne Hospital. Here the hospital ward-research institute milieu was ideally suited to the pursuit of clinical research. A 27 bed ward of patients was linked by a door to laboratories that were wholly dedicated to clinical research and these laboratories were part of * Corresponding author. Tel.: þ61 3 9905 1438; fax: þ61 3 9905 3726. E-mail address: [email protected] (S. Whittingham). 0896-8411/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2008.04.004
WEHI then under the directorship of Macfarlane Burnet (later Nobel Laureate). The hepatitis viruses had not been discovered and adult patients with chronic liver disease not due to alcohol or drugs, were a heterogeneous group. In the CRU a group of patients had been observed to have chronic relapsing hepatocyte damage that had been nominated ‘active chronic hepatitis’, and in this group there was a preponderance of female patients with hyperglobulinemia whose blood tested positive for lupus erythematosus (LE) cells. Ian gave their hepatitis the descriptive name ‘lupoid hepatitis’ [1] because of the LE association although later, when the nature of the illness was unveiled as autoimmune, he revised the name to autoimmune hepatitis (AIH) [2]. Apart from the LE association these patients also demonstrated serologic reactivity with fractions of cytoplasm from liver tissue by a complement fixation test that a visiting scientist to WEHI, Carlton Gajdusek (later Nobel Laureate), was investigating as a possible test for hepatitis virus. Further studies showed that this test was not a test for hepatitis virus and although it demonstrated auto-reactivity and became known as the autoimmune complement fixation (AICF) test, it was not specific for lupoid hepatitis. High titers of auto-reactivity by the AICF test were reported by Ian in primary biliary cirrhosis [3] and historically, that was an important finding because it was the first demonstration of antimitochondrial antibody (AMA) in PBC. Apart from AIH, PBC became one of Ian’s major interests, particularly when techniques for cloning autoantigens became available. However, it was some 30 years later before Eric Gershwin came to the CRU as a visiting professor and successfully cloned the mitochondrial autoantigen [3], and Eric and Ian opened up an exciting new field of research in PBC. Ian’s contribution to the characterization of the autoimmune hepatic diseases, AIH and PBC,
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is immeasurable. He quite courageously, gave immunosuppressive treatment to young women with AIH when immunosuppressive drugs were still crude preparations and for this, his reward was not only dramatic improvement in the health of these women but also their greatly prolonged survival. He developed reliable diagnostic serology for AIH that led to elegant studies on F actin with his former registrar, Ban Hock Toh, and more recently Cris dos Remedios, and he demonstrated the strong association of AIH with HLA-B8-DR3. As the group of patients with AIH expanded it became clear to Ian that these and patients with other autoimmune diseases (AID) fulfilled a set of diagnostic criteria. These criteria were: preponderance in women, presence of autoantibodies in serum, a raised level of serum globulin, histological evidence of chronic inflammation in the target organ, a response to corticosteroid drugs, and the presence of other autoimmune diseases in the same subject or a family member. By 1963 Ian had amassed sufficient clinical and laboratory evidence to publish a book that he coauthored with Macfarlane Burnet [4]. In their book that was first devoted to AID, they nominated chronic diseases that they believed, in time, would be proven to be autoimmune. Their predictions were not far off the mark and there were few omissions. While Ian was gathering proof for autoimmunity in liver disease, some stunning experiments were being undertaken in the USA. There was little support for the concept of autoimmunity in the USA in the early 1950s, so when Noel Rose a student of Ernst Witebsky, obtained evidence for an experimental animal model of autoimmune thyroiditis, Witebsky, a revered immunologist of ‘the old school’, had some difficulty accepting his student’s results. Although Noel had a sisyphean struggle to provide incontrovertible proof for his finding, the evidence was unshakeable and the model was faithful to human thyroiditis described by Ivan Roitt and Deborah Doniach in London. The trajectory for future research on autoimmunity in clinical and experimental medicine was largely determined by these studies from Australia, USA and the UK. Staunch non-believers became converts to autoimmunity and the field of autoimmunity became richer for the warm friendship that developed between Ian Mackay and Noel Rose. They not only co-edited a book that became the definitive reference book on autoimmunity and is now in the 4th edition [5], but they have been active in establishing interest groups and promoting training programs in clinical immunology and autoimmunity in their respective countries. When Ian Mackay succeeded Ian Wood as head of the CRU he assembled a team of young enthusiastic scientists and clinicians to undertake research in autoimmunity and care for patients with autoimmune disease. One of the strengths of the CRU was the team spirit. Each member, whatever position they held, was encouraged to actively participate in discussion ranging from interpretation of results of laboratory experiments and clinical findings to theories on the concept of autoimmunity. Socially, Ian was a generous host. Medical students and members of the CRU will remember many a party held around and sometimes in the swimming pool at Ian’s home where his partner Pat, a distinguished anesthetist, as a gracious hostess supervised the serving of food and drinks by the Mackay children. As the CRU was part of WEHI and this same family spirit was fostered by Macfarlane Burnet and then by Gustav Nossal (later Sir Gustav Nossal) when he became director, there was ample opportunity for collaboration with those undertaking research in basic immunology. Indeed, the tearoom was as important as the seminar room for the exchange of ideas and active and often spirited discussion. There were many highlights to research in the CRU during Ian’s watch, spanning the years 1963–1987. Ian always encouraged the pursuit of work at the cutting edge of research and for some projects was ‘a man before his time’. An example of the latter was an attempt
to develop a computer-based medical record in the late 1960s. The system devised by two PhD students, Vance Gledhill and Alex McPherson, worked well as a pilot scheme, but at that time the computer hardware was inadequate and the minds of clinicians unprepared for application of such a system to a large general hospital. Ian’s search for sensitive diagnostic markers of autoimmunity was ongoing as were his attempts to develop simple tests for the measurement of immune function. This led to numerous studies on normal subjects including those on a rural population of some 7500 subjects in Busselton, Western Australia to establish the prevalence of autoimmunity and its effect on the community. The results not only clearly demonstrated the influence of gender, age, and inheritance on the development of autoantibodies but also the role autoantibodies have in predicting the development of AID and, in subjects with no overt signs of AID, the risk of morbidity and premature death from cardiovascular disease. Never far from Ian’s thoughts was the part played by the thymus gland in autoimmunity. In the 1960s he pondered on the presence of lymphoid follicles with germinal centers and plasma cells in the medulla of older NZB mice with autoimmune hemolytic anemia (AHA) and reports of a beneficial effect of thymectomy in children with intractable, life-threatening AHA. With his radiologist colleague, Bill Hare, he showed that the shape and size of the human thymus could be measured accurately on the shadow obtained by pneumomediastinography. Thymectomy performed in patients with systemic lupus erythematosus had little, if any, beneficial effect but notable success, even cure, was observed long-term in subjects with myasthenis gravis. The experimental work in the CRU and ideas on the role of the thymus in autoimmunity have been described in a book Ian co-authored with Gideon Goldstein [6]. Ian’s long-term interest in experimental allergic encephalomyelitis (EAE) as a model of multiple sclerosis began when his biochemist colleague, Pat Carnegie, characterized encephalitogenic peptides that were used as autoantigens to set up various experimental models of EAE. Soon joined by Claude Bernard who came to the CRU as a post-doctoral fellow, the trio continued the collaboration for many years. The two PhD students in this research program went on to carve out illustrious careers elsewhere, one in medicine and politics in Alberta, Canada and the other in neuroimmunology at the Salk Institute and Mayo Clinic, USA. The simple classification of AIDs proposed by Ian in 1969 grouped them in two clusters, the multisystem and thyrogastric clusters [7]. There was some disease overlap but, in the main, the association of AIDs in individual subjects and their families was unique to the cluster. ‘Guilt by association’ was a term favored by Ian when he suspected a disease might be autoimmune because of the company it kept. It was long suspected from various studies in the CRU that diabetes mellitus was an AID and a member of the thyrogastric cluster but an autoantibody specific for diabetes eluded detection until Bottazzo, in London, discovered the pancreatic islet cell autoantibody. In 1949 Ian Wood designed a flexible gastric biopsy tube that for the first time enabled the study of multiple samples of gastric mucosa from living subjects. Meticulous in his research Ian Wood had in one publication alone reported his experience of gastric biopsy in over 1000 subjects. When Ian Mackay joined the CRU in 1956 he was exposed to this research and when he became head in 1963 he inherited this wealth of experience in gastric histopathology. Gastric atropy was known to be associated with pernicious anemia (PA) but why it was associated was unknown and the majority of patients with chronic gastritis comprised a heterogeneous group in whom the cause was unknown. When gastric parietal cell and intrinsic factor autoantibodies were discovered in patients with PA markers became available for studying chronic gastritis due to autoimmunity at its various stages of evolution. In 1973, in a landmark study [8], Ian with Reg Strickland proposed
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a classification for chronic gastritis: Type A gastritis was autoimmune and confined to the body of the stomach and Type B gastritis was mainly antral. Infection was presumed to be the cause of Type B gastritis but proof of that did not come until a decade later when Helicobacter pylori was discovered to be the causative organism. When Ian retired from the CRU in 1987 he allowed no time to reflect on any void that might be created by the cessation of a busy and challenging life spent on clinical duties and research. Due to his interest in the role of mitochondria in the immune response in PBC, he had, prior to retirement, set up collaborative studies with Tony Linnane, an expert in mitochondria at Monash University. This resulted in an invitation from Tony Linnane to establish an Autoimmunity Laboratory in his department to expand the existing research on autoimmunity and mitochondria. Ian sought competitive research funding for this new venture and was soon joined by the first PhD student he had supervised when he became head of the CRU, Merrill Rowley, who brought with her the laboratory expertise and experience in research required for the establishment of such a laboratory. This was the start of a productive period of research, focusing mainly on PBC initially but soon also on type 1 diabetes and rheumatoid arthritis. The main thrust of the research has been the study of epitopes on molecules that behave as autoantigens in these diseases and for this work experience in a variety of techniques has been developed. These techniques included immunoassays for the detection of autoantibodies, enzyme inhibition assays to measure functional impairment due to autoantibody, phage display to identify conformational epitopes, and Fourier transform infrared microscopy to correlate changes in chemical composition of tissues produced by autoantibody with the structural changes observed by light microscopy. Ian has continued his collaborative studies on PBC with Eric Gershwin and various Japanese colleagues. He has also worked closely with Paul Zimmet on epidemiologic studies on type 1 diabetes, particularly on autoantibodies to glutamic acid decarboxylase (GAD). It was in such studies that apparently healthy adults were observed to have anti-GAD demonstrable for up to 10 years before expression of disease and anti-GAD were also present in a subset of people with type 2 diabetes who subsequently required insulin for treatment. This led Ian to coin the term LADA (Latent Autoimmune Diabetes of Adults) to describe their form of type 1 diabetes. The study of the two isoforms of GAD, GAD65 and GAD67 has been a major part of the research in the laboratory and the highlight for 2007 was the solution of the crystal structures of these two isoforms. Over the years Ian has spent countless hours at his desk in his study at home. He enjoys writing. Indeed, writing has been a necessary part of life for him, and his study has always been a special place. The entire wall of a former study featured the spectacular night skyline of New York but now in his new home the scene is more subdued. His desk overlooks a peaceful, attractive garden lovingly tended by Pat. Ian has authored over 700 full-length articles on clinical and experimental research on autoimmunity in respected journals, as well as in many books. He has always been generous with the time he has given to committee work, editorial boards, reviewing grants, theses, reports and articles in journals, and the endless requests for help with tasks related to research. He is a Member of the Order of Australia and a Fellow of the Australian Academy of Science, and in his wardrobe of honors and awards he has many caps. There are many who have worked or collaborated with Ian in research who have not been named in this tribute. Ian will remember you with affection and would wish to acknowledge your contribution in introducing the concept of autoimmunity to the world of clinical medicine and for providing the intellectual sustenance for him to ponder on yet ‘unfinished business’ in autoimmunity [9].
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The 8th Australasian Autoimmunity Workshop marked his 80th birthday, and there was a dinner attended by many of his friends and past students, who provided vignettes from their memories of their time with Ian. We note some interesting comments from Dr. Brian Youl, a former clinical Registrar. ‘‘Dr IR Mackay caught me on the rebound from a disastrous first attempt at the Australasian Fellowship examinations – I had confidently diagnosed cystic fibrosis in an elderly chap with chronic lung disease in the long case. I went on to spend a year as his senior registrar in the Clinical Research Unit. Bizarrely, the highly talented Elsdon Storey was our junior registrar. Sandwiched between these marvelous intellects I couldn’t help but improve. The Problem Oriented approach to medical clerking, while irritating in its rigor, seemed to clarify my analysis of cases, and Ian’s ward rounds were undoubtedly more frightening than anything I was to encounter on my second, successful attempt at the ‘‘Part II’’. I hope I will never forget the time on Ward 3 East when, horrified at being asked the mechanism of action of digoxin on a ward round attended by, among others, two of the then authors of ‘‘Harrison’s Textbook of Medicine’’, I instantly dropped to the floor and underwent a grand mal convulsion. Ian, the consumate diagnostician, having quite correctly recognized this to be a pseudoseizure, immediately turned to Storey and grilled him about the early works of Ovid. They went on to argue about the relative merits of his ‘Tristia’ and ‘Epistulae ex Ponto’. At the next bed I chipped in with ‘‘What about Patterson, Dr Mackay? You know, ‘There was movement at the station, and the word had passed around’’’. Ian glared at me and retorted, ‘‘The word had GOT around, Youl. We’ll move on!’’ In addition, from Len Harrison, current Head of the Clinical Research Unit at WEHI, and collected by another clinical Registrar of Ian Mackay, Dr. Alan Ebringer, come under the following 10 aphorisms of Ian Mackay: 1. If you have done only 10 drafts of your paper, then you have not really read it. 2. Once you have done 20 drafts, your paper is approaching the publishable ideal. (My paper on ‘‘chloroquine neuromyopathy’’ went through 22 drafts.) 3. Do not quote a paper in your references that you have not read; sooner or later you will be found out. 4. Every chronic disease is autoimmune unless proved otherwise. 5. An alcoholic patient is usually dominated by a strong willed mother or wife, and sometimes both. 6. When giving a research talk, remember there are only two or three people in the audience to whom your presentation is addressed; the others don’t count. 7. There is no such thing as a ‘‘slough’’ or routine case in your ward; every patient can teach you good medicine. 8. You have no right to play ‘‘god’’ with incurable diseases; you must do your best till the end. 9. The concept of ‘‘euthanasia’’ interferes with clear medical thinking and has been banished. 10. Mouse immunologists usually have a poor grasp of medicine and inevitably will make fools of themselves during ward rounds. Although Ian retired from the Hall Institute in 1987, his work has continued virtually unabated and since 1987, Mackay and Gershwin have co-authored 39 papers [10–48]. At the 8th Australasian Autoimmunity Workshop Ian’s work was noted as follows. ‘‘Ian was at WEHI for 32 years, 24 years as Head of the Clinical Research Unit (1963–1987). During that time he laid the foundations for the modern understanding of autoimmune diseases. His interest in this area dated from the 1950s when, with Carlton Gajdusek (who later received the Nobel Prize for his work on kuru), he recognized that a laboratory test developed by Gajdusek to demonstrate hepatitis A
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virus was actually detecting an autoimmune reaction between human serum and liver. The autoimmune complement fixation test developed by Ian and Gajdusek was the first to demonstrate autoantibodies in liver disease. This led him to describe autoimmune chronic active hepatitis, a paradigm for other autoimmune diseases. His subsequent description in 1957 of autoimmune primary biliary cirrhosis was capped 30 years later by the cloning of the gene for the M2 mitochondrial autoantigen of this disease, in a collaborative study with Eric Gershwin’’. It is fitting to update our tribute to Ian on the occasion of his 85th birthday.
References [1] Cowling DC, Mackay IR, Taft LI. Lupoid hepatitis. Lancet 1956;271:1323–6. [2] Mackay IR, Weiden S, Hasker J. Autoimmune hepatitis. Ann N Y Acad Sci 1965; 124:767–80. [3] Mackay IR. Primary biliary cirrhosis showing a high titer of autoantibody; report of a case. N Engl J Med 1958;258:185–8. [4] Mackay I, Burnet F. Autoimmune diseases, pathogenesis, chemistry and therapy. Springfield: Thomas; 1963. [5] Rose N, Mackay I. Amsterdam: Elsevier; 2006. [6] Goldstein G, Mackay I. The human thymus. London: William Heinemann; 1969. [7] Mackay IR. Autoimmune disease. Med J Aust 1969;1:696–9. [8] Strickland RG, Mackay IR. A reappraisal of the nature and significance of chronic atrophic gastritis. Am J Dig Dis 1973;18:426–40. [9] Mackay IR. Autoimmune diseases of the liver, autoimmune hepatitis and primary biliary cirrhosis: unfinished business. Hepatol Res 2007;37(Suppl. 3): S357–64. [10] Aoki CA, Roifman CM, Lian ZX, Bowlus CL, Norman GL, Shoenfeld Y, et al. IL-2 receptor alpha deficiency and features of primary biliary cirrhosis. J Autoimmun 2006;27:50–3. [11] Gershwin ME, Ansari AA, Mackay IR, Nakanuma Y, Nishio A, Rowley MJ, et al. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells. Immunol Rev 2000;174:210–25. [12] Gershwin ME, Coppel RL, Bearer E, Peterson MG, Sturgess A, Mackay IR. Molecular cloning of the liver-specific rat F antigen. J Immunol 1987;139:3828–33. [13] Gershwin ME, Coppel RL, Mackay IR. Primary biliary cirrhosis and mitochondrial autoantigens–insights from molecular biology. Hepatology 1988;8:147–51. [14] Gershwin ME, Mackay IR. Primary biliary cirrhosis: paradigm or paradox for autoimmunity. Gastroenterology 1991;100:822–33. [15] Gershwin ME, Mackay IR. New knowledge in primary biliary cirrhosis. Hosp Pract (Minneap) 1995;30:29–36. [16] Gershwin ME, Mackay IR. The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 2008;47:737–45. [17] Gershwin ME, Mackay IR, Sturgess A, Coppel RL. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 1987;138:3525–31. [18] Gershwin ME, Rowley M, Davis PA, Leung P, Coppel R, Mackay IR. Molecular biology of the 2-oxo-acid dehydrogenase complexes and anti-mitochondrial antibodies. Prog Liver Dis 1992;10:47–61. [19] Invernizzi P, Selmi C, Mackay IR, Podda M, Gershwin ME. From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2005;3:401–10. [20] Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R, et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006; 203:1209–19. [21] Iwayama T, Leung PS, Rowley M, Munoz S, Nishioka M, Nakagawa T, et al. Comparative immunoreactive profiles of Japanese and American patients with primary biliary cirrhosis against mitochondrial autoantigens. Int Arch Allergy Immunol 1992;99:28–33. [22] Kinoshita H, Omagari K, Whittingham S, Kato Y, Ishibashi H, Sugi K, et al. Autoimmune cholangitis and primary biliary cirrhosis–an autoimmune enigma. Liver 1999;19:122–8. [23] Kita H, Mackay IR, Van De Water J, Gershwin ME. The lymphoid liver: considerations on pathways to autoimmune injury. Gastroenterology 2001;120: 1485–501.
[24] Lan RY, Mackay IR, Gershwin ME. Regulatory T cells in the prevention of mucosal inflammatory diseases: patrolling the border. J Autoimmun 2007;29: 272–80. [25] Lleo A, Invernizzi P, Selmi C, Coppel RL, Alpini G, Podda M, et al. Autophagy: highlighting a novel player in the autoimmunity scenario. J Autoimmun 2007; 29:61–8. [26] Mackay IR, Gershwin ME. Molecular basis of mitochondrial autoreactivity in primary biliary cirrhosis. Immunol Today 1989;10:315–8. [27] Mackay IR, Gershwin ME. Primary biliary cirrhosis: current knowledge, perspectives, and future directions. Semin Liver Dis 1989;9:149–57. [28] Mackay IR, Gershwin ME. Primary biliary cirrhosis: considerations on pathogenesis based on identification of the M2 autoantigens. Springer Semin Immunopathol 1990;12:101–19. [29] Mackay IR, Gershwin ME. The nature of autoimmune disease. Semin Liver Dis 1997;17:3–11. [30] Mackay IR, Van de Water J, Gershwin ME. Autoimmunity. Thoughts for the millennium. Clin Rev Allergy Immunol 2000;18:87–117. [31] Mackay IR, Whittingham S, Fida S, Myers M, Ikuno N, Gershwin ME, et al. The peculiar autoimmunity of primary biliary cirrhosis. Immunol Rev 2000;174: 226–37. [32] Moehario LH, Smooker PM, Devenish RJ, Mackay IR, Gershwin ME, Marzuki S. Nucleotide sequence of a cDNA encoding the lipoate acetyl transferase (E2) of human heart pyruvate dehydrogenase complex differs from that of human placenta. Biochem Int 1990;20:417–22. [33] Moritoki Y, Lian ZX, Wulff H, Yang GX, Chuang YH, Lan RY, et al. AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers. Hepatology 2007;45:314–22. [34] Mu FT, Alderuccio F, Toh BH, Gershwin ME, Coppel R, Mackay IR. Murine monoclonal antibody to mitochondria reacts with the 72 kD antigen of primary biliary cirrhosis. Clin Exp Immunol 1988;71:100–6. [35] Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, et al. Antimitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 2006;177:1655–60. [36] Parikh-Patel A, Gold E, Mackay IR, Gershwin ME. The geoepidemiology of primary biliary cirrhosis: contrasts and comparisons with the spectrum of autoimmune diseases. Clin Immunol 1999;91:206–18. [37] Reynoso-Paz S, Coppel RL, Mackay IR, Bass NM, Ansari AA, Gershwin ME. The immunobiology of bile and biliary epithelium. Hepatology 1999;30:351–7. [38] Rieger R, Leung PS, Jeddeloh MR, Kurth MJ, Nantz MH, Lam KS, et al. Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun 2006;27:7–16. [39] Rowley MJ, Cook AD, Mackay IR, Teuber SS, Gershwin ME. Comparative epitope mapping of antibodies to collagen in women with silicone breast implants, systemic lupus erythematosus and rheumatoid arthritis. Curr Top Microbiol Immunol 1996;210:307–16. [40] Rowley MJ, Gershwin ME, Mackay IR. Collagen antibodies in juvenile arthritis and adult rheumatoid arthritis: differences in levels and type-specificity. J Rheumatol 1988;15:289–94. [41] Selmi C, Mackay IR, Gershwin ME. The immunological milieu of the liver. Semin Liver Dis 2007;27:129–39. [42] Shoenfeld Y, Blank M, Abu-Shakra M, Amital H, Barzilai O, Berkun Y, et al. The mosaic of autoimmunity: prediction, autoantibodies, and therapy in autoimmune diseases–2008. Isr Med Assoc J 2008;10:13–9. [43] Surh CD, Danner DJ, Ahmed A, Coppel RL, Mackay IR, Dickson ER, et al. Reactivity of primary biliary cirrhosis sera with a human fetal liver cDNA clone of branched-chain alpha-keto acid dehydrogenase dihydrolipoamide acyltransferase, the 52 kD mitochondrial autoantigen. Hepatology 1989;9:63–8. [44] Teoh KL, Rowley MJ, Zafirakis H, Dickson ER, Wiesner RH, Gershwin ME, et al. Enzyme inhibitory autoantibodies to pyruvate dehydrogenase complex in primary biliary cirrhosis: applications of a semiautomated assay. Hepatology 1994;20:1220–4. [45] Teuber SS, Coppel RL, Ansari AA, Leung PS, Neve R, Mackay IR, et al. The identification and cloning of the murine genes encoding the liver specific F alloantigens. J Autoimmun 1991;4:857–70. [46] Tsuneyama K, Harada K, Yasoshima M, Hiramatsu K, Mackay CR, Mackay IR, et al. Monocyte chemotactic protein-1, -2, and -3 are distinctively expressed in portal tracts and granulomata in primary biliary cirrhosis: implications for pathogenesis. J Pathol 2001;193:102–9. [47] Van de Water J, Surh CD, Leung PS, Krams SM, Fregeau D, Davis P, et al. Molecular definitions, autoepitopes, and enzymatic activities of the mitochondrial autoantigens of primary biliary cirrhosis. Semin Liver Dis 1989;9:132–7. [48] Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH, et al. IL2 receptor alpha(/) mice and the development of primary biliary cirrhosis. Hepatology 2006;44:1240–9.