In 1963, the first textbook on autoimmune diseases was published and written by Ian R. Mackay and F. Macfarlane Burnet. Mackay is perhaps the best known figure in liver autoimmunity and was a pioneer in a variety of contributions, including epidemiology, serology, and clinical diagnosis. At the time, Mackay worked at the Walter and Eliza Hall Institute (WEHI) for medical research. Macfarlane Burnet was the Director of WEHI and had received the Nobel Prize for his thesis on the forbidden clone.

This textbook is noteworthy for many features, not the least of which is that it was published in the Living Chemistry series. Because of the myriad and diversity of manuscripts within this special volume, we think it is appropriate to quote from the first three paragraphs of the preface [1]. “One of the greatest developments in Medicine during recent years has been the growing recognition of the importance of processes in which the immune mechanisms of the body are, as it were, turned against the body’s own components. This topic is in many ways in a pre-scientific phase. Many clinical scientists are skeptical of the reality of autoimmune processes and would prefer to look for antigens derived from the environment to account for the serological results observed. They are inclined to look on autoimmune disease as a currently fashionable diagnostic label, which can be attached to many diseases of still undefined etiology. We disagree strongly with this view, and in this short monograph, we have tried to provide an up to date and reasonably self-consistent account of those diseases for which an autoimmune etiology has been established either as a primary or an associated factor, or in which there is some likelihood that autoimmune processes are concerned. Allergic diseases, which are associated with extrinsic antigens, were not considered to be within the scope of this monograph. During the last 5 years, work in this Institute has centered on theoretical, experimental, and clinical aspects of immunity and an important part in the development of elective theories of immunity by Burnet came from association with the problems arising in clinical work. This has been the main stimulus for the production of this monograph. We believe that the central concept expressed in the term ‘forbidden clone’ is a valuable help to the understanding of autoimmune disease, and this concept is used as the basis of our present approach. The book is written more for physicians than for immunologists, and we have thought it would be helpful to include a glossary of immunological terms. Some of these terms have been used in a slightly different sense from the usual, but only when this was necessary to clarify the point of view we have adopted.”

Indeed, this pioneering textbook was only 323 pages long and included a glossary in which so-called “frequently used immunological terms” were included. Interestingly, among those terms was antigenic determinant, which we now know as epitopes, and autoclasia, a term which we no longer use, but which implies “a vicious cycle of immunologically induced damage, liberation of more antigen, fresh antigenic stimulation, further damage and so on”; perhaps an early term for apoptosis. But among the glossary is the key phrase “immunological tolerance.” Indeed, it is ironic that the liver, which itself is the basis of immune tolerance, becomes the victim in autoimmune liver disease.

In this respect, autoimmune/immune-mediated hepatobiliary diseases are attracting increasing attention based in no small part on the enormous contributions in basic biologic science that have allowed us to define more appropriate diagnostic and prognostic markers and an increasing recognition of the clinical significance of disease. It is also particularly important in understanding the geoepidemiology of autoimmunity.

Autoimmunity is clearly a result of a genetic predisposition superimposed on environmental factors. These are best illustrated in studies of concordance in identical twins as well as the data that suggests that the only thing non-identical about identical twins is the immune response. On the other hand, the genetic predisposition, whose solution was once thought to be the defining moment in our understanding of autoimmunity, has become a disappointing quagmire despite enormous efforts in multiple autoimmune diseases [2–15]. For example, with rare exceptions, the major genetic contribution to the risk of autoimmunity remains the major histocompatibility complex. There have been no smoking guns in autoimmune liver disease and, in fact, in both primary biliary cirrhosis and autoimmune hepatitis, as well as numerous other human autoimmune diseases, the concepts of epigenetics are gaining increasing recognition [16–25]. Furthermore, despite a significant body of data on the microenvironment of the liver, the role of effector pathways, the development of animal models, and the use of biologics in other human autoimmune diseases, therapeutic advances in autoimmune liver disease, have been few and not of the rigor as in, for example, rheumatoid arthritis [2, 26–52].

Primary biliary cirrhosis (PBC), as the most frequent of the autoimmune/immune-mediated hepatobiliary diseases, reaches a prevalence of about 25–40 per 100,000 in North America and Northern Europe [53–55]. Genetic [56, 57], environmental [58], and endogenous factors [59–61] potentially contributing to the pathogenesis of PBC have been unraveled. Appropriate animal models are still in need [47, 62]. The association of PBC with numerous other autoimmune conditions is striking [63, 64] as is the female preponderance [65, 66]. The rates of extrahepatic malignancies associated with PBC [63] are much less intimidating than in primary sclerosing cholangitis (PSC), but deserve attention. Ursodeoxycholic acid (UDCA) remains the mainstay of therapy and enables a normal life expectancy for two of three patients when adequately responding to UDCA therapy [67–70]. New therapies, mostly in combination with UDCA, are under evaluation in phase 2 and 3 studies for treatment of those patients who do not adequately respond to UDCA alone [71–73]. The most frequent extrahepatic manifestations of PBC, fatigue [74] and pruritus [75], remain by far the major burden for the patients.

PSC has an about three times lower prevalence than PBC and affects most patients at younger age than PBC [54]. Two of three patients are male, and two of three suffer from inflammatory bowel disease (IBD). Genome-wide association studies have disclosed various risk genes in PSC [76–78], the majority of which do affect immune responses, but some may notably also affect cholangiocyte and intestinal barrier function [76, 79, 80] and the stability of the “biliary bicarbonate umbrella” [59, 81]. The search for adequate animal models of PSC is ongoing [62, 82], and the immunopathogenesis of PSC is increasingly unraveled [61, 83]. In clinical practice, a differentiation of PSC from various causes of secondary sclerosing cholangitis remains challenging, particularly when patients do not suffer from IBD, a characteristic feature of PSC, but not secondary forms of sclerosing cholangitis [54]. For PSC patients, pruritus is a major and sometimes barely tolerable complaint. An enormous burden for PSC patients is the high risk of hepatobiliary and extrahepatic malignancies, among them cholangiocarcinoma, gallbladder carcinoma, and colon carcinoma, which require annual (or biennial in selected cases) screening efforts [54, 84]. No medical treatment of proven benefit for long-term prognosis has been documented so far. UDCA improves serum liver tests and prognostic surrogate markers of PSC, but no survival benefit has been shown, whereby limited numbers of patients included and/or limited periods of follow-up may have contributed to the so far negative results [54]. The ongoing demand and unchanged rates of liver transplantation in PSC underline the urgent need for novel treatment options in PSC. Of note, the so far largest population-based analysis revealed a median survival of 21 years for a large cohort of 590 PSC patients from the Netherlands, 90 % of them under treatment with standard dose UDCA, a markedly longer median survival than that reported in previous selected cohorts mainly from tertiary centers.

IgG4-related disease (IgG4-RD) with its biliary and pancreatic manifestations, IgG4-associated cholangitis (IAC) and autoimmune pancreatitis (AIP), has most recently received attention as an important differential diagnosis of PSC, but also of cholangiocarcinoma and pancreatic carcinoma [85]. The recent finding of a few dominant IgG4+ B cell clones in blood and affected tissue of patients with IgG4-RD [86], meanwhile confirmed extramurally [87], allows a new look on the so far elusive pathogenesis of this rare multi-organ disorder and makes the potential risk of long-term exposure to environmental toxins such as solvents, oil products, and paints, for developing IgG4-RD [88] more plausible. Still, the exact role of IgG4 and B and T cells in IgG4-RD remains obscure. The striking effect of immunosuppressive treatment in IAC and rapid disappearance of IgG4+ B cell clones [85, 86] reminds clinical hepatologists of autoimmune hepatitis (AIH) as does the frequent relapse after tapering down corticosteroids [89].

Finally, physicians are increasingly aware of the extrahepatic manifestations of autoimmune liver disease, including the roles of inflammation, the development of hepatocarcinoma, and, interestingly, the co-existence in many patients of Sjogren’s syndrome and scleroderma [64, 90–92]. There are several papers in this issue which are devoted to this theme, and, importantly, they illustrate the contributions of geoepidemiology in our understanding of immune tolerance. Of greatest importance is the absence of a major therapeutic advance. Certainly, the use of liver transplantation has been life-saving for many patients but, on the other hand, there are numerous new molecules and pathways being described in the immune response and hepatobiliary pathophysiology and it will be only through the molecular dissection of these pathways that will allow for adequate medical treatment. This is what we owe our patients and this is what we all strive for.