oa Editorial [Hot Topic: IgG4-Related Disease: A Unique and Emerging Entity (Guest Editors: Susumu Sugai, Shigeyuki Kawa, Yoh Zen)]

People believe that most human diseases have already been described, and new disease entities are very rarely proposed. Recently, however, a new clinical concept, IgG4-related disease, was established. This new concept was first evidenced in a report in 2001 on sclerosing (autoimmune) pancreatitis by Hamano and Kawa et al. [1] and in a report differentiating Mikulicz's disease from Sjogren's syndrome by Yamamoto et al. in 2002 [2]. These reports promptly attracted much attention from clinicians and pathologists in Japan, who recognized that IgG4-related disease involves multiple organs in addition to the pancreas and lacrimal or salivary glands. IgG4-related lesions in various organs have been described, based on histological features such as lymphoplasmacytic infiltration, storiform fibrosis, and more importantly IgG4+ cell infiltration. Because of the broad spectrum of the affected organs and the similarity of clinical and pathological findings, many researchers understood that this condition may be a new systemic disease resulting from the same or similar etiology. This led to novel concepts of IgG4- related disease, including IgG4-related systemic sclerosing disease (Kamisawa et al. [3]), IgG4-systemic plasmacytic syndrome (SIPS, Yamamoto et al. [4]) and IgG4-related multiorgan lymphoproliferative disease (IgG4+MOLPS, Masaki et al. [5]). This disorder is characterized by presentation with symptoms due to mass lesions, which show unique radiological abnormalities; the occurrence of similar lesions in other organs synchronously or metachronously over a lifetime; and the rapid response of lesions to corticosteroid therapy. In this special issue, we have attempted to clarify and describe the clinical features of IgG4-related disease, which may open the way to detailed pathogenesis and to a consensus surrounding its diagnostic criteria. Kawa et al. describe the clinical features, extra-pancreatic lesions and diagnostic criteria of autoimmune pancreatitis. Yamamoto et al. describe Mikulicz's disease and its extraglandular lesions, which indicate that Mikulicz's disease is a member of a broader entity of systemic IgG4-related disease. Masaki et al. discuss the problems diagnosing IgG4-related disease and its differential diagnosis. Kamisawa et al. propose the concept of IgG4-related sclerosing disease from a standpoint of autoimmune pancreatitis, stressing the pathological features of tissue fibrosis with obliterative phlebitis. Fujinaga et al. describe the radiologic findings in IgG4-related disease, which will help in its diagnosis. Okazaki et al. describe the immunological aspect of this disease. Notohara et al. review the basic histological features of this disease and its differential diagnosis based on pathology, with an emphasis on the classification of autoimmune pancreatitis. Cheuk and Chan review the histological variations observed in IgG4-related lymphadenopathy, and its possible relationship to malignant lymphoma. Sah and Chari describe the long term prognosis of patients with IgG4-related systemic disease, with special emphasis on the functional and pathological changes that occur during autoimmune pancreatitis, its relapse, the role of corticosteroid therapy and the association with malignancies. Kawano et al. summarize the current understanding of the usefulness and limitations of corticosteroid treatment as well as other treatment modalities. Okazaki et al. recently proposed a hypothesis for the pathogenesis of autoimmune pancreatitis [6]. In these patients, the initial response to self antigens (e.g. lactoferrin and carbonic anhydrase II) is induced by a decreased naive Treg immune response followed by a Th1 type immune response with release of pro-inflammatory cytokines (e.g. IL-2, IL-6, IFN-γ.). This may induce a Th2 type immune response, with the production of IgG, IgG4 and autoantibodies. Zen et al. reported that lymphocytes infiltrating into the tissue showed a Th2-dominant cytokine expression profile and an increase of Tregs [7]. The IL-10 and TGF-β produced by these Tregs direct B cells to produce IgG4 and have a strong fibrogenic function in tissue. These findings may provide clues to our understanding of the pathologic features of IgG4-related disease. Target organs for IgG4-related disease are mainly those organs containing duct-glandular complexes (e.g. liver, gall bladder, pancreas, salivary glands, lungs, and kidneys), mucosal organs (stomach), exocrine glands (lacrimal glands and prostate), and endocrine glands (pituitary and thyroid glands). Given the common development in the mucosal tissue, mucosa-associated lymphoid tissue (MALT) may be involved in the immunological dysregulation and persistent inflammation observed in IgG4- related disease. Lymphocytes activated in MALT return to the original MALT tissue or related organs through the systemic circulation. One of the notable features of this disease is that, although affected organs differ among patients, those organs show diffuse or localized tumorous lesions. Organ and site selectivity may be affected by the homing patterns of committed lymphocytes, directed by various cell adhesion molecules and chemokines expressed on activated vascular endothelial cells, which bind to the appropriate homing receptors of circulating lymphocytes. This kind of homing may cause acquired MALT at a particular area of an affected organ, eventually leading to the lymphoplasmacytic lesions observed in IgG4-related disease. The endothelial cells may be activated by Th1 cytokines such as TNF-α and IFN-γ due to local inflammation caused, for example, by bacterial or viral infection. However, it should be noted that IgG4-related disease sometimes develops in tissues apparently unrelated to mucosal tissue, such as retroperitoneal soft tissue or aortic walls. Although high serum IgG4 concentrations and abundant IgG4-bearing plasma cell infiltration are the key features of IgG4- related disease, the role of IgG4 in its pathogenesis is not clear. IgG4 may have rheumatoid factor-like activity as reported by Kawa et al. [8], in which IgG4 Fc binds to IgG Fc. Because IgG4 does not activate the complement system, this kind of rheumatoid factor-like activity may function to evade possible local inflammation caused by IgG or IgM rheumatoid factor through complement activation. RECENT PROGRESS IN RESEARCH IN JAPAN The Welfare and Labor Ministry of Japan launched a sponsorship for research on IgG4-related disease in 2009 by forming 3 independent research groups. One, chaired by Prof. Kazuichi Okazaki is involved in the clinical study of the pathophysiology of IgG4-related systemic disease, to establish it as a disease entity. The second group, chaired by Prof. Hisanori Umehara, is conducting research to establish IgG4+MOLPS as a new disease. The third group, chaired by Prof. Yasuyoshi Naishiro, is analyzing the pathophysiology of Mikulicz's disease and IgG4-related disease. Many researchers, including clinicians from various fields, pathologists and other related fields, are now intensively studying and discussing the etiology, pathophysiology, and diagnostic criteria of this disease. We hope that the tight collaboration of doctors of various backgrounds can provide new data beneficial for patients. Almost a decade has passed since the first report by Hamano and Kawa et al. [1]. This is the first review journal of IgG4- related disease. We hope that this issue provides a summary of the first decade of research on IgG4-related disease and a guidepost for the next stage.