Current Immunology Reviews (v.7, #2)

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-and#947;.). 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-and#946; 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-and#945; and IFN-and#947; 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.

History of Autoimmune Pancreatitis and Mikulicz's Disease by Shigeyuki Kawa, Susumu Sugai (137-143).
The concept of a new class of systemic disease, IgG4-related disease, was established from findings in patients with autoimmune pancreatitis and Mikulicz's disease, showing the involvement of other organs. Autoimmune pancreatitis presents as a swollen pancreas that mimics pancreatic cancer and was first recognized by its characteristic findings of lymphoplasmacytic sclerosing pancreatitis (LPSP) and irregular narrowing of the main pancreatic duct. It was later found to be associated with autoimmunity and with high serum IgG4 concentrations and IgG4-bearing plasma cell infiltration. Autoimmune pancreatitis is also characterized by the systemic distribution of extra-pancreatic lesions and shows similar pathological findings of IgG4-bearing plasma cell infiltration, suggesting that autoimmune pancreatitis is a systemic, IgG4-related disease. Mikulicz's disease is another type of IgG4-related disease, presenting as symmetrical, painless enlargement of the lacrimal and salivary glands. Mikulicz's disease was considered as a complex of symptoms, rather than a disease entity. Furthermore, this disease had been regarded as one manifestation of a more generalized symptom complex known as Sjogren's syndrome. Mikulicz's disease was later distinguished from Sjogren's syndrome by its high serum IgG4 concentration and several characteristic clinical features. Mikulicz's disease shows similar systemic organ involvements as autoimmune pancreatitis. At present, autoimmune pancreatitis and Mikulicz's disease are recognized as major constituents of IgG4-relatated disease.

Autoimmune Pancreatitis and Diagnostic Criteria by Shigeyuki Kawa, Yasunari Fujinaga, Masao Ota, Hideaki Hamano, Seiamak Bahram (144-161).
Autoimmune pancreatitis is a unique form of chronic pancreatitis with autoimmune phenomena, including hypergammaglobulinemia, lymphoplasmacytic infiltration, and responsiveness to corticosteroid therapy. Autoimmune pancreatitis tends to affect elderly males and it presents with pancreatic swelling and irregular narrowing of the pancreatic duct. The symptoms of autoimmune pancreatitis mimic the clinical features of pancreatic cancer; thus, it is important to differentiate between the two conditions. Autoimmune pancreatitis is also characterized by high serum IgG4 concentrations and infiltration of IgG4-bearing plasma cells into the pancreatic tissue. Although these are considered serological and histological hallmarks of autoimmune pancreatitis, the role of IgG4 in the pathogenesis of the disease remains unclear. Furthermore, many cases are complicated by extra-pancreatic manifestations with pathological findings similar to those observed in the pancreatic lesions; these extra-pancreatic manifestations tend to respond favorably to corticosteroid therapy. Autoimmune pancreatitis is now regarded as a member of a new class of IgG4-related disease. Due to inconsistencies in the diagnostic criteria for autoimmune pancreatitis, there is a need for an international consensus on this disease.

Mikulicz's Disease and its Extraglandular Lesions by Motohisa Yamamoto, Hiroki Takahashi, Yasuhisa Shinomura (162-171).
Mikulicz's disease has been considered a part of primary Sjogren's syndrome since Morgan's 1953 report. Mikulicz's disease is a unique condition involving enlargement of the lacrimal and salivary glands, as is also seen in Sjogren's syndrome; however, Mikulicz's disease is clinically characterized by infrequent autoimmune reactions and responsiveness to glucocorticoid. Fifty years after Morgan's study, the understanding of Mikulicz's disease has changed considerably. We first found elevated levels of serum IgG4 and prominent infiltration by plasmacytes bearing IgG4 in the lacrimal and salivary glands in Mikulicz's disease. These findings do not occur in Sjogren's syndrome. The various extraglandular complications of Mikulicz's disease, including autoimmune pancreatitis, tubulointerstitial nephritis, have gradually been clarified in recent reports. These conditions show similar histopathological findings to Mikulicz's disease, indicating that Mikulicz's disease is a part of a broader entity of systemic IgG4-related disease. We herein describe the clinical features of Mikuliczs disease and its extraglandular lesions.

IgG4-Related Disease (IgG4+MOLPS) - Diagnostic Criteria and Diagnostic Problems by Yasufumi Masaki, Haruka Iwao, Akio Nakajima, Miyuki Miki, Susumu Sugai, Hisanori Umehara (172-177).
Since the first report on patients with elevated serum IgG4 in sclerosing pancreatitis in 2001, various systemic disorders, described by many names, have been reported. Despite similarities in the organs involved in IgG4-related Mikulicz's disease and Sjogren's syndrome, there are marked clinical and pathological differences between the two conditions. On the other hand, differential diagnosis of IgG4-related Mikulicz's disease and Kuttner's tumor is very difficult, since their pathological features are closely related except severe fibrosis. Most patients diagnosed with autoimmune pancreatitis in Japan have IgG4-related sclerosing pancreatitis, a disease distinct from the western type. It is likely that patients formerly diagnosed with Castleman's disease with good response to glucocorticoid treatment may have had IgG4-related lymphadenopathy, and should be re-assessed in light of recent findings. Diagnosis of IgG4-related disease is characterized by both 1) elevated serum IgG4 ( > 135 mg/dl) and 2) histopathological features including lymphocyte and IgG4+ plasma cell infiltration (IgG4+ plasma cells/IgG+plasma cells > 40and#x25; on a highly-magnified slide checked at five points). Differential diagnosis from other distinct disorders, such as sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, cancer, and other existing conditions that show the high serum IgG4 level or abundant IgG4-bearing plasma cells in tissues is necessary.

Systemic Involvement of IgG4-related Sclerosing Disease by Terumi Kamisawa, Kensuke Takuma, Taku Tabata, Naoto Egawa, Keigo Setoguchi, Koji Tsuruta, Tsuneo Sasaki (178-185).
A novel clinicopathological entity of and#x201C;IgG4-related sclerosing diseaseand#x201D; has been proposed, based on histological and immunohistochemical examination of various organs of patients with autoimmune pancreatitis (AIP). This is a systemic disease that is characterized by extensive IgG4-positive plasma cell and T lymphocyte infiltration of various organs. Clinical manifestations are apparent in organs where tissue fibrosis with obliterative phlebitis is pathologically induced. AIP may be a pancreatic lesion reflecting an IgG4-related sclerosing disease. This disease includes AIP, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related sialadenitis, IgG4-related retroperitoneal fibrosis, IgG4-related tubulointerstitial nephritis, IgG4-related interstitial pneumonia, IgG4-related prostatitis, and IgG4-related inflammatory pseudotumor. Many cases are associated with IgG4-related lymphadenopathy. Most IgG4-related sclerosing diseases have been found to be associated with AIP, but IgG4-related sclerosing diseases without pancreatic involvement have been reported. In some cases, only 1 or 2 organs are clinically involved, while in others 3 or 4 organs are affected. The disease occurs predominantly in elderly males and responds well to steroid therapy. Serum IgG4 levels and immunostaining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.

Radiologic Findings of IgG4-Related Disease by Yasunari Fujinaga, Masumi Kadoya, Hideaki Hamano, Shigeyuki Kawa, Mitsuhiro Momose, Satoshi Kawakami, Tomoharu Watanabe, Yukiko Sugiyama, Takeshi Uehara (186-203).
Autoimmune pancreatitis (AIP), characterized by an autoimmune phenomenon of prominent lymphocytes, IgG4-bearing plasma cell infiltration and storiform fibrosis, has been widely reported as a specific type of chronic pancreatitis. Typical image findings of this disease are reported as diffuse pancreatic swelling and a capsule-like rim on CT or MRI. However, AIP presents with a variable morphology, such as focal, segmental and multifocal swellings. Because imaging findings for AIP can look like those of pancreatic cancer, AIP has often been treated with unnecessary surgical resection. In addition, AIP is complicated by the involvement of various other organs besides the pancreas that show lymphoplasmacytic infiltration and fibrosis. These are frequently misdiagnosed as inherent lesions of corresponding organs. Furthermore, these extra-pancreatic lesions show systemic distribution and share common features of IgG4- bearing plasma cell infiltration as well as favorable responses to corticosteroid, indicating the presence of systemic condition, IgG4-related diseases. AIP is now recognized as an IgG4-related disease. Detailed evaluations of imaging findings of CT, MRI and Gallium-67 (Ga-67) scintigraphy for the involvement of these various organs are useful for a correct diagnosis of this systemic disease.

Immunological Aspects of IgG4-Related Disease by Kazuichi Okazaki, Kazushige Uchida (204-211).
Recent advances support the concept of IgG4-related disease as a unique systemic disease, because autoimmune pancreatitis, sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis show similar pathological features with an abundant infiltration of IgG4 positive plasma cells and fibrosis, and steroid responsive. Based on these findings, a novel concept of IgG4-related disease such as IgG4-related systemic sclerosing disease, IgG4-systemic plasmacytic syndrome (SIPS), and IgG4-related multiorgan lymphoproliferative disease (IgG4-MOLPS) have been proposed. However, pathogenetic mechanisms still remain unclear. For clarifying it, genetic background, humoral immunity, complement system, disease-related antibodies, cellular immunity, and regulatory T cells were reviewed. Although the significance of IgG4 in the development of IgG4-related disease still remains unclear, we have proposed a hypothesis for the pathogenesis in AIP, one of IgG4-related diseases. In induction of lesions, the initial response to selfantigens or molecular mimicry for components of H. pylori may be induced by decreased naive-Tregs, and Th1 cells release proinflammatory cytokines. In progression, increased memory-Tregs and Th2 immune responses regulate IgG4 production. Further studies are necessary to clarify the pathogenesis.

Pathologic Findings of Autoimmune Pancreatitis and IgG4-Related Disease by Kenji Notohara, Yoji Wani, Masayoshi Fujisawa (212-220).
Autoimmune pancreatitis (AIP) is pathologically characterized by lymphoplasmacytic infiltration and fibrosis. However, AIP is not a single entity, but rather includes two histological types - lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric chronic pancreatitis (IDCP) - of which the former constitutes the pancreatic manifestation of IgG4-related disease. The inflammation seen in peripancreatic adipose tissue and the interlobular area in LPSP, such as dense lymphoplasmacytic infiltration with fibrosis, storiform fibrosis, and obliterative phlebitis, is common among the various lesions that belong to IgG4-related disease. However, some lesions in the family of IgG4-related disease, such as IgG4-related sclerosing sialadenitis and lymphadenopathy, often lack prominent fibrosis, suggesting the histological variation of this entity. Nonetheless, histological features are important in the formation of a pathological diagnosis of IgG4-related disease because the presence of numerous IgG4-positive plasma cells is not necessarily specific to this disease.

Lymphoproliferative Lesions in IgG4-Related Disease by Wah Cheuk, John K.C. Chan (221-231).
IgG4-related disease is a reactive lymphoproliferative-sclerosing lesion that can involve various organ systems of the body, with autoimmune pancreatitis being the prototype. This review article focuses on the various lymphoproliferative lesions that can occur in this disease. The first is IgG4-related lymphadenopathy, which can accompany typical IgG4-related disease or occur ab initio. The morphologic spectrum of the affected lymph nodes ranges from multicentric Castleman disease-like, to follicular hyperplasia, marked interfollicular expansion mimicking peripheral T-cell lymphoma, progressive transformation of germinal center-like, and nodal inflammatory pseudotumor-like. The diagnosis can be confirmed by demonstration of an increase in IgG4+ plasma cells. The second is the development of lymphoma in patients with IgG4-related disease. The lymphoma can occur in the sites affected by IgG4-related disease, where the most common type is extranodal marginal zone lymphoma; or in other nodal and extranodal sites, where the most common type is diffuse large B-cell lymphoma. The third is florid lymphoid hyperplasia as the dominant morphologic feature of IgG4-related disease in various extranodal sites, mimicking malignant lymphoma. Such findings appear to be particularly common in the salivary gland, lacrimal gland, skin and breast, probably attributable to early discovery of mass lesions involving these sites, before the sclerosing process has time to take over.

Pathophysiology of IgG4-Related Disease by Yoh Zen, Yasuni Nakanuma (232-238).
It is still a mystery what is the role of immunoglobulin G4 (IgG4) in IgG4-related disease, or which kinds of immune responses are involved in the pathogenesis. Possible involvement of autoimmunity is supported by the fact that the patients commonly have antinuclear antibodies or hyper and#947;-globulinemia. The expression of human leukocyte DR antigen in epithelia of the affected organs, and possible reactivity of serum IgG4 of the patients with tissue specimens also support an autoimmune etiology. On the other hand, the Th2-dominant cytokine expression profile resembles allergic disorders rather than classical autoimmune diseases. Another unique point is that many regulatory T-cells infiltrate into the inflamed sites, being associated with the active expression of regulatory cytokines. IL-10 and TGF-and#946; might be the key molecules involved in the two major histological findings of IgG4-related disease: IgG4 class switch and diffuse fibrosis, because IL-10 and TGF-and#946; have a potent function in directing B cells to produce IgG4 and a strong fibrogenic function, respectively. The function of IgG4 in this disorder is still unknown. Unique characters of IgG4 might suggest that IgG4 is not a pathogenetic antibody, but acts as an anti-inflammatory factor by binding to other types of IgG. Recent proteomics studies have discovered possible autoantigens and autoantibodies. Several hypotheses have been proposed so far, but the consensus remains to be reached. Immunopathology in IgG4-related disease is not typical for known disease entities.

Long Term Prognosis in IgG4-Related Systemic Disease (ISD) by Raghuwansh P. Sah, Suresh T. Chari (239-245).
IgG4-related Systemic Disease (ISD) is a chronic fibro-inflammatory disorder affecting exocrine and several other organs characterized by the presence of IgG4-positive cellular infiltrates in affected organs and elevated serum IgG4 levels. Autoimmune Pancreatitis (AIP) is the pancreatic manifestation of ISD. Responsiveness to steroid is a characteristic feature ISD and consistently leads to improvement of most lesions including AIP, at least in the short term. However, relapse is common in ISD though there is lack of agreement among different studies on the rates of relapse and factors predicting relapse, with estimates from 25and#x25; to upto 50and#x25;. Proximal bile duct involvement appears to be predictive of relapse in several studies. Corticosteroids are effective in treating relapses as well and long term maintenance therapy may be necessary in patients who relapse. The role of maintenance of corticosteroid therapy for primary prevention of relapses and utility of immunosuppressive drugs like azathioprine in refractory cases remain to be studied in controlled studies, though there is some experience with successful use of immunosuppressive drugs in refractory cases with frequent relapses. In light of several reports of malignancies, long term follow-up of patients is recommended. Long term survival is currently unknown in ISD due to short-term follow-up and preponderance in older population, and as more follow-up data become available, it will be clear if the consequence of ISD and AIP decreases patient survival.

Treatment of IgG4-Related Disease by Mitsuhiro Kawano, Kazunori Yamada (246-251).
Corticosteroids are commonly used to treat autoimmune pancreatitis (AIP) and IgG4-related disease other than AIP, and a dramatic response is expected. Although spontaneous improvement is sometimes observed, steroid therapy is useful to relieve the clinical features including obstructive jaundice and abdominal pain. Deteriorated endocrine and exocrine pancreatic function is also a target of treatment. Due to the relatively high recurrence rate of IgG4-related disease, maintenance therapy with low dose corticosteroids or combination therapy with corticosteroid and immunosuppressive drugs including azathioprine, mycophenolate, or 6-mercaptopurine is sometimes required. However, there is no consensus about when to stop steroid therapy, the necessity of maintenance therapy, or what marker(s) to use to monitor disease activity. Moreover, experience with IgG4-related disease other than AIP is very limited, making worldwide accumulation of such cases and a prospective controlled trial with steroid therapy necessary to establish the optimal treatment strategy.