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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Veterans Affairs Medical Center, Univ. California San Francisco
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    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
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Recent Advances in the Concept and Pathogenesis of IgG4-Related Disease in the Hepato-Bilio-Pancreatic System

Kazuichi Okazaki, Masahito Yanagawa, Toshiyuki Mitsuyama, and Kazushige Uchida

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Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan

Correspondence to: Kazuichi Okazaki, Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Shinmachi, Hirakata, Osaka 573-1197, Japan, Tel: +81-72-804-0101 (ext 2520), Fax: +81-72-804-2061, E-mail: okazaki@hirakata.kmu.ac.jp

Received: March 24, 2014; Accepted: April 15, 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2014;8(5):462-470. https://doi.org/10.5009/gnl14107

Published online August 18, 2014, Published date September 29, 2014

Copyright © Gut and Liver.

INTRODUCTION

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In 1961, Sarles et al.1 observed a case of particular pancreatitis with hypergammaglobulinaemia, which is supposed to be a prototype of autoimmune pancreatitis (AIP) (Table 1). In 1995, Yoshida et al.2 proposed a novel concept of AIP, which has been accepted as type 1 AIP (IgG4-related pancreatitis), the pancreatic manifestation of IgG4-related disease (IgG4-RD).3 IgG4-RD is recognized worldwide as a novel clinical entity following the epoch-making evidence of increased serum levels of IgG4 in the history of AIP.4 The histopathological findings are characterized by the periductal localization of predominantly CD4 positive T cells, IgG4-positive plasma cells, storiform fibrosis with acinar cell atrophy, and obliterative fibrosis,5,6 which is also called lymphoplasmacytic sclerosing pancreatitis (LPSP).7 On the other hand, mainly in the Western countries, histological analyses using resected pancreatic samples in patients with chronic non-alcoholic pancreatitis demonstrated a different histological pattern of pancreatitis from LPSP, so called idiopathic duct-centric pancreatitis (IDCP) or AIP with granulocytic epithelial lesion. In 2003, Kamisawa et al.8 first suggested that AIP showing LPSP is a systemic sclerosing disease based on the concept of multifocal fibrosclerosis proposed by Comings et al.,9 because the pancreas and other involved organs have fibrosis with abundant infiltration of IgG4-positive plasma cells. On the other hand, patients with IDCP, rarely observed in Japan, are not associated with either serum IgG4 elevation or with other organ involvement typically seen in LPSP. AIP is subclassified according to the International Consensus of Diagnostic Criteria for AIP as either type 1 (LPSP) or type 2 (IDCP).10 Type 2 AIP, unlike type 1 AIP, is thought to be a specific pancreatic disease with occasional coexistence with ulcerative colitis.10,11

On the other hand, in 1892, Mikulicz12 first observed a patient with symmetrical swelling of the lachrymal, parotid and submandibular glands, with massive infiltration of mononuclear cells. The condition was called Mikulicz’s disease; however, it has since been classified as an atypical type of Sjögren’s syndrome, which also presents with bilateral, painless, and symmetrical swelling of the lachrymal, parotid, and submandibular glands. Küttner13 reported a tumor-like enlargement of the submandibular gland that was sometimes a result of stones in the Wharton duct. These patients, lacking anti-SS-A/Ro or anti-SS-B/La antibodies, often show other systemic organ involvement with elevated serum levels of IgG4, infiltration of IgG4-positive plasma cells into the glands, and recovery of secretion with steroid treatment similar to AIP.4–6 Referring to the original concept of multifocal fibrosclerosis, recent studies led us to develop a novel concept of a systemic disease such as IgG4-related systemic sclerosing disease,14 systemic IgG4-related plasmacytic syndrome,15 or IgG4-positive multiorgan lymphoproliferative syndrome,16 all of which may refer to the same conditions. Based on these findings, although it is unclear whether the pathogenetic mechanisms in individual organs are same or not,3,17 the comprehensive term “IgG4-related disease IgG4-RD,” which was internationally endorsed with the proposal of nomenclatures for individual organ lesions as well as pathological consensus, and diagnostic criteria have been proposed from the Japanese investigators.17 In this review, we discussed the current concepts of hepato-bilio-pancreatic lesions and recent advances in our understanding of the pathogenesis of IgG4-RD.

CURRENT CONCEPTS OF IgG4-RD IN THE HEPATO-BILIO-PANCREATIC SYSTEM

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1. Type 1 AIP (IgG4-related pancreatitis)

AIP is a distinct form of pancreatitis clinically characterized by frequent presentation with obstructive jaundice with or without a pancreatic mass, histologically by a lymphoplasmacytic infiltrate and fibrosis and therapeutically by a dramatic response to steroids.5,21 Recent studies have suggested that “AIP” manifests two distinct subtypes, type 1 and type 2 AIP (Table 3).10,11 Type 1 AIP (IgG4-related pancreatitis) is more prevalent in Japan and Korea, whereas type 2 AIP, with granulocytic epithelial lesion, is more commonly observed in Europe and the United States.

In type 1 AIP, the pancreatic histopathology shows the following characteristic features of LPSP: 1) abundant infiltration of plasma cells (IgG4+ cells; >10/hpf, 40%>IgG4/IgG cells) and lymphocytes, 2) peculiar storiform or swirling fibrosis, and 3) perivenular infiltration with lymphocytes and plasma cells often leading to obliterative phlebitis. Clinically, it is characterized by swelling of the pancreas, elevated serum IgG4 levels and extra-pancreatic lesions (e.g., sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis) associated with infiltration of abundant IgG4+ plasma cells. Patients with type 1 AIP often have obstructive jaundice in elderly males, and the pancreatic and extrapancreatic manifestations respond to steroid therapy.21 Therefore, it is a pancreatic manifestation of a systemic disorder, IgG4-RD.19,21

2. IgG4-SC

About 60% to 80% of patients with type 1 AIP are associated with IgG4-SC,5,20–22 in which cholangiographic features are similar to those of primary sclerosing cholangitis (PSC), pancreatic cancer, and cholangiocarcinoma. The steroid responses and the prognoses of IgG4-SC differ from patients with PSC, which suggests different pathological conditions.5,20–22 Four types of the characteristic cholangiographic features of IgG4-SC have been proposed based on the regions of stricture (Fig. 1).22 IgG4-SC with only stenosis of the distal common bile duct (type 1) is difficult to differentiate from pancreatic cancer. This stricture might be due to both the thickening of bile duct and the effect of inflammation and/or edema of pancreas without wall thickness. IgG4-SC with diffuse stenosis throughout the intrahepatic/proximal bile ducts (type 2) is similar to PSC. IgG4-SC with stenosis in the hilar hepatic bile duct (type 3 and 4) is difficult to differentiate from hepatic hilar colangiocarcinoma.22 In addition to stenosis of bile ducts, circular and symmetric thickening of the bile duct wall, smooth outer and inner margin, and homogenous internal echo demonstrated by abdominal ultrasonography, abdominal computed tomography, abdominal magnetic resonance imaging, endoscopic ultrasonography, and intraductal ultrasonography are most characteristic images.22 These characteristic features are recognized not only in the stenotic areas or occasionally in the gallbladder but also in areas without stenosis that appear normal in cholangiogram. Most cases of IgG4-SC (80% to 90%) are associated with AIP.20–22 It is particularly difficult to accurately diagnose IgG4-SC without AIP. In contrast to PSC, inflammatory bowel disease is rarely observed in the patients with IgG4-SC.20–22

Histopathologically, similar to LPSP in type 1 AIP, massive infiltration of IgG4-positive plasma cells, storiform fibrosis and/or obliterative phlebitis in the bile duct wall are characteristic and called as lymphoplasmacytic sclerosing cholangitis.19,22 Such fibroinflammatory involvement is mainly observed in the submucosa of the bile duct wall, whereas the epithelium of the bile duct is intact.23 Endoscopic transpapillary bile duct biopsy or cytological examinations are useful for differential diagnosis of cholangiocarcinoma, although it is difficult to take enough biopsy samples for characteristic histopathological findings of IgG4-SC.22 Liver biopsy is sometimes useful in the diagnosis of IgG4-SC in cases of intrahepatic bile duct involvement.22

3. IgG4-related hepatopathy

Liver dysfunction is frequently observed in AIP patients and most of them show various pathological changes with infiltration of IgG4-bearing plasma cells in the liver; portal inflammation with or without interface hepatitis, large bile duct obstructive features, portal sclerosis, lobular hepatitis, and canalicular cholestasis.24 As a very few of IgG4-RD patients without AIP or IgG4-SC show the same histological features as autoimmune hepatitis (AIH), a novel concept of IgG4-related AIH has been proposed.25,26 To establish the concept of IgG4-related AIH, further studies are required.

RECENT ADVANCES IN THE PATHOGENIC MECHANISMS OF IgG4-RD IN THE HEPATO-BILIO-PANCREATIC SYSTEM

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1. Immunogenic backgrounds

Although immunogenic backgrounds of IgG4-RD are not well understood, Japanese patients with AIP, most of whom are IgG4-related, may be associated with class II antigen haplotype of the major histocompatibility complex (HLA-DRB1*0405-DQB1*0401),27 polymorphism of nuclear factor-κB and Fc-receptor-like 3 genes expressed on B cells.28 An inhibitory molecule, cytotoxic T lymphocyte antigen-4 (CTLA-4; CD152) expressed on the activated memory T cells or CD4+CD25+ regulatory T cells (Tregs), was independently reported as a susceptibility factor.29,30 Based on immunogenic backgrounds, abnormal conditions of immune responses may be involved in the development of type 1 AIP, although the precise pathogenic mechanisms remain unclear.5

2. Innate immunity

Recently, abnormal innate immunity has been demonstrated in some patients with IgG4-RD.5,21 Activation of NOD-2 and TLR ligands on monocytes or basophils from patients with IgG4-related AIP enhances IgG4 responses via B cell activating factor (BAFF) and interleukin (IL)-13, although specific pathogens still remain unclear.31,32 In animal models, activation of TLR3 by polyinosinic:polycytidylic acid or TLR4 by lipopolysaccharide can induce immune-mediated cholangitis, pancreatitis and sialadenitis similar to human IgG4-RD.33

3. Possible roles of IgG4 in IgG4-RD

Although the association of IgE-mediated allergy and IgG4 antibodies is well known, IgG4 characteristics are still poorly understood. IgG4 is involved in an immune process referring to as ‘Fab-arm exchange,’ which is a swapping of a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule; this usually results in asymmetric antibodies with two different antigen-combining sites.34 While these modified antibodies are hetero-bivalent, they behave as monovalent antibodies. Another aspect of IgG4 is that it mimics IgG rheumatoid factor activity by interacting with IgG, namely Fc-mediated aggregation.35 IgG4 seems to be associated with a pathogenic effect in a few situations. In pemphigus, recognition of skin autoantigens (desmogleins) by IgG4 is at the origin of the disease process.36 A most recent study of structural determinants of human IgG4-Fc by crystallography suggested that Fc-Fc interactions are compatible with intact IgG4 molecules and may provide a model for the formation of aggregates of IgG4 that can cause disease pathology in the absence of antigen.37

Another recent data on regulation of IgG4 showed that IgG4-RD may reflect an excessive production of anti-inflammatory cytokines such as IL-10 that triggers an overwhelming expansion of IgG4-producing plasma cells.38–42 Increased peripheral inducible-memory Tregs are positively correlated with serum levels of IgG4.39 In addition, prominent infiltration of Tregs up-regulated IL-10 in livers of the patients with IgG4-SC.40 These findings suggest that IgG4 do not act as a pathogenic factor, but as an anti-inflammartory factor in IgG4-RD. Further studies are necessary to clarify the precise role of IgG4 in IgG4-RD.

4. The complement system

Patients in active stages of AIP occasionally show decreased complement (C3, C4) with elevated circulating immune complex as well as serum levels of IgG4 and the IgG4 subclass of immune complexes.43 However, a previous study showed that the classical pathway of complement activation through IgG1 may be involved in the development of AIP rather than mannose-binding lectin or alternative pathways through IgG4.43

5. Autoantibodies and candidate of target antigens

Although some patients with IgG4-RD have nonspecific antibodies such as an antinuclear antibody, there is scarce association of IgG4-RD. From the view of IgG4 function, the big mystery is whether IgG4-RD is an autoimmune or an allergic disease. Although disease specific targets are unknown, the occasional coexistence of multiorgan involvements leads us to consider that there may be common target antigens. Among candidate antigens previously reported, lactoferrin (LF),44,45 carbonic anhydrase (CA)-II,44–47 CA-IV,48 and pancreatic secretory trypsin inhibitor (PSTI)49 are expressed in the pancreas, salivary glands, biliary duct, lungs, renal tubules, and so forth. Immunization with CA-II or LF induced systemic lesions such as pancreatitis, sialadenitis, cholangitis, interstitial nephritis in the mice models similar to human IgG4-RD.50 Amylase α-2A,51 HSP-10,52 and Helicobacter pylori53–56 are also candidates of disease-associated antigens. Among the involved organs in IgG4-RD, recent studies suggest an extremely high association of pancreatic and biliary lesions.5,20,21 As both peribiliary glands in the biliary tract and pancreatic duct glands associated with pancreatic ducts in human are intermingled with small amounts of pancreatic exocrine acini,57 and the biliary tree-derived stem cells may be involved in a pancreatic organogenesis in mice.58 Nakanuma et al.59 have proposed a new concept of the “biliary diseases with pancreatic counterparts,” in which targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts. Further studies of the biliary tract’s patho-physiology based on its similarity to pancreatic counterparts are warranted.

6. Role of B cells

In addition to steroid and immune-modulators, the B cell depletion by rituximab, which reduces only IgG4, but not IgG1, IgG2, or IgG3, is useful in the therapeutic strategy in IgG4-RD.60,61 A recent study showed expansion of IgG4+ B cell receptor clones in blood and tissue of patients with active IgG4-chol-angiopathy, and disappearance by corticosteroid treatment.62 A recent study showed that the increased CD19+CD24highCD38high Bregs may suppress the disease activity of type 1 AIP, whereas the decreased CD19+CD24highCD27+ Bregs might be involved in the development of type 1 AIP.63 These findings suggest that specific B cell responses may have a pivotal role in the pathogenesis of IgG4-RD such as type 1 AIP and IgG4-SC.

7. Th1 and Th2 immune balance

The effector cells in IgG4-RD have been poorly understood. The CD4+ T cells differentiate from naive T cells (Th0) to Th1, Th2, Th17, and Treg cells. In the livers of IgG4-SC patients, a Th2 type immune reaction38,42 is induced in addition to the Th1 responses.45,50 Th2 cytokines may be involved in the progression of the disease process, especially the maturation and proliferation of local B cells and plasmacytes.

8. Tregs

Foxp3 is a member of the forkhead/winged-helix family of transcriptional regulators, and functions as the master regulator in the development and function of CD4+CD25+ Tregs classified as naturally occurring naive-Tregs originating in the thymus and adaptively induced memory-Tregs in the periphery by different antigens.64 In type 1 AIP, circulatory naive (CD45RA+) Tregs are significantly decreased in the peripheral blood, whereas memory (CD45RA−)-Tregs are significantly increased.39 In addition, prominent infiltration of Tregs with upregulation of IL-10 is observed in the liver of type 1 AIP and IgG4-SC patients.40,41 These findings suggest that increased memory-Tregs in the periphery and local tissues may be an inhibitory immune response against inflammation, although decreased naive Tregs may be pathogenic.

9. Our hypothesis for the pathogenesis of IgG4-SC

The neonatally thymectomized (nTx)-BALB/c mice models showed that immunization with CA-II or LF induced pancreatitis, cholangitis, and sialadenitis similar to human IgG4-RD.50 These findings suggest that depletion of naive Tregs may induce macrophage/T cell activation and further proinflammatory reactions during the early stage of the disease as direct cytotoxicity effects through Fas ligand expression. WBN/Kob rat models with congenital decreased peripheral Tregs spontaneously develop sclerotic cholangitis, sialadenitis, thyroiditis, and tubulointerstitial nephritis.65 These animal models suggest that CD4+/CD8+ T cells play major roles in the development of primary lesions similarly to human IgG4-RD; however, the counterpart of IgG4 in mice IgG subclasses has not been identified.

Based on these findings, we proposed the pathogenesis of type 1 AIP (Fig. 2).5 The basic concept is the biphasic mechanism of “induction” and “progression.” An initial response to unknown disease specific antigens including self-antigens (LF, CA-II, CA-IV, and PSTI) or microorganisms (bacteria or virus) might be induced by decreased naive-Tregs followed by a Th1 type immune response with the release of proinflammatory cytokines (interferon γ, IL-1β, IL-2, tumor necrosis factor α). In progression, Th2 type immune responses producing IgG, IgG4, and autoantibodies may be involved in pathophysiology. IgG4 and fibrosis may be regulated by increased IL-10 and transforming growth factor β secreted from inducible T cell co-stimulator (ICOS)-positive and ICOS-negative inducible adaptive Tregs, respectively. Production of IgG4 may be also upregulated by BAFF from monocytes and basophils.

CONCLUSIONS

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Recent advances support the concept of IgG4-RD, a unique clinical entity, in the hepato-bilio-pancreas system. Although the pathogenic mechanism remains unclear, innate and acquired immunity, Tregs, and B cells may be involved in the development of these lesions. Further studies are necessary to clarify the pathogenesis including genetic backgrounds, disease-specific antigens, and the role of IgG4.

Figures

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Fig. 1.Classification of cholangiography in IgG4-related sclerosing cholangitis (IgG4-SC). The characteristic features of IgG4-SC can be classified into four types, based on the regions of stricture as revealed by cholangiography and differential diagnosis. Type 1 IgG4-SC shows stenosis only in the lower part of the common bile duct, which should be differentiated from chronic pancreatitis, pancreatic cancer, or cholangiocarcinoma. Type 2 IgG4-SC, in which stenosis is diffusely distributed throughout the intrahepatic and extrahepatic bile ducts, should be differentiated from primary sclerosing cholangitis. Type 2 is further subdivided into two types. Type 2a has a narrowing of the intrahepatic bile ducts with prestenotic dilation, and Type 2b has a narrowing of the intrahepatic bile ducts without prestenotic dilation and reduced bile duct branches, caused by marked lymphocytic and plasmacyte infiltration into the peripheral bile ducts. Type 3 IgG4-SC is characterized by stenosis in both the hilar hepatic lesions and the lower portion of the common bile duct. Type 4 IgG4-SC shows strictures of the bile duct only in the hilar hepatic lesions. Cholangiographic findings of types 3 and 4 need to be discriminated from those of cholangiocarcinoma. From Ohara H, et al. J Hepatobiliary Pancreat Sci 2012;19:536–542, with permission from Springer.22

IDUS, intraductal ultrasonography; EUS, endoscopic ultrasonography; EUS-FNA, EUS-guided fine-needle aspiration; IBD, inflammatory bowel disease.

Fig. 2.Hypothesis for the pathogenesis of autoimmune pancreatitis (AIP) and IgG4-related disease. In central tolerance, naturally occurring naive regulatory T cells (n-Tregs) derived from the thymus suppress autoreactive CD4 or CD8 cells in the normal state. In the IgG4-related disease, the basic concept is a biphasic mechanism of “induction” and “progression.” Initial response to antigens (lactoferrin [LF], carbonic anhydrase II [CA-II], CA-IV, pancreatic secretory trypsin inhibitor [PSTI], α-amylase, plasminogen binding protein peptide of Helicobacter pylori, etc.) might be induced by decreased n-Tregs. Th2 immune responses were followed by Th1-type immune responses, with releases of proinflammatory cytokines (interferon γ [IFN-γ], interleukin [IL]-1b, IL-2, tumor necrosis factor α [TNF-α]). In progression, Th2-type immune responses producing IgG, IgG4 and autoantibodies may be involved in pathophysiology. IgG4 and fibrosis may be regulated by increased IL-10 and transforming growth factor β (TGF-β) secreted from inducible memory-Tregs (i-Tregs), respectively. However, activation of nucleotide-binding oligomerization domain (NOD) receptor or TLRs on monocytes or basophils increases IgG4 via the upregulation of B cell activating factor belonging to the tumor necrosis factor family (BAFF) and IL-13. From Okazaki K, et al. J Gastroenterol 2011;46:277–288, with permission from Springer.5

DC, ductal cell; TE, effector T cell.

Tables

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Transition of the Concept of IgG4-Related Disease

Author (Year)Evidences/Contents
Mikulicz (1892)12Mikulicz’s disease (Z Chir Fesrschr)
Sarles et al. (1961)1Hypergammaglobulinemia in CP (Am J Dig Dis)
Comings et al. (1967)9Familial multifocal fibrosclerosis (Ann Intern Med)
Küttner (1972)13Küttner tumor (Beitr Klin Chir)
Kawaguchi et al. (1991)7Lymphoplasmacytic sclerosing pancreatitis (Hum Pathol)
Yoshida et al. (1995)2Autoimmune pancreatitis (Dig Dis Sci)
Hamano et al. (2001)4High IgG4 levels in sclerosing pancreatitis (N Eng J Med)
Kamisawa et al. (2003)8IgG4-related sclerosing disease (J Gastroenterol)
Kamisawa et al. (2006)14IgG4-related sclerosing disease (J Gastroenterol)
Yamamoto et al. (2006)15IgG4-related plasmacytic disease (Mod Rheumatol)
Masaki et al. (2009)16IgG4-multiorgan lymphoproliferative syndrome (MOLPS) (Ann Rheum Dis)
Shimosegawa et al. (2011)11International Consensus Diagnostic Criteria for AIP (Pancreas)
Umehara et al.3,17Concept and comprehensive diagnostic criteria for IgG4-related disease (Mod Rheumatol)
Deshpande et al. (2012)18International Pathological Consensus for IgG4-RD (Mod Pathol)
Stone et al. (2012)19Nomenclatures of individual organ manifestation of IgG4-RD (Arthritis Rheum)

The Three Major Histopathological Features Associated with IgG4-Related Disease and the Minimal Criteria in a New Organ/Site in the International Pathological Consensus18

The three major histopathological features associated with IgG4-RD

  • Dense lymphoplasmacytic infiltrate

  • Fibrosis, arranged at least focally in a storiform pattern

  • Obliterative phlebitis

Other histopathological features associated with IgG4-RD are:

  • Phlebitis without obliteration of the lumen

  • Increased numbers of eosinophils

Minimal criteria for IgG4-RD in a new organ/site

  • Characteristic histopathological findings with an elevated IgG4t plasma cells and IgG4-to-IgG ratio

  • High serum IgG4 concentrations

  • Effective response to glucocorticoid therapy

  • Reports of other organ involvement that is consistent with IgG4-RD


Subtypes of Autoimmune Pancreatitis

Subtype of AIPType 1Type 2
Other nomenclaturesAIP without GELAIP with GEL
IgG4-relatedIgG4-unrelated
LPSPIDCP
PrevalenceAsia>USA, EUEU>USA>Asia
AgeHigh agedYounger
GenderMale>>FemaleMale=Female (NS)
Symptoms
 Obstructive jaundiceOftenOften
 Abdominal painRareCommon
Pancreas swellingCommonCommon
SerologyHigh serum IgG, IgG4, autoAbs (+)Normal IgG, normal IgG4, autoAbs (−)
OOISclerosing cholangitisUnrelated with OOI
Sclerosing sialadenitis
Reteroperitoneal fibrosis
Others
Ulcerative colitisRareOften
SteroidResponsiveResponsive
RelapseHigh rateRare

References

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  1. Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas: an autonomous pancreatic disease?. Am J Dig Dis. 1961;6;688-698.
    Pubmed CrossRef
  2. Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality: proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40;1561-1568.
    Pubmed CrossRef
  3. Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22;1-14.
    Pubmed KoreaMed CrossRef
  4. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344;732-738.
    Pubmed CrossRef
  5. Okazaki K, Uchida K, Koyabu M, Miyoshi H, Takaoka M. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol. 2011;46;277-288.
    Pubmed CrossRef
  6. Pickartz T, Mayerle J, Lerch MM. Autoimmune pancreatitis. Nat Clin Pract Gastroenterol Hepatol. 2007;4;314-323.
    Pubmed CrossRef
  7. Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita N. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol. 1991;22;387-395.
    Pubmed CrossRef
  8. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38;982-984.
    Pubmed CrossRef
  9. Comings DE, Skubi KB, Van Eyes J, Motulsky AG. Familial multi-focal fibrosclerosis: findings suggesting that retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis, Riedel’s thyroiditis, and pseudotumor of the orbit may be different manifestations of a single disease. Ann Intern Med. 1967;66;884-892.
    Pubmed CrossRef
  10. Chari ST, Kloeppel G, Zhang L, et al. Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document. Pancreas. 2010;39;549-554.
    Pubmed CrossRef
  11. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis. Guidelines of the International Association of Pancreatology. Pancreas. 2011;40;352-358.
    Pubmed CrossRef
  12. Mikulicz J. ?ber eine eigenartige symmetrishe Erkrankung der Tr?nen und Mundspeicheldr?sen. Stuttgart: Beitr z Chir Fesrschr f Theodor Billroth; 1892. p. 610-630.
  13. K?ttner H. ?ber entz?ndiche Tumoren der submaaxill?ren Speicheldr?se. Beitr Klin Chir. 1896;15;815-834.
  14. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol. 2006;41;613-625.
    Pubmed KoreaMed CrossRef
  15. Yamamoto M, Takahashi H, Ohara M, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16;335-340.
    Pubmed CrossRef
  16. Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2009;68;1310-1315.
    Pubmed CrossRef
  17. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22;21-30.
    Pubmed CrossRef
  18. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25;1181-1192.
    Pubmed CrossRef
  19. Stone JH, Khosroshahi A, Deshpande V, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum. 2012;64;3061-3067.
    Pubmed CrossRef
  20. Okazaki K, Uchida K, Matsushita M, Takaoka M. How to diagnose autoimmune pancreatitis by the revised Japanese clinical criteria. J Gastroenterol. 2007;42;32-38.
    Pubmed CrossRef
  21. Okazaki K, Kawa S, Kamisawa T, et al. Amendment of the Japanese consensus guidelines for autoimmune pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis. J Gastroenterol. 2014;49;567-588.
    Pubmed CrossRef
  22. Ohara H, Okazaki K, Tsubouchi H, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci. 2012;19;536-542.
    Pubmed CrossRef
  23. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007;37;S478-S486.
    Pubmed CrossRef
  24. Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology. 2007;46;463-471.
    Pubmed CrossRef
  25. Umemura T, Zen Y, Hamano H, et al. IgG4 associated autoimmune hepatitis: a differential diagnosis for classical autoimmune hepatitis. Gut. 2007;56;1471-1472.
    Pubmed KoreaMed CrossRef
  26. Umemura T, Zen Y, Hamano H, et al. Clinical significance of immunoglobulin G4-associated autoimmune hepatitis. J Gastroenterol. 2011;46;48-55.
    Pubmed CrossRef
  27. Kawa S, Ota M, Yoshizawa K, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002;122;1264-1269.
    Pubmed CrossRef
  28. Umemura T, Ota M, Hamano H, Katsuyama Y, Kiyosawa K, Kawa S. Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients. Gut. 2006;55;1367-1368.
    Pubmed KoreaMed CrossRef
  29. Umemura T, Katsuyama Y, Hamano H, et al. Association analysis of Toll-like receptor 4 polymorphisms with autoimmune pancreatitis. Hum Immunol. 2009;70;742-746.
    Pubmed CrossRef
  30. Chang MC, Chang YT, Tien YW, et al. T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. Clin Chem. 2007;53;1700-1705.
    Pubmed CrossRef
  31. Watanabe T, Yamashita K, Fujikawa S, et al. Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis. Arthritis Rheum. 2012;64;914-924.
    Pubmed CrossRef
  32. Watanabe T, Yamashita K, Sakurai T, et al. Toll-like receptor activation in basophils contributes to the development of IgG4-related disease. J Gastroenterol. 2013;48;247-253.
    Pubmed CrossRef
  33. Yamashina M, Nishio A, Nakayama S, et al. Comparative study on experimental autoimmune pancreatitis and its extrapancreatic involvement in mice. Pancreas. 2012;41;1255-1262.
    Pubmed CrossRef
  34. van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317;1554-1557.
    Pubmed CrossRef
  35. Kawa S, Kitahara K, Hamano H, et al. A novel immunoglobulin-immunoglobulin interaction in autoimmunity. PLoS One. 2008;3;e1637.
    Pubmed KoreaMed CrossRef
  36. Ishii K, Amagai M, Hall RP, et al. Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J Immunol. 1997;159;2010-2017.
    Pubmed
  37. Davies AM, Rispens T, Ooijevaar-de Heer P, et al. Structural determinants of unique properties of human IgG4-Fc. J Mol Biol. 2014;426;630-644.
    Pubmed KoreaMed CrossRef
  38. Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45;1538-1546.
    Pubmed CrossRef
  39. Miyoshi H, Uchida K, Taniguchi T, et al. Circulating naive and CD4+CD25high regulatory T cells in patients with autoimmune pancreatitis. Pancreas. 2008;36;133-140.
    Pubmed CrossRef
  40. Koyabu M, Uchida K, Miyoshi H, et al. Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases. J Gastroenterol. 2010;45;732-741.
    Pubmed CrossRef
  41. Kusuda T, Uchida K, Miyoshi H, et al. Involvement of inducible costimulator- and interleukin 10-positive regulatory T cells in the development of IgG4-related autoimmune pancreatitis. Pancreas. 2011;40;1120-1130.
    Pubmed CrossRef
  42. Tanaka A, Moriyama M, Nakashima H, et al. Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease. Arthritis Rheum. 2012;64;254-263.
    Pubmed CrossRef
  43. Muraki T, Hamano H, Ochi Y, et al. Autoimmune pancreatitis and complement activation system. Pancreas. 2006;32;16-21.
    Pubmed CrossRef
  44. Uchida K, Okazaki K, Konishi Y, et al. Clinical analysis of auto-immune-related pancreatitis. Am J Gastroenterol. 2000;95;2788-2794.
    Pubmed CrossRef
  45. Okazaki K, Uchida K, Ohana M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology. 2000;118;573-581.
    Pubmed CrossRef
  46. Nishi H, Tojo A, Onozato ML, et al. Anti-carbonic anhydrase II antibody in autoimmune pancreatitis and tubulointerstitial nephritis. Nephrol Dial Transplant. 2007;22;1273-1275.
    Pubmed CrossRef
  47. Aparisi L, Farre A, Gomez-Cambronero L, et al. Antibodies to carbonic anhydrase and IgG4 levels in idiopathic chronic pancreatitis: relevance for diagnosis of autoimmune pancreatitis. Gut. 2005;54;703-709.
    Pubmed KoreaMed CrossRef
  48. Nishimori I, Miyaji E, Morimoto K, Nagao K, Kamada M, Onishi S. Serum antibodies to carbonic anhydrase IV in patients with auto-immune pancreatitis. Gut. 2005;54;274-281.
    Pubmed KoreaMed CrossRef
  49. Asada M, Nishio A, Uchida K, et al. Identification of a novel auto-antibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas. 2006;33;20-26.
    Pubmed CrossRef
  50. Uchida K, Okazaki K, Nishi T, et al. Experimental immune-mediated pancreatitis in neonatally thymectomized mice immunized with carbonic anhydrase II and lactoferrin. Lab Invest. 2002;82;411-424.
    Pubmed CrossRef
  51. Endo T, Takizawa S, Tanaka S, et al. Amylase alpha-2A autoanti-bodies: novel marker of autoimmune pancreatitis and fulminant type 1 diabetes. Diabetes. 2009;58;732-737.
    Pubmed KoreaMed CrossRef
  52. Takizawa S, Endo T, Wanjia X, Tanaka S, Takahashi M, Kobayashi T. HSP 10 is a new autoantigen in both autoimmune pancreatitis and fulminant type 1 diabetes. Biochem Biophys Res Commun. 2009;386;192-196.
    Pubmed CrossRef
  53. Kountouras J, Zavos C, Gavalas E, Tzilves D. Challenge in the pathogenesis of autoimmune pancreatitis: potential role of helicobacter pylori infection via molecular mimicry. Gastroenterology. 2007;133;368-369.
    Pubmed CrossRef
  54. Kountouras J, Zavos C, Chatzopoulos D. A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis. J Cell Mol Med. 2005;9;196-207.
    Pubmed CrossRef
  55. Guarneri F, Guarneri C, Benvenga S. Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry?. J Cell Mol Med. 2005;9;741-744.
    Pubmed CrossRef
  56. Frulloni L, Lunardi C, Simone R, et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med. 2009;361;2135-2142.
    Pubmed CrossRef
  57. Nakanuma Y. A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: is the biliary tract an incomplete pancreas?. Pathol Int. 2010;60;419-429.
    Pubmed CrossRef
  58. Wang Y, Lanzoni G, Carpino G, et al. Biliary tree stem cells, precursors to pancreatic committed progenitors: evidence for possible life-long pancreatic organogenesis. Stem Cells. 2013;31;1966-1979.
    Pubmed KoreaMed CrossRef
  59. Nakanuma Y, Harada K, Sasaki M, Sato Y. Proposal of a new disease concept “biliary diseases with pancreatic counterparts”: anatomical and pathological bases. Histol Histopathol. 2014;29;1-10.
    Pubmed
  60. Topazian M, Witzig TE, Smyrk TC, et al. Rituximab therapy for refractory biliary strictures in immunoglobulin G4-associated cholangitis. Clin Gastroenterol Hepatol. 2008;6;364-366.
    Pubmed CrossRef
  61. Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. Medicine (Baltimore). 2012;91;57-66.
    Pubmed CrossRef
  62. Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, et al. Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis. Hepatology. 2013;57;2390-2398.
    Pubmed CrossRef
  63. Sumimoto K, Uchida K, Kusuda T, et al. The role of CD19+ CD-24high CD38high and CD19+ CD24high CD27+ regulatory B cells in patients with type 1 autoimmune pancreatitis. Pancreatology. 2014;14;193-200.
    Pubmed CrossRef
  64. Valencia X, Lipsky PE. CD4+CD25+FoxP3+ regulatory T cells in autoimmune diseases. Nat Clin Pract Rheumatol. 2007;3;619-626.
    Pubmed CrossRef
  65. Sakaguchi Y, Inaba M, Tsuda M, et al. The Wistar Bonn Kobori rat, a unique animal model for autoimmune pancreatitis with extrapancreatic exocrinopathy. Clin Exp Immunol. 2008;152;1-12.
    Pubmed KoreaMed CrossRef

Article

Review

Gut Liver 2014; 8(5): 462-470

Published online September 29, 2014 https://doi.org/10.5009/gnl14107

Copyright © Gut and Liver.

Recent Advances in the Concept and Pathogenesis of IgG4-Related Disease in the Hepato-Bilio-Pancreatic System

Kazuichi Okazaki, Masahito Yanagawa, Toshiyuki Mitsuyama, and Kazushige Uchida

Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan

Correspondence to: Kazuichi Okazaki, Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Shinmachi, Hirakata, Osaka 573-1197, Japan, Tel: +81-72-804-0101 (ext 2520), Fax: +81-72-804-2061, E-mail: okazaki@hirakata.kmu.ac.jp

Received: March 24, 2014; Accepted: April 15, 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

INTRODUCTION

In 1961, Sarles et al.1 observed a case of particular pancreatitis with hypergammaglobulinaemia, which is supposed to be a prototype of autoimmune pancreatitis (AIP) (Table 1). In 1995, Yoshida et al.2 proposed a novel concept of AIP, which has been accepted as type 1 AIP (IgG4-related pancreatitis), the pancreatic manifestation of IgG4-related disease (IgG4-RD).3 IgG4-RD is recognized worldwide as a novel clinical entity following the epoch-making evidence of increased serum levels of IgG4 in the history of AIP.4 The histopathological findings are characterized by the periductal localization of predominantly CD4 positive T cells, IgG4-positive plasma cells, storiform fibrosis with acinar cell atrophy, and obliterative fibrosis,5,6 which is also called lymphoplasmacytic sclerosing pancreatitis (LPSP).7 On the other hand, mainly in the Western countries, histological analyses using resected pancreatic samples in patients with chronic non-alcoholic pancreatitis demonstrated a different histological pattern of pancreatitis from LPSP, so called idiopathic duct-centric pancreatitis (IDCP) or AIP with granulocytic epithelial lesion. In 2003, Kamisawa et al.8 first suggested that AIP showing LPSP is a systemic sclerosing disease based on the concept of multifocal fibrosclerosis proposed by Comings et al.,9 because the pancreas and other involved organs have fibrosis with abundant infiltration of IgG4-positive plasma cells. On the other hand, patients with IDCP, rarely observed in Japan, are not associated with either serum IgG4 elevation or with other organ involvement typically seen in LPSP. AIP is subclassified according to the International Consensus of Diagnostic Criteria for AIP as either type 1 (LPSP) or type 2 (IDCP).10 Type 2 AIP, unlike type 1 AIP, is thought to be a specific pancreatic disease with occasional coexistence with ulcerative colitis.10,11

On the other hand, in 1892, Mikulicz12 first observed a patient with symmetrical swelling of the lachrymal, parotid and submandibular glands, with massive infiltration of mononuclear cells. The condition was called Mikulicz’s disease; however, it has since been classified as an atypical type of Sjögren’s syndrome, which also presents with bilateral, painless, and symmetrical swelling of the lachrymal, parotid, and submandibular glands. Küttner13 reported a tumor-like enlargement of the submandibular gland that was sometimes a result of stones in the Wharton duct. These patients, lacking anti-SS-A/Ro or anti-SS-B/La antibodies, often show other systemic organ involvement with elevated serum levels of IgG4, infiltration of IgG4-positive plasma cells into the glands, and recovery of secretion with steroid treatment similar to AIP.4–6 Referring to the original concept of multifocal fibrosclerosis, recent studies led us to develop a novel concept of a systemic disease such as IgG4-related systemic sclerosing disease,14 systemic IgG4-related plasmacytic syndrome,15 or IgG4-positive multiorgan lymphoproliferative syndrome,16 all of which may refer to the same conditions. Based on these findings, although it is unclear whether the pathogenetic mechanisms in individual organs are same or not,3,17 the comprehensive term “IgG4-related disease IgG4-RD,” which was internationally endorsed with the proposal of nomenclatures for individual organ lesions as well as pathological consensus, and diagnostic criteria have been proposed from the Japanese investigators.17 In this review, we discussed the current concepts of hepato-bilio-pancreatic lesions and recent advances in our understanding of the pathogenesis of IgG4-RD.

CURRENT CONCEPTS OF IgG4-RD IN THE HEPATO-BILIO-PANCREATIC SYSTEM

1. Type 1 AIP (IgG4-related pancreatitis)

AIP is a distinct form of pancreatitis clinically characterized by frequent presentation with obstructive jaundice with or without a pancreatic mass, histologically by a lymphoplasmacytic infiltrate and fibrosis and therapeutically by a dramatic response to steroids.5,21 Recent studies have suggested that “AIP” manifests two distinct subtypes, type 1 and type 2 AIP (Table 3).10,11 Type 1 AIP (IgG4-related pancreatitis) is more prevalent in Japan and Korea, whereas type 2 AIP, with granulocytic epithelial lesion, is more commonly observed in Europe and the United States.

In type 1 AIP, the pancreatic histopathology shows the following characteristic features of LPSP: 1) abundant infiltration of plasma cells (IgG4+ cells; >10/hpf, 40%>IgG4/IgG cells) and lymphocytes, 2) peculiar storiform or swirling fibrosis, and 3) perivenular infiltration with lymphocytes and plasma cells often leading to obliterative phlebitis. Clinically, it is characterized by swelling of the pancreas, elevated serum IgG4 levels and extra-pancreatic lesions (e.g., sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis) associated with infiltration of abundant IgG4+ plasma cells. Patients with type 1 AIP often have obstructive jaundice in elderly males, and the pancreatic and extrapancreatic manifestations respond to steroid therapy.21 Therefore, it is a pancreatic manifestation of a systemic disorder, IgG4-RD.19,21

2. IgG4-SC

About 60% to 80% of patients with type 1 AIP are associated with IgG4-SC,5,20–22 in which cholangiographic features are similar to those of primary sclerosing cholangitis (PSC), pancreatic cancer, and cholangiocarcinoma. The steroid responses and the prognoses of IgG4-SC differ from patients with PSC, which suggests different pathological conditions.5,20–22 Four types of the characteristic cholangiographic features of IgG4-SC have been proposed based on the regions of stricture (Fig. 1).22 IgG4-SC with only stenosis of the distal common bile duct (type 1) is difficult to differentiate from pancreatic cancer. This stricture might be due to both the thickening of bile duct and the effect of inflammation and/or edema of pancreas without wall thickness. IgG4-SC with diffuse stenosis throughout the intrahepatic/proximal bile ducts (type 2) is similar to PSC. IgG4-SC with stenosis in the hilar hepatic bile duct (type 3 and 4) is difficult to differentiate from hepatic hilar colangiocarcinoma.22 In addition to stenosis of bile ducts, circular and symmetric thickening of the bile duct wall, smooth outer and inner margin, and homogenous internal echo demonstrated by abdominal ultrasonography, abdominal computed tomography, abdominal magnetic resonance imaging, endoscopic ultrasonography, and intraductal ultrasonography are most characteristic images.22 These characteristic features are recognized not only in the stenotic areas or occasionally in the gallbladder but also in areas without stenosis that appear normal in cholangiogram. Most cases of IgG4-SC (80% to 90%) are associated with AIP.20–22 It is particularly difficult to accurately diagnose IgG4-SC without AIP. In contrast to PSC, inflammatory bowel disease is rarely observed in the patients with IgG4-SC.20–22

Histopathologically, similar to LPSP in type 1 AIP, massive infiltration of IgG4-positive plasma cells, storiform fibrosis and/or obliterative phlebitis in the bile duct wall are characteristic and called as lymphoplasmacytic sclerosing cholangitis.19,22 Such fibroinflammatory involvement is mainly observed in the submucosa of the bile duct wall, whereas the epithelium of the bile duct is intact.23 Endoscopic transpapillary bile duct biopsy or cytological examinations are useful for differential diagnosis of cholangiocarcinoma, although it is difficult to take enough biopsy samples for characteristic histopathological findings of IgG4-SC.22 Liver biopsy is sometimes useful in the diagnosis of IgG4-SC in cases of intrahepatic bile duct involvement.22

3. IgG4-related hepatopathy

Liver dysfunction is frequently observed in AIP patients and most of them show various pathological changes with infiltration of IgG4-bearing plasma cells in the liver; portal inflammation with or without interface hepatitis, large bile duct obstructive features, portal sclerosis, lobular hepatitis, and canalicular cholestasis.24 As a very few of IgG4-RD patients without AIP or IgG4-SC show the same histological features as autoimmune hepatitis (AIH), a novel concept of IgG4-related AIH has been proposed.25,26 To establish the concept of IgG4-related AIH, further studies are required.

RECENT ADVANCES IN THE PATHOGENIC MECHANISMS OF IgG4-RD IN THE HEPATO-BILIO-PANCREATIC SYSTEM

1. Immunogenic backgrounds

Although immunogenic backgrounds of IgG4-RD are not well understood, Japanese patients with AIP, most of whom are IgG4-related, may be associated with class II antigen haplotype of the major histocompatibility complex (HLA-DRB1*0405-DQB1*0401),27 polymorphism of nuclear factor-κB and Fc-receptor-like 3 genes expressed on B cells.28 An inhibitory molecule, cytotoxic T lymphocyte antigen-4 (CTLA-4; CD152) expressed on the activated memory T cells or CD4+CD25+ regulatory T cells (Tregs), was independently reported as a susceptibility factor.29,30 Based on immunogenic backgrounds, abnormal conditions of immune responses may be involved in the development of type 1 AIP, although the precise pathogenic mechanisms remain unclear.5

2. Innate immunity

Recently, abnormal innate immunity has been demonstrated in some patients with IgG4-RD.5,21 Activation of NOD-2 and TLR ligands on monocytes or basophils from patients with IgG4-related AIP enhances IgG4 responses via B cell activating factor (BAFF) and interleukin (IL)-13, although specific pathogens still remain unclear.31,32 In animal models, activation of TLR3 by polyinosinic:polycytidylic acid or TLR4 by lipopolysaccharide can induce immune-mediated cholangitis, pancreatitis and sialadenitis similar to human IgG4-RD.33

3. Possible roles of IgG4 in IgG4-RD

Although the association of IgE-mediated allergy and IgG4 antibodies is well known, IgG4 characteristics are still poorly understood. IgG4 is involved in an immune process referring to as ‘Fab-arm exchange,’ which is a swapping of a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule; this usually results in asymmetric antibodies with two different antigen-combining sites.34 While these modified antibodies are hetero-bivalent, they behave as monovalent antibodies. Another aspect of IgG4 is that it mimics IgG rheumatoid factor activity by interacting with IgG, namely Fc-mediated aggregation.35 IgG4 seems to be associated with a pathogenic effect in a few situations. In pemphigus, recognition of skin autoantigens (desmogleins) by IgG4 is at the origin of the disease process.36 A most recent study of structural determinants of human IgG4-Fc by crystallography suggested that Fc-Fc interactions are compatible with intact IgG4 molecules and may provide a model for the formation of aggregates of IgG4 that can cause disease pathology in the absence of antigen.37

Another recent data on regulation of IgG4 showed that IgG4-RD may reflect an excessive production of anti-inflammatory cytokines such as IL-10 that triggers an overwhelming expansion of IgG4-producing plasma cells.38–42 Increased peripheral inducible-memory Tregs are positively correlated with serum levels of IgG4.39 In addition, prominent infiltration of Tregs up-regulated IL-10 in livers of the patients with IgG4-SC.40 These findings suggest that IgG4 do not act as a pathogenic factor, but as an anti-inflammartory factor in IgG4-RD. Further studies are necessary to clarify the precise role of IgG4 in IgG4-RD.

4. The complement system

Patients in active stages of AIP occasionally show decreased complement (C3, C4) with elevated circulating immune complex as well as serum levels of IgG4 and the IgG4 subclass of immune complexes.43 However, a previous study showed that the classical pathway of complement activation through IgG1 may be involved in the development of AIP rather than mannose-binding lectin or alternative pathways through IgG4.43

5. Autoantibodies and candidate of target antigens

Although some patients with IgG4-RD have nonspecific antibodies such as an antinuclear antibody, there is scarce association of IgG4-RD. From the view of IgG4 function, the big mystery is whether IgG4-RD is an autoimmune or an allergic disease. Although disease specific targets are unknown, the occasional coexistence of multiorgan involvements leads us to consider that there may be common target antigens. Among candidate antigens previously reported, lactoferrin (LF),44,45 carbonic anhydrase (CA)-II,44–47 CA-IV,48 and pancreatic secretory trypsin inhibitor (PSTI)49 are expressed in the pancreas, salivary glands, biliary duct, lungs, renal tubules, and so forth. Immunization with CA-II or LF induced systemic lesions such as pancreatitis, sialadenitis, cholangitis, interstitial nephritis in the mice models similar to human IgG4-RD.50 Amylase α-2A,51 HSP-10,52 and Helicobacter pylori53–56 are also candidates of disease-associated antigens. Among the involved organs in IgG4-RD, recent studies suggest an extremely high association of pancreatic and biliary lesions.5,20,21 As both peribiliary glands in the biliary tract and pancreatic duct glands associated with pancreatic ducts in human are intermingled with small amounts of pancreatic exocrine acini,57 and the biliary tree-derived stem cells may be involved in a pancreatic organogenesis in mice.58 Nakanuma et al.59 have proposed a new concept of the “biliary diseases with pancreatic counterparts,” in which targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts. Further studies of the biliary tract’s patho-physiology based on its similarity to pancreatic counterparts are warranted.

6. Role of B cells

In addition to steroid and immune-modulators, the B cell depletion by rituximab, which reduces only IgG4, but not IgG1, IgG2, or IgG3, is useful in the therapeutic strategy in IgG4-RD.60,61 A recent study showed expansion of IgG4+ B cell receptor clones in blood and tissue of patients with active IgG4-chol-angiopathy, and disappearance by corticosteroid treatment.62 A recent study showed that the increased CD19+CD24highCD38high Bregs may suppress the disease activity of type 1 AIP, whereas the decreased CD19+CD24highCD27+ Bregs might be involved in the development of type 1 AIP.63 These findings suggest that specific B cell responses may have a pivotal role in the pathogenesis of IgG4-RD such as type 1 AIP and IgG4-SC.

7. Th1 and Th2 immune balance

The effector cells in IgG4-RD have been poorly understood. The CD4+ T cells differentiate from naive T cells (Th0) to Th1, Th2, Th17, and Treg cells. In the livers of IgG4-SC patients, a Th2 type immune reaction38,42 is induced in addition to the Th1 responses.45,50 Th2 cytokines may be involved in the progression of the disease process, especially the maturation and proliferation of local B cells and plasmacytes.

8. Tregs

Foxp3 is a member of the forkhead/winged-helix family of transcriptional regulators, and functions as the master regulator in the development and function of CD4+CD25+ Tregs classified as naturally occurring naive-Tregs originating in the thymus and adaptively induced memory-Tregs in the periphery by different antigens.64 In type 1 AIP, circulatory naive (CD45RA+) Tregs are significantly decreased in the peripheral blood, whereas memory (CD45RA−)-Tregs are significantly increased.39 In addition, prominent infiltration of Tregs with upregulation of IL-10 is observed in the liver of type 1 AIP and IgG4-SC patients.40,41 These findings suggest that increased memory-Tregs in the periphery and local tissues may be an inhibitory immune response against inflammation, although decreased naive Tregs may be pathogenic.

9. Our hypothesis for the pathogenesis of IgG4-SC

The neonatally thymectomized (nTx)-BALB/c mice models showed that immunization with CA-II or LF induced pancreatitis, cholangitis, and sialadenitis similar to human IgG4-RD.50 These findings suggest that depletion of naive Tregs may induce macrophage/T cell activation and further proinflammatory reactions during the early stage of the disease as direct cytotoxicity effects through Fas ligand expression. WBN/Kob rat models with congenital decreased peripheral Tregs spontaneously develop sclerotic cholangitis, sialadenitis, thyroiditis, and tubulointerstitial nephritis.65 These animal models suggest that CD4+/CD8+ T cells play major roles in the development of primary lesions similarly to human IgG4-RD; however, the counterpart of IgG4 in mice IgG subclasses has not been identified.

Based on these findings, we proposed the pathogenesis of type 1 AIP (Fig. 2).5 The basic concept is the biphasic mechanism of “induction” and “progression.” An initial response to unknown disease specific antigens including self-antigens (LF, CA-II, CA-IV, and PSTI) or microorganisms (bacteria or virus) might be induced by decreased naive-Tregs followed by a Th1 type immune response with the release of proinflammatory cytokines (interferon γ, IL-1β, IL-2, tumor necrosis factor α). In progression, Th2 type immune responses producing IgG, IgG4, and autoantibodies may be involved in pathophysiology. IgG4 and fibrosis may be regulated by increased IL-10 and transforming growth factor β secreted from inducible T cell co-stimulator (ICOS)-positive and ICOS-negative inducible adaptive Tregs, respectively. Production of IgG4 may be also upregulated by BAFF from monocytes and basophils.

CONCLUSIONS

Recent advances support the concept of IgG4-RD, a unique clinical entity, in the hepato-bilio-pancreas system. Although the pathogenic mechanism remains unclear, innate and acquired immunity, Tregs, and B cells may be involved in the development of these lesions. Further studies are necessary to clarify the pathogenesis including genetic backgrounds, disease-specific antigens, and the role of IgG4.

Fig 1.

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Figure 1.Classification of cholangiography in IgG4-related sclerosing cholangitis (IgG4-SC). The characteristic features of IgG4-SC can be classified into four types, based on the regions of stricture as revealed by cholangiography and differential diagnosis. Type 1 IgG4-SC shows stenosis only in the lower part of the common bile duct, which should be differentiated from chronic pancreatitis, pancreatic cancer, or cholangiocarcinoma. Type 2 IgG4-SC, in which stenosis is diffusely distributed throughout the intrahepatic and extrahepatic bile ducts, should be differentiated from primary sclerosing cholangitis. Type 2 is further subdivided into two types. Type 2a has a narrowing of the intrahepatic bile ducts with prestenotic dilation, and Type 2b has a narrowing of the intrahepatic bile ducts without prestenotic dilation and reduced bile duct branches, caused by marked lymphocytic and plasmacyte infiltration into the peripheral bile ducts. Type 3 IgG4-SC is characterized by stenosis in both the hilar hepatic lesions and the lower portion of the common bile duct. Type 4 IgG4-SC shows strictures of the bile duct only in the hilar hepatic lesions. Cholangiographic findings of types 3 and 4 need to be discriminated from those of cholangiocarcinoma. From Ohara H, et al. J Hepatobiliary Pancreat Sci 2012;19:536–542, with permission from Springer.22

IDUS, intraductal ultrasonography; EUS, endoscopic ultrasonography; EUS-FNA, EUS-guided fine-needle aspiration; IBD, inflammatory bowel disease.

Gut and Liver 2014; 8: 462-470https://doi.org/10.5009/gnl14107

Fig 2.

Download
Figure 2.Hypothesis for the pathogenesis of autoimmune pancreatitis (AIP) and IgG4-related disease. In central tolerance, naturally occurring naive regulatory T cells (n-Tregs) derived from the thymus suppress autoreactive CD4 or CD8 cells in the normal state. In the IgG4-related disease, the basic concept is a biphasic mechanism of “induction” and “progression.” Initial response to antigens (lactoferrin [LF], carbonic anhydrase II [CA-II], CA-IV, pancreatic secretory trypsin inhibitor [PSTI], α-amylase, plasminogen binding protein peptide of Helicobacter pylori, etc.) might be induced by decreased n-Tregs. Th2 immune responses were followed by Th1-type immune responses, with releases of proinflammatory cytokines (interferon γ [IFN-γ], interleukin [IL]-1b, IL-2, tumor necrosis factor α [TNF-α]). In progression, Th2-type immune responses producing IgG, IgG4 and autoantibodies may be involved in pathophysiology. IgG4 and fibrosis may be regulated by increased IL-10 and transforming growth factor β (TGF-β) secreted from inducible memory-Tregs (i-Tregs), respectively. However, activation of nucleotide-binding oligomerization domain (NOD) receptor or TLRs on monocytes or basophils increases IgG4 via the upregulation of B cell activating factor belonging to the tumor necrosis factor family (BAFF) and IL-13. From Okazaki K, et al. J Gastroenterol 2011;46:277–288, with permission from Springer.5

DC, ductal cell; TE, effector T cell.

Gut and Liver 2014; 8: 462-470https://doi.org/10.5009/gnl14107

Table 1 Transition of the Concept of IgG4-Related Disease

Author (Year)Evidences/Contents
Mikulicz (1892)12Mikulicz’s disease (Z Chir Fesrschr)
Sarles et al. (1961)1Hypergammaglobulinemia in CP (Am J Dig Dis)
Comings et al. (1967)9Familial multifocal fibrosclerosis (Ann Intern Med)
Küttner (1972)13Küttner tumor (Beitr Klin Chir)
Kawaguchi et al. (1991)7Lymphoplasmacytic sclerosing pancreatitis (Hum Pathol)
Yoshida et al. (1995)2Autoimmune pancreatitis (Dig Dis Sci)
Hamano et al. (2001)4High IgG4 levels in sclerosing pancreatitis (N Eng J Med)
Kamisawa et al. (2003)8IgG4-related sclerosing disease (J Gastroenterol)
Kamisawa et al. (2006)14IgG4-related sclerosing disease (J Gastroenterol)
Yamamoto et al. (2006)15IgG4-related plasmacytic disease (Mod Rheumatol)
Masaki et al. (2009)16IgG4-multiorgan lymphoproliferative syndrome (MOLPS) (Ann Rheum Dis)
Shimosegawa et al. (2011)11International Consensus Diagnostic Criteria for AIP (Pancreas)
Umehara et al.3,17Concept and comprehensive diagnostic criteria for IgG4-related disease (Mod Rheumatol)
Deshpande et al. (2012)18International Pathological Consensus for IgG4-RD (Mod Pathol)
Stone et al. (2012)19Nomenclatures of individual organ manifestation of IgG4-RD (Arthritis Rheum)

CP, chronic pancreatitis; AIP, autoimmune pancreatitis.

Table 2 The Three Major Histopathological Features Associated with IgG4-Related Disease and the Minimal Criteria in a New Organ/Site in the International Pathological Consensus18

The three major histopathological features associated with IgG4-RD

Dense lymphoplasmacytic infiltrate

Fibrosis, arranged at least focally in a storiform pattern

Obliterative phlebitis

Other histopathological features associated with IgG4-RD are:

Phlebitis without obliteration of the lumen

Increased numbers of eosinophils

Minimal criteria for IgG4-RD in a new organ/site

Characteristic histopathological findings with an elevated IgG4t plasma cells and IgG4-to-IgG ratio

High serum IgG4 concentrations

Effective response to glucocorticoid therapy

Reports of other organ involvement that is consistent with IgG4-RD

IgG4-RD, IgG4-related disease.

Table 3 Subtypes of Autoimmune Pancreatitis

Subtype of AIPType 1Type 2
Other nomenclaturesAIP without GELAIP with GEL
IgG4-relatedIgG4-unrelated
LPSPIDCP
PrevalenceAsia>USA, EUEU>USA>Asia
AgeHigh agedYounger
GenderMale>>FemaleMale=Female (NS)
Symptoms
 Obstructive jaundiceOftenOften
 Abdominal painRareCommon
Pancreas swellingCommonCommon
SerologyHigh serum IgG, IgG4, autoAbs (+)Normal IgG, normal IgG4, autoAbs (−)
OOISclerosing cholangitisUnrelated with OOI
Sclerosing sialadenitis
Reteroperitoneal fibrosis
Others
Ulcerative colitisRareOften
SteroidResponsiveResponsive
RelapseHigh rateRare

AIP, autoimmune pancreatitis; GEL, granulocytic epithelial lesion; LPSP, lymphoplasmacytic sclerosing pancreatitis; IDCP, idiopathic duct-centric chronic pancreatitis; NS, not significant; OOI, other organ involvement.

References

  1. Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas: an autonomous pancreatic disease?. Am J Dig Dis. 1961;6;688-698.
    Pubmed CrossRef
  2. Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality: proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40;1561-1568.
    Pubmed CrossRef
  3. Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22;1-14.
    Pubmed KoreaMed CrossRef
  4. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344;732-738.
    Pubmed CrossRef
  5. Okazaki K, Uchida K, Koyabu M, Miyoshi H, Takaoka M. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol. 2011;46;277-288.
    Pubmed CrossRef
  6. Pickartz T, Mayerle J, Lerch MM. Autoimmune pancreatitis. Nat Clin Pract Gastroenterol Hepatol. 2007;4;314-323.
    Pubmed CrossRef
  7. Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita N. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol. 1991;22;387-395.
    Pubmed CrossRef
  8. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38;982-984.
    Pubmed CrossRef
  9. Comings DE, Skubi KB, Van Eyes J, Motulsky AG. Familial multi-focal fibrosclerosis: findings suggesting that retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis, Riedel’s thyroiditis, and pseudotumor of the orbit may be different manifestations of a single disease. Ann Intern Med. 1967;66;884-892.
    Pubmed CrossRef
  10. Chari ST, Kloeppel G, Zhang L, et al. Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document. Pancreas. 2010;39;549-554.
    Pubmed CrossRef
  11. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis. Guidelines of the International Association of Pancreatology. Pancreas. 2011;40;352-358.
    Pubmed CrossRef
  12. Mikulicz J. ?ber eine eigenartige symmetrishe Erkrankung der Tr?nen und Mundspeicheldr?sen. Stuttgart: Beitr z Chir Fesrschr f Theodor Billroth; 1892. p. 610-630.
  13. K?ttner H. ?ber entz?ndiche Tumoren der submaaxill?ren Speicheldr?se. Beitr Klin Chir. 1896;15;815-834.
  14. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol. 2006;41;613-625.
    Pubmed KoreaMed CrossRef
  15. Yamamoto M, Takahashi H, Ohara M, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16;335-340.
    Pubmed CrossRef
  16. Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2009;68;1310-1315.
    Pubmed CrossRef
  17. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22;21-30.
    Pubmed CrossRef
  18. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25;1181-1192.
    Pubmed CrossRef
  19. Stone JH, Khosroshahi A, Deshpande V, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum. 2012;64;3061-3067.
    Pubmed CrossRef
  20. Okazaki K, Uchida K, Matsushita M, Takaoka M. How to diagnose autoimmune pancreatitis by the revised Japanese clinical criteria. J Gastroenterol. 2007;42;32-38.
    Pubmed CrossRef
  21. Okazaki K, Kawa S, Kamisawa T, et al. Amendment of the Japanese consensus guidelines for autoimmune pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis. J Gastroenterol. 2014;49;567-588.
    Pubmed CrossRef
  22. Ohara H, Okazaki K, Tsubouchi H, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci. 2012;19;536-542.
    Pubmed CrossRef
  23. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007;37;S478-S486.
    Pubmed CrossRef
  24. Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology. 2007;46;463-471.
    Pubmed CrossRef
  25. Umemura T, Zen Y, Hamano H, et al. IgG4 associated autoimmune hepatitis: a differential diagnosis for classical autoimmune hepatitis. Gut. 2007;56;1471-1472.
    Pubmed KoreaMed CrossRef
  26. Umemura T, Zen Y, Hamano H, et al. Clinical significance of immunoglobulin G4-associated autoimmune hepatitis. J Gastroenterol. 2011;46;48-55.
    Pubmed CrossRef
  27. Kawa S, Ota M, Yoshizawa K, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002;122;1264-1269.
    Pubmed CrossRef
  28. Umemura T, Ota M, Hamano H, Katsuyama Y, Kiyosawa K, Kawa S. Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients. Gut. 2006;55;1367-1368.
    Pubmed KoreaMed CrossRef
  29. Umemura T, Katsuyama Y, Hamano H, et al. Association analysis of Toll-like receptor 4 polymorphisms with autoimmune pancreatitis. Hum Immunol. 2009;70;742-746.
    Pubmed CrossRef
  30. Chang MC, Chang YT, Tien YW, et al. T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. Clin Chem. 2007;53;1700-1705.
    Pubmed CrossRef
  31. Watanabe T, Yamashita K, Fujikawa S, et al. Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis. Arthritis Rheum. 2012;64;914-924.
    Pubmed CrossRef
  32. Watanabe T, Yamashita K, Sakurai T, et al. Toll-like receptor activation in basophils contributes to the development of IgG4-related disease. J Gastroenterol. 2013;48;247-253.
    Pubmed CrossRef
  33. Yamashina M, Nishio A, Nakayama S, et al. Comparative study on experimental autoimmune pancreatitis and its extrapancreatic involvement in mice. Pancreas. 2012;41;1255-1262.
    Pubmed CrossRef
  34. van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317;1554-1557.
    Pubmed CrossRef
  35. Kawa S, Kitahara K, Hamano H, et al. A novel immunoglobulin-immunoglobulin interaction in autoimmunity. PLoS One. 2008;3;e1637.
    Pubmed KoreaMed CrossRef
  36. Ishii K, Amagai M, Hall RP, et al. Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J Immunol. 1997;159;2010-2017.
    Pubmed
  37. Davies AM, Rispens T, Ooijevaar-de Heer P, et al. Structural determinants of unique properties of human IgG4-Fc. J Mol Biol. 2014;426;630-644.
    Pubmed KoreaMed CrossRef
  38. Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45;1538-1546.
    Pubmed CrossRef
  39. Miyoshi H, Uchida K, Taniguchi T, et al. Circulating naive and CD4+CD25high regulatory T cells in patients with autoimmune pancreatitis. Pancreas. 2008;36;133-140.
    Pubmed CrossRef
  40. Koyabu M, Uchida K, Miyoshi H, et al. Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases. J Gastroenterol. 2010;45;732-741.
    Pubmed CrossRef
  41. Kusuda T, Uchida K, Miyoshi H, et al. Involvement of inducible costimulator- and interleukin 10-positive regulatory T cells in the development of IgG4-related autoimmune pancreatitis. Pancreas. 2011;40;1120-1130.
    Pubmed CrossRef
  42. Tanaka A, Moriyama M, Nakashima H, et al. Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease. Arthritis Rheum. 2012;64;254-263.
    Pubmed CrossRef
  43. Muraki T, Hamano H, Ochi Y, et al. Autoimmune pancreatitis and complement activation system. Pancreas. 2006;32;16-21.
    Pubmed CrossRef
  44. Uchida K, Okazaki K, Konishi Y, et al. Clinical analysis of auto-immune-related pancreatitis. Am J Gastroenterol. 2000;95;2788-2794.
    Pubmed CrossRef
  45. Okazaki K, Uchida K, Ohana M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology. 2000;118;573-581.
    Pubmed CrossRef
  46. Nishi H, Tojo A, Onozato ML, et al. Anti-carbonic anhydrase II antibody in autoimmune pancreatitis and tubulointerstitial nephritis. Nephrol Dial Transplant. 2007;22;1273-1275.
    Pubmed CrossRef
  47. Aparisi L, Farre A, Gomez-Cambronero L, et al. Antibodies to carbonic anhydrase and IgG4 levels in idiopathic chronic pancreatitis: relevance for diagnosis of autoimmune pancreatitis. Gut. 2005;54;703-709.
    Pubmed KoreaMed CrossRef
  48. Nishimori I, Miyaji E, Morimoto K, Nagao K, Kamada M, Onishi S. Serum antibodies to carbonic anhydrase IV in patients with auto-immune pancreatitis. Gut. 2005;54;274-281.
    Pubmed KoreaMed CrossRef
  49. Asada M, Nishio A, Uchida K, et al. Identification of a novel auto-antibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas. 2006;33;20-26.
    Pubmed CrossRef
  50. Uchida K, Okazaki K, Nishi T, et al. Experimental immune-mediated pancreatitis in neonatally thymectomized mice immunized with carbonic anhydrase II and lactoferrin. Lab Invest. 2002;82;411-424.
    Pubmed CrossRef
  51. Endo T, Takizawa S, Tanaka S, et al. Amylase alpha-2A autoanti-bodies: novel marker of autoimmune pancreatitis and fulminant type 1 diabetes. Diabetes. 2009;58;732-737.
    Pubmed KoreaMed CrossRef
  52. Takizawa S, Endo T, Wanjia X, Tanaka S, Takahashi M, Kobayashi T. HSP 10 is a new autoantigen in both autoimmune pancreatitis and fulminant type 1 diabetes. Biochem Biophys Res Commun. 2009;386;192-196.
    Pubmed CrossRef
  53. Kountouras J, Zavos C, Gavalas E, Tzilves D. Challenge in the pathogenesis of autoimmune pancreatitis: potential role of helicobacter pylori infection via molecular mimicry. Gastroenterology. 2007;133;368-369.
    Pubmed CrossRef
  54. Kountouras J, Zavos C, Chatzopoulos D. A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis. J Cell Mol Med. 2005;9;196-207.
    Pubmed CrossRef
  55. Guarneri F, Guarneri C, Benvenga S. Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry?. J Cell Mol Med. 2005;9;741-744.
    Pubmed CrossRef
  56. Frulloni L, Lunardi C, Simone R, et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med. 2009;361;2135-2142.
    Pubmed CrossRef
  57. Nakanuma Y. A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: is the biliary tract an incomplete pancreas?. Pathol Int. 2010;60;419-429.
    Pubmed CrossRef
  58. Wang Y, Lanzoni G, Carpino G, et al. Biliary tree stem cells, precursors to pancreatic committed progenitors: evidence for possible life-long pancreatic organogenesis. Stem Cells. 2013;31;1966-1979.
    Pubmed KoreaMed CrossRef
  59. Nakanuma Y, Harada K, Sasaki M, Sato Y. Proposal of a new disease concept “biliary diseases with pancreatic counterparts”: anatomical and pathological bases. Histol Histopathol. 2014;29;1-10.
    Pubmed
  60. Topazian M, Witzig TE, Smyrk TC, et al. Rituximab therapy for refractory biliary strictures in immunoglobulin G4-associated cholangitis. Clin Gastroenterol Hepatol. 2008;6;364-366.
    Pubmed CrossRef
  61. Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. Medicine (Baltimore). 2012;91;57-66.
    Pubmed CrossRef
  62. Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, et al. Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis. Hepatology. 2013;57;2390-2398.
    Pubmed CrossRef
  63. Sumimoto K, Uchida K, Kusuda T, et al. The role of CD19+ CD-24high CD38high and CD19+ CD24high CD27+ regulatory B cells in patients with type 1 autoimmune pancreatitis. Pancreatology. 2014;14;193-200.
    Pubmed CrossRef
  64. Valencia X, Lipsky PE. CD4+CD25+FoxP3+ regulatory T cells in autoimmune diseases. Nat Clin Pract Rheumatol. 2007;3;619-626.
    Pubmed CrossRef
  65. Sakaguchi Y, Inaba M, Tsuda M, et al. The Wistar Bonn Kobori rat, a unique animal model for autoimmune pancreatitis with extrapancreatic exocrinopathy. Clin Exp Immunol. 2008;152;1-12.
    Pubmed KoreaMed CrossRef
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