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Recent advances in basic science
Recent advances in autoimmune pancreatitis
  1. D H Park1,
  2. M-H Kim1,
  3. S T Chari2
  1. 1Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
  2. 2Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr S T Chari, Miles & Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA; chari.suresh{at}mayo.edu

Abstract

Autoimmune pancreatitis (AIP) is distinct from calcifying and obstructive forms of chronic pancreatitis. Clinically and histologically it has two distinct subsets: (i) lymphoplasmacytic sclerosing pancreatitis or type 1 AIP which appears to be a systemic disease characterised by abundant infiltration of affected organs with immunoglobulin G4 (IgG4)-positive plasma cells and (2) duct-centric or type 2 AIP characterised by granulocyte epithelial lesions in the pancreas without systemic involvement. In AIP a marked lymphoplasmacytic infiltrate that responds dramatically to steroid therapy suggests an autoimmune aetiology. However, the target autoantigen(s) and the effector cells in AIP remain speculative. Despite the consistent elevation in serum IgG4 levels and tissue infiltration with IgG4-positive plasma cells in type 1 AIP, the role of IgG4 in its pathogenesis remains unknown. Recent development of animal models of AIP will help improve our understanding of the pathogenesis of these newly described forms of chronic pancreatitis.

https://doi.org/10.1136/gut.2008.155853

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    Introduction

    A form of idiopathic chronic pancreatitis associated with minimal pain, obstructive jaundice and hypergammaglobulinaemia was first described by Sarles et al1 in 1961 who suspected it was an autoimmune process. Subsequently, cases of pancreatic involvement in other autoimmune diseases (mostly Sjögren and primary sclerosing cholangitis) were reported. In 1995 Yoshida et al2 reported a case of a 68-year-old woman with obstructive jaundice, diffusely enlarged pancreas with diffusely irregular narrow pancreatic duct, hypergammaglobulinaemia and fibrosis on needle biopsy. The clinical and radiological manifestations of the disease resolved following steroid therapy. Drawing parallels from the literature on autoimmune hepatitis, the authors coined the term “autoimmune pancreatitis” (AIP) which has since remained the most popular name for this disease entity.

    Histological subtypes of AIP

    There is growing evidence that there are two clinical and histological patterns in patients diagnosed as having AIP,3 4 which we will call type 1 and type 2 AIP (table 1). Type 1 AIP fits the classic description of the disease reported from Japan2 5 and is associated with the histological pattern known as lymphoplasmacytic sclerosing pancreatitis (LPSP)6 characterised by three key features: (1) dense periductal lymphoplasmacytic infiltrate; (2) a swirling or storiform fibrosis; and (3) obliterative venulitis7 8 (fig 1). Its serological hallmark is the elevation in serum levels of the immunoglobulin G4 (IgG4) subclass of IgG9 and the lymphoplasmacytic infiltrate is rich in IgG4-positive cells. Type 1 AIP appears to be the pancreatic manifestation of a systemic disease called IgG4-associated systemic disease (ISD) which affects not only the pancreas but also other organs including the bile duct, retroperitoneum, kidney, lymph nodes and salivary glands.10 11

    Figure 1
    Figure 1

    Features of lymphoplasmacytic sclerosing pancreatitis (LPSP) on an endoscopic ultrasound-guided pancreatic core biopsy (A): periductal lymphoplasmacytic infiltrate (B), obliterative phlebitis (C) and abundant immunoglobulin G4 (IgG4)-positive cells (D).

    View this table:
    Table 1

    Comparison of type 1 and type 2 AIP

    Type 2 AIP is a form of idiopathic chronic pancreatitis which also presents with obstructive jaundice and is characterised by a distinct histology called non-alcoholic duct-destructive pancreatitis,12 idiopathic duct-centric pancreatitis (IDCP)3 or granulocyte epithelial lesion (GEL)-positive pancreatitis.13 In this form of AIP, neutrophils are sometimes so numerous that microabscesses may be seen in the lobules and ducts.3 4 Usually, the entire wall of the duct is infiltrated by neutrophils, lymphocytes and plasma cells (fig 2). The infiltrate frequently involves the duct epithelium and lumen often obliterating and destroying the epithelium. This characteristic ductal lesion is called GEL3 4 (fig 2). Obliterative phlebitis, which is characteristic of LPSP, is not a prominent feature of IDCP.3 In IDCP, lobular and periductal inflammatory infiltrates of the main and interlobular pancreatic ducts have few IgG4-positive cells.8

    Figure 2
    Figure 2

    Idiopathic duct-centric pancreatitis diagnosed postresection in a 43-year-old woman with multiple discrete episodes of abdominal pain. (A) CT scan showed pancreatic duct dilatation in the body and tail of pancreas without a mass. (B) Endoscopic retrograde cholangiopancreatography confirmed the presence of a long pancreatic duct stricture which did not show evidence of malignancy on brushing and biopsies. However, due to concern regarding the possibility of a small malignancy, pancreatic resection was undertaken which showed classic features of duct-centric pancreatitis with periductal inflammation and intraepithelial neutrophilic infiltrate causing ductal damage and disruption (C).

    While far less is known about the clinical spectrum of type 2 AIP than is known about type 1 AIP, the existing literature shows important clinical and histological differences between the two forms of AIP which justifies their classification as separate entities (table 1).

    Clinical spectrum of AIP

    Demographics

    Type 1 AIP is a disease of older men, with >80% of patients being over the age of 50 years and >80% being men.14 15 16 17 Type 2 AIP, based on early reports, appears to affect younger patients and may not have the male predominance seen in type 1 AIP.3 4

    Clinical presentation

    Type 1 has a varied clinical presentations (fig 3), the best known being acute with obstructive jaundice and pancreatic enlargement mimicking pancreatic cancer.14 15 16 17 Such patients also experience weight loss and new onset of diabetes, making the clinical distinction between AIP and pancreatic cancer difficult. Less commonly it may present with features suggestive of acute pancreatitis with acute abdominal pain and elevated pancreatic enzymes, and rarely complications such as pseudocyst.18 AIP may come to clinical attention late in the course of the disease due to a persistent pancreatic mass, an atrophic pancreas with or without calcification or due to unexplained pancreatic steatorrhoea.14 Thus its pancreatic manifestations can mimic pancreatic cancer, acute pancreatitis, painless chronic pancreatitis or unexplained exocrine insufficiency. The extrapancreatic manifestations are equally diverse (see the section “Other organ involvement”). Other organ involvement may be seen simultaneously with AIP, may precede it or occur many years later when the pancreas may or may not be symptomatic.

    Figure 3
    Figure 3

    Clinical presentations of type 1 autoimmune pancreatitis.

    Type 2 AIP is also reported to present with obstructive jaundice, although it has also been described in patients with idiopathic pancreatic duct strictures with or without a mass.3 4 As it is a relatively new entity, the full spectrum of the clinical profile of type 2 AIP remains to be described.

    Pancreatic imaging

    The characteristic imaging features of type 1 AIP on CT scan or magnetic resonance imaging (MRI) include a diffuse “sausage-shaped” enlargement of the gland with delayed and peripheral (rim) enhancement (fig 4).19 20 On pancreatography a diffusely irregular, narrow pancreatic duct or multiple strictures without intervening or upstream ductal dilation are highly suggestive of AIP20 (fig 4).2 21 These typical features are found in about half the patients. Others may have focal masses or strictures, and show evidence of acute pancreatitis or rarely calcification. A focal low-density mass with dilated pancreatic duct and/or upstream pancreatic atrophy is very unusual in the acute presentation of AIP (although it can occur in relapses, late presentation) and should be treated as pancreatic cancer unless proven otherwise.

    Figure 4
    Figure 4

    Typical imaging features of type 1 autoimmune pancreatitis: (A) CT shows a diffusely enlarged gland with loss of lobulation (“sausage-shaped”). Other features include rim-like enhancement (arrows) and delayed enhancement. (B) Endoscopic retrograde cholangiopancreatography shows the pancreatic duct with multiple strictures not associated with ductal dilatation.

    On endoscopic ultrasonography, typical features during acute presentation include a diffusely enlarged, hypoechoic, lobular gland with smooth borders and a diminutive pancreatic duct. A capsule-like rim may also be seen around the gland. A mass mimicking pancreatic cancer may also be seen.22 The bile duct shows diffuse, smooth and concentric thickening which extends well into the extrapancreatic bile duct. When expertise is available, the beefy enlarged gland is amenable to an endoscopic ultraound (EUS)-guided core biopsy of the pancreas.23

    Serology

    Type 1 AIP is associated with a variety of serological abnormalities including elevated titres of γ-globulin, IgG and its subset IgG4, as well as rheumatoid factor.24 In addition, titres of anticarbonic anhydrase, antilactoferrin and antinuclear antibodies (ANAs) are also variably increased.25 However, the single best marker of AIP is elevated serum levels of IgG4.9 26 27 The initial report suggested that elevated serum IgG4 levels may be nearly pathognomonic of AIP9; however, subsequent studies have shown that it is characteristic but not diagnostic of AIP (sensitivity 75%, specificity 93%).26 27 Most importantly, approximately 7–10% of patients with pancreatic cancer27 28 and >10% of patients with cholangiocarcinoma (unpublished data from the Mayo Clinic) have elevated serum IgG4 levels. Because of the rarity of AIP, the positive predictive value of serum IgG4 elevation for AIP is low and it should not be used alone to make the diagnosis of AIP.27 Serum IgG4 levels >2 times upper limit of normal are highly specific for AIP.27 Initial reports suggest that the typical serological abnormalities seen in type 1 AIP are not seen in type 2 AIP. There is currently no serological marker that is specific for type 2 AIP.

    Other organ involvement

    Type 1 AIP is part of a systemic disease called IgG4-associated systemic disease which can involve multiple organs, most notably proximal extrahepatic and intrahepatic bile ducts, kidneys, retroperitoneum, lymph nodes and salivary glands (fig 5).10 11 29 30 31 The most common extrapancreatic organ involved is the biliary tree where distal biliary involvement mimics pancreatic cancer-related stricture.32 33 More proximal involvement may cause suspicion of cholangiocarcinoma or primary sclerosing cholangitis.34 Other well described manifestations include salivary gland involvement resembling Sjögren syndrome, mediastinal adenopathy resembling sarcoidosis, retroperitoneal fibrosis, orbital pseudolymphoma and tubulointerstitial nephritis.19 The presence of radiological abnormalities suggestive of renal, retroperitoneal and proximal biliary involvement is often seen in type 1 AIP (fig 5) and these are important diagnostic clues. In addition, the ampulla, gallbladder and stomach can, like the other organs affected, show characteristic intense infiltration with IgG4-positive plasma cells.7

    Figure 5
    Figure 5

    Spectrum of other organ involvement in acute pancreatitis. (A) Renal lesions as described by Takahashi et al.34 (B) Synchronous pancreatic, renal, biliary and retroperitoneal involvement. (C) Orbital pseudolymphoma. (D) Mesenteritis. (E) Sclerosing cholangitis. (F1) Hilar bile duct stricture. (F2) The same stricture after 6 weeks of steroids. (With thanks to Dr Thomas Witzig for providing the photograph in Figure 5(C)).

    Type 2 AIP has been reported to be associated with inflammatory bowel disease in 20–30% of patients.3 4 The other typical associations with type 1 AIP (retroperitoneal fibrosis, Sjogren-like salvary gland involvement and proximal biliary strictures) are not reported in type 2 AIP.

    Diagnosis of AIP

    A number of diagnostic criteria have been proposed that define who has (type 1) AIP. These have come from the Japan Pancreas Society (JPS I, JPS II),35 36 the Mayo Clinic (HISORt criteria)14 and South Korea.37 Recently the Asian consensus diagnostic criteria were proposed by Japanese and Korean investigators.38 A detailed comparison of the criteria is beyond the scope of this review. However, the interested reader is referred to an overview of the first three criteria provided by Kwon et al.37

    Diagnosis of type 1 AIP

    This can be established in one of three ways by the HISORt criteria,14 and, barring minor differences, by the Asian consensus criteria as well.38

    Typical imaging + serology or compatible histology

    All the diagnostic criteria noted above agree that in patients with typical imaging findings (a combination of a diffusely enlarged “sausage-shaped” gland and a diffusely irregular, narrow pancreatic duct), an elevation in serum IgG4 or compatible histology is diagnostic of AIP. In such patients, less specific autoimmune serological markers, such as high titres of ANAs and rheumatoid factor, may also be used if serum IgG4 cannot be measured.35 The criteria differ in the need for an endoscopic pancreatogram (JPS, Consensus) versus a magnetic resonance pancreatogram (Korean).

    Diagnostic histology/immunostaining

    That histology of AIP is unique and sufficient to make the diagnosis of AIP was initially proposed in the HISORt criteria.14 Subsequently, the histological evidence for diagnosis of AIP has been included in the Consensus Asian Criteria38; however, the Asian criteria only allow diagnosis to be made on resection specimens, not on pancreatic biopsy. The diagnosis of AIP can be made if pancreatic histology shows all three features of LPSP (dense lymphoplasmacytic infiltrate often surrounding small ducts, storiform fibrosis and obliterative phlebitis). On core biopsies the diagnosis can be made (by HISORt criteria) if it shows classic features of LPSP, which are present in only 20% of biopsies, or by IgG4 immunostaining, if there are ⩾10 IgG4-positive cells per high power field. False-positive IgG4 staining in the setting of cancer has been described.8 39 However, patients with false-positive stains do not have other features of LPSP noted earlier. IgG4 immunostaining without any other features of LPSP should not be used to diagnose AIP.

    Response to steroids

    AIP responds consistently and often dramatically to steroid therapy.40 During the acute presentation, patients often have a swollen pancreas associated with biliary obstruction. Even after just a few weeks of steroids the pancreatic swelling dramatically decreases and the biliary stricture improves.41 This consistent response to steroids can be both diagnostic and reassuring (fig 5F1,F2). Steroid trial as a diagnostic test for AIP is included in the HISORt,14 the Korean criteria37 and the most recent Asian Consensus criteria.38 Steroid trials should be used sparingly and in specific subsets of patients as there are growing concerns regarding their use.42 43 However, a recent report suggests that they are safe even in pancreatic cancer patients.41 When a steroid trial is given, the diagnosis of AIP can be confirmed if the manifestations, pancreatic and/or extrapancreatic, resolve or markedly improve with steroid therapy.

    Diagnosis of type 2 AIP

    The published criteria for AIP are geared towards diagnosing type 1 AIP. One can suspect type 2 AIP in young patients with obstructive jaundice (with negative investigations for cancer) who are seronegative and have no other organ involvement other than possibly inflammatory bowel disease. However, up to 25% of those with type 1 (histologically confirmed) are seronegative and 30–40% of those with type 1 have no discernible other organ involvement. Thus, without a surrogate biomarker that accurately correlates with histology of type 2 AIP, it is hard to diagnose this variant definitively without histology. Whether type 2 AIP can be consistently and reliably diagnosed on pancreatic core biopsy remains to be established. This may also be the reason why the number of reported cases of type 2 AIP is far fewer than that of type 1 AIP.

    Treatment of AIP

    Induction of remission in type 1 AIP can be achieved with a dose of steroids of 30–40 mg/day, and steroids are tapered while monitoring serum IgG4 levels and imaging findings.44 Distal bile duct strictures respond promptly to steroids, and bile duct stents placed for relieving obstructive jaundice can often be removed in 2–4 weeks. However, relapses either in the pancreas or more often in the bile duct occur in up to 40% of patients40 during steroid taper or following withdrawal of steroids. Long-term maintenance steroids have been used to prevent relapses. Whether immunomodulators such as azathioprine can maintain remission, thus avoiding long-term steroids, remains to be proven. There are no large series of medically treated type 2 AIP patients. Therefore, the response and relapse rates to steroids of this variant of AIP remain to be established.

    Prognosis

    Patients with AIP may suffer from pancreatic exocrine and endocrine insufficiency.40 They may suffer relapses in the pancreas or other organs. There have been recent case reports of pancreatic cancer complicating AIP.45 However, there are no case–control studies to determine if AIP predisposes to pancreatic cancer.

    Pathogenesis of AIP

    It is quite evident that AIP is a form of chronic pancreatitis with distinct clinical, morphological, serological and histopathological features that distinguish it from usual chronic pancreatitis. Histological findings of abundant lymphoplasmacytic infiltrate and a dramatic response to steroid treatment suggest an autoimmune aetiology for the disease. While many clinical reviews on AIP have been published,17 24 46 47 48 49 limited information is available on the pathogenesis of the disease. Here we discuss the key features that suggest that AIP is caused by autoimmune mechanism (see table 2).

    View this table:
    Table 2

    Features of autoimmunity seen in AIP

    Genetic factors in AIP

    Human susceptibility to AIP may be associated with the class II antigen of the major histocompatibility complex (MHC).50 The susceptibility factors vary among different ethnic groups and geographical regions. This diversity suggests that the indigenous antigen triggers the disease by naturally selecting individuals with genetic predispositions that favour their acquisition. To date, HLA association studies for AIP have been conducted only in Asia. Kawa et al50 reported the association of AIP with human leucocyte antigen (HLA) haplotype DRB1*0405-DQB1*0401 in Japanese patients. In contrast, a recent Korean study failed to distinguish any significant susceptible alleles associated with AIP among the HLA class I and class II antigens.51

    Recently, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), acting as a negative regulator of T cell responses, a non-HLA gene, was reported as a susceptibility factor for AIP in the Taiwanese population.52 The investigators found a significant increase in CTLA-4 49A carriers among AIP patients, compared with the healthy population. The −318C/+49A/CT60G haplotype was associated with higher susceptibility to AIP. Tumour necrosis factor α (TNFα) promoter −863A was correlated with extrapancreatic involvement in patients with AIP in this study.52 Thus, it appears that non-HLA genes are additionally involved in the development of this autoimmune disease. Umemura et al53 also reported that a single nucleotide polymorphism (SNP) at +6230 in the 3′-untranslated region of CTLA-4 plays a pivotal role in both susceptibility to (+6230G/G genotype) and protection from (haplotype of the +6230A allele) AIP, while an exon 1+49 SNP is not associated with AIP in Japanese patients.

    Humoral immunity and target antigens

    The definitive autoantigen for AIP remains to be established. The frequent coexistence of pancreatitis with other organ involvement in type 1 AIP suggests common target antigens in the pancreas and other exocrine organs, such as the salivary gland, biliary tract and renal tubules.48 Antilactoferrin (ALF) and anticarbonic anhydrase II or IV (ACA-II, IV) are the most frequently detected autoantibodies in AIP.54 55 56 LF and CA-II are distributed in the cells of several exocrine organs, including the pancreas, salivary gland, biliary duct and distal renal tubules.48 The high prevalence of autoantibodies to these antigens and the wide distribution of antigens in the pancreas and other exocrine organs support the theory that CA-II and LF are candidate target antigens in AIP. Moreover, the wide distribution of these antigens may explain the involvement of other organs in AIP. α-Fodrin is another autoantigen of AIP, as reported in a number of patients with Sjögren syndrome and AIP.57 58 Recently, Asada et al59 reported the presence of autoantibodies against pancreatic secretory trypsin inhibitor (PSTI) in 30–40% of patients with AIP. Interestingly, two of three patients negative for both ALF and ACA-II were positive for anti-PSTI antibodies.59 These findings suggest that PSTI is another target antigen for AIP.

    Though elevation of serum IgG4 is a typical characteristic of type 1 AIP9 26 60 and several reports confirm increased numbers of IgG4-positive plasma cells in the pancreatic tissue of type 1 AIP,7 39 61 the role of IgG4 in AIP is unknown at present. IgG4, the least common of the four IgG isoforms in humans, produces bispecific antibodies that act as pathogenetic or suppressive autoantibodies, depending on the disease condition (autoimmune or allergic disease). One popular theory is that the consistently high number of IgG4-positive plasma cells may merely represent a secondary response to an as yet unidentified primary trigger of the inflammatory process in AIP.39

    Interestingly, anti-PSTI antibodies in the sera of patients with AIP were classified as the IgG1 subtype, and not IgG4. Moreover, no significant correlations were evident between the serum levels of IgG4 and anti-PSTI IgG antibodies in AIP patients. This finding is inconsistent with a recent report showing a strong association between increased serum IgG4 and ACA-II levels in AIP patients.55

    Cellular immunity and effector cells

    The effector cells of AIP are yet to be established. Activated CD4+ and CD8+ T cells bearing HLA-DR and CD45RO are increased in peripheral blood lymphocytes as well as the pancreas in AIP, compared with alcoholic or gallstone-related pancreatitis.48 62 CD4+ T cells are further subdivided into T helper 1 (Th1) and Th2 populations on the basis of cytokine production profiles. The two T cell populations counter-regulate each other. Th1 cells produce interleukin-2 (IL-2), TNFα and interferon γ (IFNγ) These cells mediate cellular immunity, macrophage activation, cytotoxicity and B cell production of opsonising and complement-fixing antibodies.48 Abnormal skewing towards Th1 or Th2 cells is significant in the pathogenesis of autoimmune disorders. The Th1/Th2 paradigm continues to serve as an effective model for elucidating the pathogenesis pathways of several conditions.63

    Th1 cytokines are essential for the induction and/or maintenance of Sjögren syndrome, while Th2 cytokines are involved in disease progression, particularly local B cell activation.24 Similarly, Th1 cytokines may be essential for the induction and/or maintenance of AIP, and Th2 cytokines for disease progression. Okazaki et al62 suggest that elevation of the serum Th1 over the Th2 type immune response may be required for AIP pathogenesis. In contrast, Zen and colleagues report the significant involvement of Th2 in AIP pathogenesis.64 As this study involved AIP patients with positive IgG4 immunostaining of the extrapancreatic organ, AIP with a more active state may be included65 or there may be an inherent discrepancy between the Th1/Th2 immune response results of sera and tissue specimens.64

    Role of the complement system

    AIP is occasionally associated with decreased complement levels. Muraki et al66 reported high serum circulating immune complex values, which decreased significantly after corticosteroid therapy. In patients with AIP, elevated circulating immune complex levels, determined with the C1q assay, were significantly linked to increased serum IgG1 and decreased C4, as well as decreased C3 levels. No major differences were observed in the serum levels of mannose-binding lectin or the frequency of a mutant allele of mannose-binding lectin between AIP and chronic calcifying pancreatitis patients. Furthermore, corticosteroid therapy had no effect on the mannose-binding lectin level. Thus, AIP may present high serum circulating immune complex values in its active state, which link to a complement activation system via the classic pathway, rather than mannose-binding lectin or alternative pathways.66 In this situation, increased serum IgG1, and not IgG4, is significantly associated with AIP. Recently, the same investigators reported that IgG4 bound to IgG1, 2 and 3 forms an Fc–Fc interaction immune complex in patients with AIP.67 Based on these findings, it is suggested that IgG1-type immune complexes trigger the complement system via the classical pathway, and IgG4 contributes to the clearance of immune complexes and termination of the inflammatory process. Another possibility is that IgG4 blocks Fc-mediated effector functions of IgG1 and dampens the inflammatory response.66 67

    Microbial infection

    Molecular mimicry is a possible mechanism used by microbes to break down immune tolerance. The underlying concept is that infectious agents share one or more epitopes with various self-components. An alternative hypothesis is that infectious agents cause bystander activation of immune cells with autoaggressive potential.68 Helicobacter pylori infection is strongly associated with peptic ulcer and gastric autoimmunity. Patients infected with H pylori possess autoantibodies that cross-react with antigens expressed on the gastric mucosa. As in the case of AIP, H pylori may be associated, via molecular mimicry of host structures by its constituents, with the same autoimmune conditions, including primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis and Sjögren syndrome, or hepatitis C virus-related liver diseases that trigger autoimmune sequelae.68 69 70 Guarneri and colleagues70 showed significant homology between human CA-II and α-CA of H pylori, a fundamental enzyme for bacterial survival and proliferation in the gastric environment. Moreover, the homologous segments contain the binding motif of DRB1*0405. Notably, possession of the HLA DRB1*0405-DQB1*0401 genotype confers a risk for AIP development. These data suggest that gastric H pylori infection triggers AIP in genetically predisposed subjects.70

    Role of regulatory T cells (Tregs)

    Regulatory T cells that originate in the thymus are naturally occurring CD4+CD25+ Tregs (nTregs), and therefore distinguishable from CD4+CD25+ Tregs induced in the periphery by different antigens, which are denoted adaptive Tregs (aTregs).71 CD4+CD25+ T cells play an important role in immune suppression through the production of transforming growth factor β (TGFβ) and IL-10, and ligation of CTLA-4. These immunoregulatory T cells prevent CD4+ T cell-mediated disease (eg, autoimmune disease).72 However, increased prevalence of circulating CD4+CD25+ T cells or a similar level of peripheral CD4+CD25+ T cells was observed in rheumatoid arthritis patients with Sjögren syndrome, compared with healthy controls.73 Thus, the reduced prevalence of circulating Tregs may not be a general finding in all patients with autoimmune diseases. In inflammatory bowel disease, expansion of the CD4+CD25+ Treg cell pool during remission and its contraction during relapse is inverse to the expansion and contraction of inflammatory (Th1 or Th2 cell) populations during these phases.74 Thus, Tregs may participate in autoimmune disease activity via modulation of Th1 or Th2.75

    A number of recent studies focus on the role of Tregs in AIP. Zen et al64 reported that the immune reaction of AIP is predominantly mediated by Th2 and CD4+CD25+Foxp3 Tregs in the liver of patients with sclerosing cholangitis with AIP. Miyoshi et al76 also reported that circulatory naïve (CD45RA+) Tregs are significantly decreased in peripheral blood of patients with AIP, while memory (CD45RA–) Tregs are significantly increased.

    Experimental autoimmune pancreatitis in animal models

    To date, several animal models of AIP, including extraglandular inflammation, have been described. There are similarities between the proposed classification of AIP and the two animal models of AIP.39 62 64 The first model involves the adoptive transfer of amylase-specific (an antigen mainly located in acinar cells) CD4+ T cells and results in pancreatitis in naïve syngenic recipient animals.64 Notably, the histological lesions of this model mimic the lobulocentric inflammatory reaction in type 1 AIP. This experimental model of autoimmune pancreatitis was characterised histologically as overwhelmingly lymphocytic with occasional plasma cells, neutrophils and mast cells. Acinar tissue destruction and ductular inflammation were common features, with less frequent involvement of larger ducts. Immunohistochemical analysis revealed the presence of large numbers of CD4+ T cells as well as CD8+ T cells, macrophages and dendritic cells. Expression of MHC I and MHC II additionally increased at the site of the lesion.

    A model developed by the immunisation of neonatally thymectomised mice with CA (an antigen mainly located on the pancreatic epithelium) and later the transfer of CD4+ lymphocytes results in a duct-centric pattern of pancreatitis resembling type 2 AIP.62 Of interest, patients with an elevated CA demonstrated a clinical profile more akin to type 2 AIP.32 T cells specific for CA-II and LF were also unable to induce pancreatitis in adoptive transfer of an amylase-specific rat model.77 However, the authors speculated that autoantibodies against these enzymes in AIP represent a late consequence of tissue destruction, and not the fundamental pathogenic mechanism. In such a scenario, autoantibodies against CA-II and LF would arise via epitope spreading.77 Recently, Kojima et al78 showed polyclonal patterns of T cell receptor γ and IgH-FR3 genes in AIP. This finding supports the “epitope spreading theory” in AIP.

    In another model, NTx-NFS/sld mice spontaneously developed sialoadenitis in which α-fodrin was involved as an autoantigen, as reported in some patients with Sjögren syndrome and AIP.57 The amino acid sequences of CA-II, LF and 120 kDa α-fodrin were less than 10% homologous without cross-reactivity. Thus, different target antigens, such as CA-II, LF and α-fodrin, may be involved in the development of AIP, which is additionally dependent on genetic susceptibility.48 Several animal models without distinct antigen specificity—for example, alymphoplastic (aly–/aly–) mice79 and MRL/lpr mice80—spontaneously develop pancreatitis or sialoadenitis in which T cells act as the effector cells (table 3), particularly, Th1 type CD4+ T cells.

    View this table:
    Table 3

    Experimental animal models of autoimmune pancreatitis or exocrinopathy

    TGFβ appears to be an important regulatory factor in maintaining immune homeostasis. Loss of TGFβ signalling contributes to AIP in TGFβ dominant-negative mutant mice.81

    Similar to animal models of other organ involvement in AIP, subcutaneous immunisation with CA-II induced sialoadenitis in PL/J and SJL/JCr mice, but not in other mouse strains.82 Conversely, BALB/c and DBA/1 mice intraperitoneally immunised with CA-II had cholangitis, but not sialoadenitis.83 Mice which have undergone neonatal thymectomy (nTx) in a hyperimmune state spontaneously develop various organ-specific autoimmune diseases, such as gastritis, thyroiditis, oophoritis and orchitis. Recently two more animal models for AIP were proposed. The WBN/Kob rat model, associated with congenital decreased peripheral Tregs, spontaneously develops sialoadenitis, thyroiditis, sclerosing cholangitis and tubulointerstitial nephritis.84 Although the target antigens remain unclear, CD8+ cells may be the effector cell in this rat model.69 Another recently described animal model of AIP is the Treg-deficient NOD mouse.85 CD28KO mice spontaneously develop AIP that closely resembles the human disease.85 In this study, autoantibodies and autoreactive cells from affected mice recognised a 50 kDa protein identified as pancreatic amylase. Interestingly, administration of tolerogenic amylase-coupled fixed splenic cells significantly ameliorated disease activity. The authors therefore speculate that this protein functions as a key autoantigen.85

    Existing animal models for AIP have several limitations. In most models the disease is induced by adoptive transfer of autoreactive cells and/or antibodies rather than spontaneous development of disease with identical antigen specificity. The distribution of lesions produced in animal models for AIP is also variable. This may be attributed to diversity of target antigens, different methods of immune staining and different mouse strains. In addition, typical histopathological findings of AIP (eg, lymphoplasmacytic infiltration with fibrosis, obliterative phlebitis and GELs) are rarely observed in animal models. Thus, there is a need to develop spontaneous animal models with identical autoantigens and typical histopathological finding for AIP.

    Our proposed model for the pathogenesis of AIP

    Here, we propose a plausible model for the pathogenesis of AIP. An important concept of our model is the biphasic elements in AIP initiation and progression with the support of Tregs (fig 6). Induction of a response to self-autoantigens (ALF, ACA-II, PSTI and α-fodrin), and molecular mimicry (H pylori) may activate antigen-presenting cells. In this milieu with depleted Tregs, Th1 cells may activate and release inflammatory cytokines (IFNγ, IL-2 and TNFα), thus inducing the cellular immune reaction. Complement activation by the IgG1 immune complex is another possible pathway of AIP initiation. Upon activation of Tregs (not sufficient for suppression of AIP), Th2 may be stimulated and the cytokines IL-4, IL-5, IL-6, IL-10 and TGFβ released. This pathway activates the humoral reaction. The IgG4 immune complex may be related to the differentiation phase of AIP or Treg function. During the evolution of AIP, Treg activity may be related to specific amino acid substitution at HLA class II.

    Figure 6
    Figure 6

    Proposed model for the pathogenesis of autoimmune pancreatitis (AIP). A concept of the proposed model is the biphasic elements in AIP initiation and progression with the support of regulatory T cells (Tregs). Induction of a response to self-autoantigens and molecular mimicry (H pylori) may activate antigen-presenting cells (APCs). In this milieu with depleted Tregs, T helper 1 (Th1) cells may activate and release inflammatory cytokines (interferon γ (IFNγ), interleukin 2 (IL-2) and tumour necrosis factor α (TNFα)), thus inducing the cellular immune reaction. Complement activation by the IgG1 immune complex is another possible pathway of AIP initiation. Upon activation of Tregs, Th2 may be stimulated and the cytokines IL-4, IL-5, IL-6, IL-10 and transforming growth factor β (TGFβ) released. The immunoglobulin G4 (IgG4) immune complex may be related to the differentiation phase of AIP or Treg function. During the evolution of AIP, Treg activity may be related to specific amino acid substitution at human leucocyte antigen (HLA) class II. Finally, the IgG1 immune complex may be related to IgG4-negative and granulocyte epithelial lesion (GEL)-positive AIP (idiopathic duct-centric pancreatitis (IDCP)), whereas the IgG4 immune complex may be correlated to IgG4-positive and GEL-negative AIP (lymphoplasmacytic sclerosing pancreatitis (LPSP)). CA-II, carbonic anhydrase II; PSTI, pancreatic secretory trypsin inhibitor.

    As noted earlier, at least two forms of AIP may exist, only one of which is associated with elevated serum IgG4 (type 1 AIP). Type 2 AIP has an increased association with chronic inflammatory bowel disease which may be associated with elevation of the serum level of IgG1 rather than serum IgG4.86 87 We therefore speculate that the IgG1 immune complex may be related to IgG4-negative AIP (IDCP) and the IgG4 immune complex may be associated with IgG4-positive AIP (LPSP).

    Summary of the pathogenesis of AIP and future directions

    Further studies are required to address the roles of Tregs and substitution of amino acids of the HLA class II molecule in disease activity or relapse. The functions of IgG1 and IgG4, ideal animal models and actual autoantigens in AIP should additionally be analysed to ensure comprehensive understanding of the pathogenesis. Moreover, multinational clinical and genetic data collection for genome-wide studies, including SNPs, is warranted to identify susceptibility factors. An ideal model for AIP pathogenesis should also be established based on the proposed autoimmune mechanism. These measures should lead to a better understanding of the pathogenesis of the disease which in turn should lead to a more rational management of AIP.

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    View Abstract

    Footnotes

    • Funding This study (pathogenesis part of autoimmune pancreatitis) was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A080277).

    • Competing interests None.

    • Provenance and peer review Commissioned; externally peer reviewed.

    • Patient consent Obtained.

    Linked Articles

    • Correction
      Correction
      BMJ Publishing Group Ltd and British Society of Gastroenterology
      Gut 2010; 59 1007-1007 Published Online First: 25 Jun 2010. doi: 10.1136/gut.2008.155853corr1