Journal of Gastroenterology

, Volume 46, Issue 3, pp 277–288

Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease

Authors

    • Division of Gastroenterology and Hepatology, The Third Department of Internal MedicineKansai Medical University
  • Kazushige Uchida
    • Division of Gastroenterology and Hepatology, The Third Department of Internal MedicineKansai Medical University
  • Masanori Koyabu
    • Division of Gastroenterology and Hepatology, The Third Department of Internal MedicineKansai Medical University
  • Hideaki Miyoshi
    • Division of Gastroenterology and Hepatology, The Third Department of Internal MedicineKansai Medical University
  • Makoto Takaoka
    • Division of Gastroenterology and Hepatology, The Third Department of Internal MedicineKansai Medical University
Review

DOI: 10.1007/s00535-011-0386-x

Cite this article as:
Okazaki, K., Uchida, K., Koyabu, M. et al. J Gastroenterol (2011) 46: 277. doi:10.1007/s00535-011-0386-x

Abstract

Recent studies have suggested the existence of two subtypes of autoimmune pancreatitis (AIP): type 1 AIP, related to IgG4 (lymphoplasmacytic sclerosing pancreatitis); and type 2 AIP, related to a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis). Compared with type 2 AIP, the clinicopathological features of type 1 AIP, with increased serum IgG4/IgE levels, abundant infiltration of IgG4 + plasmacytes and lymphocytes, autoantibodies, and steroid responsiveness, are more suggestive of abnormal immunity such as allergy or autoimmunity. Moreover, patients with type 1 AIP often have extrapancreatic lesions, such as sclerosing cholangitis, sclerosing sialadenitis, or retroperitoneal fibrosis, showing pathological features similar to those of the pancreatic lesions. Based on these findings, an international concept of and diagnostic criteria for AIP have been proposed recently. Of interest, many synonyms have been proposed for the conditions of AIP and extrapancreatic lesions associated with IgG4, such as “multifocal idiopathic fibrosclerosis,” “IgG4-related autoimmune disease,” “IgG4-related sclerosing disease,” “systemic IgG4-related plasmacytic syndrome (SIPS),” and “IgG4-related multiorgan lymphoproliferative syndrome,” all of which may refer to the same conditions. Therefore, the Japanese Research Committee for “Systemic IgG4-Related Sclerosing Disease” proposed a disease concept and clinical diagnostic criteria based on the concept of multifocal fibrosclerosing disease, in 2009, in which the term “IgG4-related disease” was agreed upon as a minimal consensus to cover these conditions. Although the significance of IgG4 in the development of “IgG4-related disease” remains unclear, we have proposed a hypothesis for the development of type 1 AIP, one of the IgG4-related diseases. The concept and diagnostic criteria of “IgG4-related disease” will be changed in accordance with future studies.

Keywords

IgG4IgG4-related diseaseAutoimmune pancreatitisMikulicz diseaseRegulatory T cell (Treg)

Abbreviations

AIP

Autoimmune pancreatitis

ANA

Anti-nuclear antibody

CA-II

Carbonic anhydrase-II

CTLA-4

Cytotoxic T lymphocyte antigen-4

ERCP

Endoscopic retrograde cholangio-pancreatography

FCRL

Fc-receptor-like

IFN-γ

Interferon-γ

IL-4

Interleukin-4

LF

Lactoferrin

LPSP

Lymphoplasmacytic sclerosing pancreatitis

MD

Mikulicz disease

MHC

Major histocompatibility complex

MOLPS

Multiorgan lymphoproliferative disease

PBP

Plasminogen-binding protein

SjS

Sjögren’s syndrome

PSC

Primary sclerosing cholangitis

RF

Rheumatoid factor

SIPS

Systemic IgG4 plasmacytic syndrome

SLE

Systemic lupus erythematosus

Treg

Regulatory T cell

UBR2

Ubiquitin-protein ligase E3 component n-recognin 2

Introduction

In 1961, Sarles et al. [1] first observed a case of particular pancreatitis with hypergammaglobulinemia. Yoshida et al. [2] first proposed the concept of autoimmune pancreatitis (AIP). Hamano et al. [3] reported increased serum levels of IgG4 in Japanese patients with AIP. Thereafter, many studies of AIP were reported, mainly by Japanese investigators. The histopathological findings of AIP are characterized by the periductal localization of predominantly CD4-positive T cells, IgG4-positive plasma cells, storiform fibrosis with acinar cell atrophy frequently resulting in stenosis of the main pancreatic duct, and obliterative fibrosis [46], which is also called lymphoplasmacytic sclerosing pancreatitis (LPSP) [7]. In 2003, Kamisawa et al. [8] suggested that AIP is a systemic sclerosing disease, based on the findings that the pancreas and other involved organs have fibrosis with abundant infiltration of IgG4-positive plasma cells, which is similar to the concept of multifocal fibrosclerosis proposed by Comings et al. [9]. Further histological and clinical profiling of patients with “AIP” reveals two distinct subtypes, type 1 and type 2 AIP [10, 11]. Type 1 AIP is classified as a pancreatic manifestation of IgG4-related disease, probably a systemic disease with an autoimmune process, whereas type 2 AIP is regarded as a specific pancreatic disease with a granulocytic epithelial lesion (GEL) [12, 13] and occasional coexistence with ulcerative colitis [10, 11].

Of note, patients with Mikulicz’s disease (MD) –originally classified as an atypical type of Sjögren’s syndrome–who usually have bilateral, painless, and symmetrical swelling of the lachrymal, parotid, and submandibular glands [14], show elevated serum levels of IgG4, infiltration of IgG4-positive plasma cells into the glands, and recovery of secretion with steroid treatment. Similar to patients with AIP, these patients often show other organ involvement (OOI) such as AIP, sclerosing cholangitis, retroperitoneal fibrosis, enlarged celiac and hilar lymph nodes, chronic thyroiditis, and interstitial nephritis [46, 1416]. Recently, however, MD has been considered to be completely different from Sjögren’s syndrome because of the lack of anti-SS-A/Ro or anti-SS-B/La antibodies, and the showing of steroid responsiveness [26]. The steroid responses and the prognoses of AIP patients with sclerosing cholangitis differ from these features in patients with primary sclerosing cholangitis (PSC), which suggests different pathological conditions. These findings led us to the concept of “IgG4-related disease” such as IgG4-related systemic sclerosing disease [8, 17], systemic IgG4-related plasmacytic syndrome (SIPS) [18], and IgG4-positive multiorgan lymphoproliferative syndrome (IgG4-MOLPS) [19]. Although the pathogenesis and pathophysiology of AIP remain unclear, we will discuss the most recent advances in the concept of AIP, especially IgG4-related type 1 AIP, and the advances in the novel concept of “IgG4-related disease.”

Subtypes of autoimmune pancreatitis: type 1 and type 2 AIP

Recent studies have suggested that “AIP” manifests as two distinct subtypes, type 1 and type 2 AIP (Table 1) [10, 11]. Hypergammaglobulinemia, the deposition of immunoglobulins, the presence of autoantibodies, and steroid efficacy in Type 1 AIP confirm the definition of autoimmune disease proposed by Mackay [20]. Different from type 1 AIP, patients with type 2 AIP have no serological markers of autoimmunity. Therefore, it is still in debate as to whether or not type 2 AIP should be classified as a clinical entity of AIP, but the deposition of C3c and IgG in the basement membrane of pancreatic ducts and acini suggests an immune complex-mediated destruction of ducts and acini in type 2 AIP as well as type 1 AIP [21]. The nomenclature of the two subtypes of AIP and international consensus diagnostic criteria were proposed at the meeting of the International Association of Pancreatology held at Fukuoka in 2010 (Tables 2, 3) [22].
Table 1

Subtypes of autoimmune pancreatitis (AIP)

Subtype of AIP

Type 1

Type 2

Other nomenclatures

AIP without GEL

IgG4-related LPSP

AIP with GEL

IgG4-unrelated IDCP

Prevalence

Asia > USA, Europe

Europe > USA > Asia

Age

High age

Younger

Gender

Male ≫ female

Male = female (NS)

Symptoms

Often obstructive jaundice rare abdominal pain

Often obstructive jaundice abdominal pain like acute pancreatitis

Pancreas images

Swelling (diffuse/segmental/focal)/mass-forming

Swelling (diffuse/segmental/focal)/mass-forming

Serology

High serum IgG, IgG4, autoAbs (+)

Normal IgG, normal IgG4, autoAbs (−)

Other organ involvement (OOI)

Sclerosing cholangitis

Sclerosing sialadenitis

Retroperitoneal fibrosis

Others

Unrelated to OOI

Ulcerative colitis

Rare

Often

Steroid

Responsive

Responsive

Relapse

High rate

Rare

GEL granulocytic epithelial lesion, LPSP lymphoplasmacytic sclerosing pancreatitis, IDCP idiopathic duct-centric chronic pancreatitis, Abs antibodies, NS not significant

Table 2

Diagnosis of definitive and probable type 1 AIP using international consensus diagnostic criteria (ICDC) [22]

Diagnosis

Primary basis for diagnosis

Imaging evidence

Collateral evidence

Definitive type 1 AIP

Histology

Typical/indeterminate

Histologically confirmed LPSP (level 1 H)

Imaging

Typical

Any non-D level 1/level 2

Indeterminate

Two or more from level 1 (+level 2 D*)

Response to steroid

Indeterminate

Level 1 S/OOI + Rt or level 1 D + level 2 S/OOI/H + Rt

Probable type 1 AIP

 

Indeterminate

Level 2 S/OOI/H + Rt

 

Criterion

Level 1

Level 2

P

Parenchymal imaging

Typical

Diffuse enlargement with delayed enhancement

(sometimes associated with rim-like enhancement)

Indeterminate (including atypical*):

Segmental/focal enlargement with delayed enhancement

D

Ductal imaging (ERP)

Long (>1/3 length of the MPD) or multiple strictures

without marked upstream dilatation

Segmental/focal narrowing without marked upstream dilatation (duct size <5 mm)

S

Serology

IgG4 > 2× upper limit of normal value

IgG4 1–2× upper limit of normal value

OOI

Other organ involvement

a or b

a. Histology of extrapancreatic organs

Any three of the following

Marked lymphoplasmacytic infiltration with fibrosis and without granulocytic infiltration

Storiform fibrosis

Obliterative phlebitis

Abundant (>10 cells/hpf) IgG4 positive cells

b. Typical radiological evidence

At least one

Segmental/multiple proximal (hilar/intra hepatic) or proximal and distal bile duct stricture

Retroperitoneal fibrosis

a or b

a. Histology of extrapancreatic organs including endoscopic biopsies of bile duct**

Both of the following

Marked lymphoplasmacytic infiltration without granulocytic infiltration

Abundant (>10 cells/hpf) IgG4-positive cells

b. Physical or radiological evidence

At least one

Symmetrically enlarged salivary/lacrimal glands

Radiological evidence of renal involvement described in association with AIP

H

Histology of the pancreas

LPSP (core biopsy/resection)

At least 3 of the following

Periductal lymphoplasmacytic infiltrate without granulocytic infiltration

Obliterative phlebitis

Storiform fibrosis

Abundant (>10 cells/hpf) IgG4-positive cells

LPSP (core biopsy)

Any 2 of the following

Periductal lymphoplasmacytic infiltrate without granulocytic infiltration

Obliterative phlebitis

Storiform fibrosis

Abundant (>10 cells/hpf) IgG4positive cells

Diagnostic steroid trial

 Response to steroid (Rt)#

Rapid (≤2 weeks) radiologically demonstrable resolution or marked improvement in pancreatic/extrapancreatic manifestations

hpf high-power field, MPD main pancreatic duct, D ductal imaging, Rt response to steroid treatment, S serology, H histology, ERP endoscopic retrograde pancreatography

Table 3

Diagnosis of definitive and probable type 2 AIP using international consensus diagnostic criteria (ICDC) [22]

Diagnosis

Imaging evidence

Collateral evidence

 

Definitive type 2 AIP

Typical/indeterminate

Histologically confirmed IDCP (level 1 H) or clinical IBD + level 2 H + Rt

 

Probable type 2 AIP

Typical/indeterminate

Level 2 H/clinical IBD + Rt

 
 

Criterion

Level 1

Level 2

P

Parenchymal imaging

Typical

Diffuse enlargement with delayed enhancement

(sometimes associated with rim-like enhancement)

Indeterminate (including atypical*)

Segmental/focal enlargement with delayed enhancement

D

Ductal imaging (ERP)

Long (>1/3 length of the MPD) or multiple strictures without marked upstream dilatation

Segmental/focal narrowing without marked upstream dilatation (duct size <5 mm)

OOI

Other organ involvement

 

Clinically diagnosed inflammatory bowel disease

H

Histology of the pancreas (core biopsy/resection)

IDCP:

Both of the following

Granulocytic infiltration of duct wall (GEL) with or without granulocytic acinar inflammation

Absent or scant (0–10 cells/hpf) IgG4-positive cells

Both of the following

Granulocytic and lymphoplasmacytic acinar infiltrate

Absent or scant (0–10 cells/hpf) IgG4-positive cells

Diagnostic steroid trial

 Response to steroid (Rt)#

Rapid (<2 weeks) resolution or marked improvement in manifestations

IBD inflammatory bowel disease, D ductal imaging, Rt response to steroid treatment, H histology, ERP endoscopic retrograde pancreatography

Type 1 AIP

In type 1 AIP, whose histological description is called LPSP, the pancreatic histopathology shows the following characteristic features: (1) abundant infiltration of plasma cells (IgG4+ cells; high-power field [hpf], IgG4/IgG cells; >40%) and lymphocytes, (2) peculiar storiform or swirling fibrosis, and (3) perivenular infiltration with lymphocytes and plasma cells often leading to obliterative phlebitis. Clinically, type 1 AIP seems to be the pancreatic manifestation of the recently proposed IgG4-related disease, characterized by swelling of the pancreas, elevated serum IgG4 levels, and extrapancreatic lesions (e.g., sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis) associated with the infiltration of abundant IgG4 + plasma cells. Patients with type 1 AIP are often elderly males who have obstructive jaundice, and the pancreatic and extrapancreatic manifestations respond to steroid therapy.

Extrapancreatic lesions in type 1 AIP

A variety of extrapancreatic lesions have been noted in patients with AIP, including lachrymal and salivary gland lesions [23], pulmonary lesions including hilar lymphadenopathy [24], sclerosing cholangitis [25, 26], retroperitoneal fibrosis [27], and tubulointerstitial nephritis (TIN) [15, 28, 29]. Associations were also reported with hypophysitis [30], chronic thyroiditis [16, 31], and prostatitis [32]. Other extrapancreatic involvements have been reported in a few cases [3336]. Though it is not certain that all of these involvements have a relation with AIP, extrapancreatic lesions are prevalent systemically in various organs (Table 4) [2941], suggesting that type 1 AIP, but not type 2 AIP, may be a pancreatic manifestation of IgG4-related disease. The extrapancreatic lesions appear synchronously or metachronously with the pancreatic lesion(s), share the same pathological conditions, and show favorable responses to steroid therapy; these characteristics suggest a common pathophysiological background. The lesions are usually detected by imaging and blood tests (computed tomography [CT], magnetic resonance imaging [MRI], gallium scintigraphy, fluorodeoxyglucose positron emission tomography [FDG-PET], and IgG4); however, such findings should be confirmed by histological findings. Extrapancreatic lesions sometimes mimic, or are misdiagnosed as, primary lesions of the corresponding organs: lachrymal and salivary gland lesions for Sjögren’s syndrome, respiratory lesions for sarcoidosis, and sclerosing cholangitis for PSC. Therefore, it is necessary to differentiate between IgG4-related diseases and inherent diseases of the corresponding organs. Patients with IgG4-related sialodacryoadenitis, synonymous with IgG4-related MD [13, 41], usually have symmetrical enlargement of the salivary and lacrimal glands. The IgG4-related central nervous system lesions include infundibulohypophysitis, hypertrophic pachymeningitis, intracranial inflammatory pseudotumor, and orbital pseudotumor [2141].
Table 4

Extrapancreatic lesions complicated with autoimmune pancreatitis. (from Ref. [38])

Close association

 Lachrymal gland inflammation

 Sialoadenitis

 Hilar lymphadenopathy

 Interstitial pneumonitis

 Sclerosing cholangitis

 Retroperitoneal fibrosis

 Tubulointerstitial nephritis

Possible association

 Hypophysitis

 Autoimmune neurosensory hearing loss

 Uveitis

 Chronic thyroiditis

 Pseudotumor (breast, lung, liver)

 Gastric ulcer

 Swelling of papilla of Vater

 IgG4 hepatopathy

 Aortitis

 Prostatitis

 Schonlein-Henoch purpura

 Autoimmune thrombocytopenia

Type 2 AIP

Type 2 AIP was proposed from histological examination of pancreases resected from patients with chronic non-alcoholic pancreatitis by American and European pathologists, who reported another histopathological pattern, named idiopathic duct-centric pancreatitis (IDCP) or AIP with GEL [1113]. The most characteristic feature of type 2 AIP is the GEL, often with destruction and obliteration of the pancreatic duct. Type 2 AIP has swelling of the pancreas, but none or very few IgG4-positive plasma cells, and clinical features show a distinctly different profile from that of type 1 AIP, with no associated serum IgG4, IgG elevation, presence of autoantibodies, or other organ involvement, except for inflammatory bowel disease (approximately 30%).

The concept of IgG4-related disease and proposal of the clinical diagnostic criteria

Patients with IgG4-related disease show diffuse/focal organ enlargement, with mass-forming or nodular/thickened lesions in various organs, occurring synchronously or metachronously, due to the prominent infiltration of lymphocytes and plasmacytes with fibrosis [2141]; however, the causes of the disease are still not clear. The organs known to be affected include the pancreas, biliary duct, lacrimal/salivary glands, retroperitoneum, central nervous system, thyroid gland, lungs, liver, gastrointestinal tract, kidneys, prostate gland, and lymph nodes [2141]. Clinical symptoms vary depending on the organ in which the lesions are located, but many cases are treated effectively by steroid therapy [2141]. The prognosis is not clear; however, some patients develop serious complications such as obstructive jaundice due to hepatic, gallbladder, or pancreatic lesions; hydronephrosis due to retroperitoneal fibrosis; or respiratory symptoms due to “pulmonary lesions” [1719, 2629]. Although the infiltration of IgG4-positive cells and increased serum levels of IgG4 are characteristic of IgG4-related disease, the severity of fibrosis seems to be different among the individual involved organs. These conditions are quite similar to multifocal idiopathic fibrosclerosis (MIF) [9].

In addition to MIF, there are many synonyms, such as IgG4-related autoimmune disease [8], “IgG4-related sclerosing disease” [17], SIPS [18], and “IgG4 + MOLPS” [19], all of which may refer to the same conditions. It has been debated which term is the most appropriate. Storiform fibrosis and obliterative phlebitis are characteristic in the pancreatic and biliary tract lesions, but the degree varies depending on the individual organs, e.g., these features are very seldom found in lachrymal/salivary gland lesions or lymph node lesions. The term “IgG4-related sclerosing disease” is mainly based on fibrous swollen organs, whereas the terms “IgG4-SIPS” and “IgG4 + MOLPS” are based on lymphoplasmacytic proliferation and swollen lymph nodes without fibrosis.

Although most patients with type 1 AIP have multiorgan lesions that occur synchronously or metachronously, about 10–20% of the patients show a solitary organ involved without confirmation of other organ involvement. Therefore, it is unclear whether or not the pathogenetic mechanism is the same in individual organs. Based on these findings, the members of the Japanese Research Committees for “Systemic IgG4-Related Sclerosing Disease” (chaired by Professor K. Okazaki) [40] and “IgG4-MOLPS” (chaired by Professor H. Umehara) [41], both of which Committees were supported by the “Research for Intractable Disease Program from the Ministry of Health, Labor and Welfare of Japan”, have agreed that the term “IgG4-related disease” be regarded as minimally accepting these conditions at present. To study these conditions, the Japanese Research Committee for “Systemic IgG4-Related Sclerosing Disease” (chaired by Professor K. Okazaki) proposed a disease concept and clinical diagnostic criteria of “systemic IgG4-related sclerosing disease” in 2009 (Table 5) [40]. However, the concept and diagnostic criteria should be changed in accordance with the findings of the future studies.
Table 5

Clinical diagnostic criteria 2009 for IgG4-related disease (proposed by the Japanese Research Committee for “Systemic IgG4-related Sclerosing Disease”) [40]

(1) Clinically, diffuse/focal enlargement, or mass-forming, nodular/thickened lesions in one or more organs

(2) Elevated levels of serum IgG4 (>135 mg/dl)

(3) Histopathological findings

 ① Prominent infiltration of lymphocytes and plasmacytes with fibrosis, but no neutrophilic infiltration

 ② Abundant infiltration of IgG4-positive plasmacytes (>10/hpf) and/or a ratio of IgG4/IgG-positive cells of >40%

 ③ Storiform/swirling fibrosis

 ④ Obliterative phlebitis

Diagnosis of IgG4-related disease: (1) + (2), (1) + (3)①②, (2) + (3)①②, or (3)①②③④

The following cases must be excluded from the diagnosis: malignant tumors developed in organs (e.g., cancers, malignant lymphomas) or similar diseases (e.g., Sjögren’s syndrome, primary sclerosing cholangitis), bronchial asthma, and Castleman’s disease

Immunological approaches to the pathophysiology of AIP and IgG4-related disease

The pathogenesis and pathophysiology of AIP have been studied mainly from immunological approaches and studies have focused mainly on IgG4-related type 1 AIP, because little evidence of abnormal immunity has been reported in type 2 AIP.

Humoral immunity

IgG4 and its possible role in IgG4-related diseases

In healthy subjects, IgG1 usually accounts for most of the total IgG [42]. Generally, the amount of IgG4 does not vary with sex or age, and the quantity of IgG4 as well as the IgG4/total IgG ratio tends to remain constant [42]. The ratios for each IgG subclass are 65% of IgG1, 25% of IgG2, 6% of IgG3, and 4% of IgG4 [42]. In IgG4-related diseases, total IgG, IgG1, IgG2, IgG4, and IgE ratios are usually increased compared with healthy subjects, while IgM, IgA, and the ratios of IgG to IgM or IgA, are decreased compared with findings in healthy subjects or those with other diseases [3, 15, 19, 43]. Ratios of IgG subclasses other than IgG4 are somewhat different among individual diseases; in AIP, all subclasses (IgG1-G4) of IgG are increased compared with findings in other types of pancreatitis. In contrast, IgG1 and IgG3 in MD show significantly lower negative correlations with IgG4 than those shown in typical Sjögren’s syndrome.

Although the association of IgE-mediated allergy and IgG4 antibodies is well known [44], IgG4 characteristics are still poorly understood. Basically, IgG4 has non-active characteristics for immune responses involved in a continuous process referred to as ‘Fab-arm exchange’, which occurs by the swapping of a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule [45], which usually results in asymmetric antibodies with two different antigen-combining sites. While these modified antibodies are hetero-bivalent, they behave as monovalent antibodies [45]. Another aspect of IgG4 mimics IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support [46]. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains, but is inefficient in activating potentially dangerous effector systems due to its low affinity for C1q and the classical Fcγ-receptors.

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 [47]. IgG4 Fc–Fc binding may have a pathological role within the inflammatory process, or may even induce inflammation through the aggregation of immunoglobulins, as occurs in a mouse lupus model [48]. Although some earlier reports of AIP suggested the presence of autoantibodies against the systemically distributed antigens described above, it remains unclear whether or not IgG4-type autoantibodies have a direct role in the pathogenesis of IgG4-related diseases. To date, there have been few reports indicating IgG4 deposition in IgG4-related renal diseases [15, 29]. Therefore, in some IgG4-related diseases, the infiltration of IgG4 + plasma cells might have an association with pathological roles, similar to those in pemphigoid diseases, through IgG4 Fc–IgG Fc binding.

On the other hand, although IgG4 is associated with several clinical conditions, it is generally considered to be a benign, non-pathogenic antibody [49]. Some of these associations suggest a protective effect, such as in allergen-specific immunotherapy, tolerance induction after food avoidance [50], and protection from allergic effects during parasitosis [51, 52]. Recent data on the regulation of IgG4 showed that IgG4-related diseases may reflect an excessive production of anti-inflammatory cytokines such as interleukin (IL)-10, triggering an overwhelming expansion of IgG4-producing plasma cells. In AIP, increased peripheral inducible-memory regulatory T cells (Tregs) are positively correlated with serum levels of IgG4 [53]. In addition, prominent infiltration of Tregs upregulated IL-10 in the livers of patients with IgG4-related sclerosing cholangitis [54]. These findings suggest that IgG4 or IgG4-immune complexes do not act as a pathogenetic factor, but act as an anti-inflammatory factor in IgG4-related diseases [46]. Further studies are necessary to clarify the role of IgG4 in IgG4-related diseases.

The complement system

Patients in active stages of AIP occasionally show decreased complement (C3, C4) with elevated circulating immune complex as well as elevated serum levels of IgG4 and the IgG4 subclass of immune complexes [3, 55]. However, a recent 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 [56]. Moreover, IgG4 is bound to other isotypes such as IgG1, 2, and 3 with an Fc–Fc interaction immune complex in patients with AIP [46], and thus IgG4 may contribute to the clearance of immune complexes or termination of the inflammatory process by preventing the formation of large immune complexes by blocking the Fc-mediated effector functions of IgG1. Compared with findings in systemic lupus erythematosus (SLE), TIN is more often observed in the renal lesions of IgG4-related disease. But, in acute TIN associated with AIP, the deposition of immune complex (IgG and C3) was observed in the glomerular basement membrane but not in the tubular basement membrane, which suggests that membranous glomerulonephritis is also associated with severe TIN associated with IgG4-related disease [15, 29]. Recently, the deposition of C3 and IgG in the basement membrane of pancreatic ducts have been identified in both type 1 and 2 AIP [21].

Autoantibodies

Patients with IgG4-related diseases generally show several autoantibodies in addition to increased IgG and IgG4 [4, 5]. Although some patients with IgG4-related disease have non-specific antibodies such as anti-nuclear antibody (ANA), the association of IgG4-related disease and well-known autoimmune diseases such as Sjögren’s syndrome and SLE is rare. From the viewpoint of IgG4 function, the big mystery is whether IgG4-related disease is an autoimmune or an allergic disease. However, the occasional coexistence of other organ involvement leads us to the concept that there may be common target antigens in the involved organs such as the pancreas, salivary glands, biliary tract, lungs, and renal tubules. Although disease-specific antibodies have not been identified at present, several disease-related antibodies such as anti-lactoferrin (LF) [57, 58], anti-carbonic anhydrase (CA)-II [5760], anti-CA-IV [61], anti-pancreatic secretory trypsin inhibitor (PSTI) [62], anti-amylase-alpha [63], anti-heat-shock protein (HSP)-10 [64], and anti-plasminogen-binding protein (PBP) peptide autoantibodies [65] have been reported. Although the patients show increased serum levels of IgG4, the major subclass of these autoantibodies is not necessarily IgG4, but is often IgG1 [62]. CA-II [59], CA-IV [61], LF [58], and PSTI [62] are distributed in the ductal cells of several exocrine organs, including the pancreas, salivary glands, biliary duct, lungs, and renal tubules. Although not all peptides have been studied, immunization with CA-II or LF induced systemic lesions such as pancreatitis, sialadenitis, cholangitis, and interstitial nephritis in mouse models similar to human IgG4-related diseases [66, 67]. The high prevalence of the above antibodies suggests that they may be candidates for the target antigens in AIP [58].

Molecular mimicry among microbes and target antigens may be a possible mechanism for breaking down immune tolerance. This hypothesis is based on the concept that infectious agents share one or more epitopes with self-components, or infectious agents cause bystander activation of immune cells with autoaggressive potential [6870]. Guarneri and colleagues showed significant homology between human CA-II and alpha-CA of Helicobacter pylori, a fundamental enzyme for bacterial survival and proliferation in the stomach [70]. Moreover, the homologous segments contained the binding motif of DRB1*0405 [71], which confers a risk for AIP development [70]. The PBP peptide newly identified in European patients with AIP shows homology with an amino acid sequence of PBP of H. pylori and with the ubiquitin-protein ligase E3 component n-recognin 2 (UBR2), an enzyme highly expressed in acinar cells of the pancreas, while European patients with AIP did not necessarily show LPSP as the typical histopathology of type 1 AIP in IgG4-related diseases [65]. These findings suggest that gastric H. pylori infection might trigger AIP in genetically predisposed subjects [6870].

Diabetes mellitus (DM) complications exist in 43–68% of AIP patients, but autoantibodies against glutamic acid decarboxylase, beta-cell, or tyrosine phosphatase-like protein [67] associated with type 1A DM are rarely observed. These findings suggest that islet cells may not be targeted in the development of DM associated with AIP.

No disease-specific autoantibodies have been identified in IgG4-related disease. The rare association of IgG4-related disease and well-known autoimmune diseases such as Sjögren’s syndrome and SLE must be discussed.

Cellular immunity

Th1 and Th2 immune balance

The effector cells in IgG4-related diseases have been poorly understood. The presence of autoantibodies, the predominant infiltration of CD4+ and CD8+ T cells, and the expression of HLA-DR antigens in the pancreas [57] suggest that, as well as the infiltration of plasmacytes and B cells, an immunological mechanism may be involved in the development of AIP. CD4+ T cells differentiate from naïve T cells (Th0) to Th1, Th2, Th17, and Treg cells [72]. IL-12 induces Thl cells, which produce IL-2, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, and mediate cellular immunity, macrophage activation, and cytotoxicity, as well as helping B-cell production of opsonizing and complement fixing antibodies [4]. IL-4 induces Th2 cells, which produce IL-4, IL-5, IL-6, and IL-10, promoting humoral and allergic responses [4]. Transforming growth factor (TGF)-beta, IL-6, IL-21, and IL-23 induce Th17 cells, which secrete IL-17, and may be involved in inflammation in mice [73].

In some patients with AIP, Th1 cells are predominant over Th2 type cells in the periphery [58, 74]. On the other hand, a Th2-type immune reaction, as well as the Th1 responses, is induced in the livers of patients with IgG4-related sclerosing cholangitis [54]. This discrepancy may be explained by the shift of Th2 cells from the periphery to local tissues, or by different disease stages. Mouse models with depletion of Tregs induced by neonatal thymectomy (nTx) support the hypothesis that Th1 cells act mainly as effectors in the initial early stage [75]. In Sjögren’s syndrome [76] and PSC [77], the major infiltrating cells in the tissue are CD4+HLA-DR+Th1 cells, although CD8+ and B cells are also present. Similar to Sjögren’s syndrome, Th1 cytokines may be essential in the induction of AIP, while Th2 cytokines may be involved in the progression of the disease process, especially the maturation and proliferation of local B cells and plasmacytes [4].

Regulatory T cells

From naïve Th0 cells, TGF-beta can induce CD4+CD25+ Tregs, which have a potent inhibitory function, via the transcription factor Foxp3, to show CD4+ T cell-mediated immune responses such as Th1, Th2, and Th17 [73]. 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 Tregs. This suppressive function is mediated by TGF-beta and IL-10, and/or cell-to-cell contact via ligation of cytotoxic T lymphocyte antigen-4 (CTLA-4). Recent studies have clarified several subtypes of Tregs [78]. Tregs originating in the thymus are naturally occurring CD4+CD25+ Tregs (nTregs), which are different from adaptive Tregs (aTregs) induced in the periphery by different antigens [78]. As Tregs expressing Foxp3 are critical in the transfer of immune tolerance, Treg deficiency has been shown to induce various autoimmune diseases in animal experimental models [73]. However, in humans, an increased prevalence of circulating CD4+CD25+ T cells or a similar level of peripheral CD4+CD25+ T cells was observed in patients with rheumatoid arthritis, Sjögren’s syndrome, and inflammatory bowel disease, compared with healthy controls [79]. Therefore, the evidence of decreased circulating Tregs as shown in the animal studies may not be a general finding in human autoimmune diseases. In IgG4-related diseases, the role of Tregs remains unclear. In AIP, in addition to increased soluble CTLA4, circulatory naïve (CD45RA+) Tregs are significantly decreased in the peripheral blood of patients with AIP, whereas the major population of memory (CD45RA−)-Tregs is significantly increased [53]. In addition, prominent infiltration of Tregs with upregulation of IL-10 is observed in the livers of patients with IgG4-related sclerosing cholangitis [58]. These findings suggest that increased memory-Tregs in the periphery and local tissues may be inhibitory immune responses against inflammation in patients with AIP, although decreased naïve Tregs may be pathogenetic.

Our hypothesis for the pathogenesis of AIP as IgG4-related disease

In nTx-BALB/c mouse models immunized with CA-II or LF, CD4+ T cells, rather than B cells, are the predominant infiltrates in pancreatitis, sialoadenitis, and cholangitis, which is similar to human AIP [75]. These findings suggest that the depletion of naïve Tregs in the periphery [80] and major histocompatibility complex (MHC)-class II restricted-autoreactive CD4+ T cells that escape from positive selection in the thymus, may play important roles in the induction of systemic organ lesions. These CD4+ T cells probably induce macrophage activation and further proinflammatory reactions during the early stage of AIP as direct cytotoxic effects through Fas ligand expression [81]. On the other hand, CD8+ T cells may play roles as effector cells in the MHC class II-deficient mouse [82] and in WBN/Kob rat models [83]. WBN/Kob rats with congenitally decreased peripheral Tregs spontaneously develop sialadenitis, thyroiditis, sclerotic cholangitis, and TIN. Although the target antigens remain unclear, CD8+ cells also seem to be effectors. Although rodents lack the IgG4 subclass, deposits of tissue-specific IgG2b, in electrophoretic position similar to human IgG4, were observed in the injured pancreas and lachrymal glands in WBN/Kob rats [83]. These animal models suggest that although CD8+ T cells may be partially involved, CD4+ T cells play major roles in the development of experimental systemic lesions, which are similar to the lesions in human IgG4-related diseases [4, 58], although the counterpart of IgG4 in mouse IgG subclasses has not been identified. As TGF-beta is an important regulatory factor in maintaining immune homeostasis [84], TGF-beta-dominant negative mutant mice suggest that the loss of TGF-beta signaling may contribute to AIP [85].

From the above findings, we propose a hypothesis for the pathogenesis of AIP (Fig. 1). The basic concept is a biphasic mechanism of “induction” and “progression.” An initial response to self-antigens (e.g., LF, CA-II, CA-IV, PSTI, amylase-alpha, and PBP peptide of H. pylori) might be induced by decreased naïve Tregs, followed by a Th1-type immune response with the release of proinflammatory cytokines (IFN-gamma, IL-1-beta, IL-2, TNF-alpha). Then Th2-type immune responses producing IgG, IgG4, and autoantibodies may be involved in the pathophysiology of progression. IgG4 and fibrosis may be regulated by increased IL-10 and TGF-beta, respectively, secreted from inducible memoryTregs. The classical pathway of the complement system may be activated by the IgG1 immune complex.
https://static-content.springer.com/image/art%3A10.1007%2Fs00535-011-0386-x/MediaObjects/535_2011_386_Fig1_HTML.gif
Fig. 1

Hypothesis for the pathogenesis of autoimmune pancreatitis (AIP) in IgG4-related disease. In regard to central tolerance, naïve and natural regulatory T cells (Tregs) derived from the thymus suppress autoreactive CD4 or CD8 cells in the normal state. In IgG4-related disease, the basic concept is a biphasic mechanism of “induction” and “progression”. Initial response to self-antigens (e.g., lactoferrin [LF], carbonic anhydrase II [CA-II], CA-IV, pancreatic secretory trypsin inhibitor [PSTI], amylase-alpha, and plasminogen-binding protein [PBP] peptide of Helicobacter pylori) might be induced by decreased naïve Tregs. Th2 immune responses are followed by a Th1-type immune response with the release of proinflammatory cytokines (interferon-γ [IFN-γ], interleukin [IL]-1beta, IL-2, tumor necrosis factor-α [TNF-α]). Th2-type immune responses, producing IgG, IgG4, and autoantibodies may be involved in the pathophysiology of progression. IgG4 and fibrosis may be regulated by increased IL-10 and transforming growth factor-β (TGF-β), respectively, secreted from inducible memory Tregs. DC ductal cell, iTreg inducible Treg, TE effector T cell, nTreg natural Treg

Conclusion

In conclusion, recent advances support the concept of IgG4-related disease, a unique clinical entity, as a systemic disease. As Tregs seem to play important roles in the progression as well as the induction of the disease, further studies are necessary to clarify the pathogenesis, including studies of genetic backgrounds, disease-specific antigens, and the role of IgG4.

Acknowledgments

This study was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Culture and Science of Japan (20590810), and a Grant-in-Aid for the “Research for Intractable Disease” Program from the Ministry of Health, Labor and Welfare of Japan.

Copyright information

© Springer 2011