Kazushige Uchida

Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012

BackgroundIgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4-SC are similar to those of the above progressive or malignant diseases.MethodsThe Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012.ResultsThe diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC.ConclusionThese diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists.

Circulating naïve and CD4+CD25high regulatory T cells in patients with autoimmune pancreatitis.

Objective: Autoimmune pancreatitis (AIP) is a new clinical entity of pancreatic disorder. There are several immunologic and histological abnormalities specific for the disease, including increased levels of serum IgG4 and infiltration of lymphocytes and IgG4-positive plasmacytes. The role of IgG4 is unclear. Recently, regulatory T cells (Tregs) have been reported to be involved in the development of various autoimmune diseases as well as B cell shifting to IgG4-producing plasmacytes. To clarify the role of Tregs in the pathophysiology of AIP, we analyzed circulating Tregs in AIP. Methods: We recruited 27 patients with AIP for this study. For comparison, we also recruited 23 patients with other pancreatic disease and 32 healthy subjects as controls. We analyzed Tregs as CD4+CD25high and CD4+CD25+CD45RA+ (naïve) from peripheral blood by flow cytometry. Results: In peripheral blood, CD4+CD25high Tregs were significantly increased in AIP patients (3.01% ± 1.77%) compared with alcoholic chronic pancreatitis (CP) (1.65% ± 0.58%), idiopathic CP (1.53% ± 0.56%), and healthy control (1.72% ± 0.81%, P < 0.05). Naïve Tregs significantly decreased in AIP (0.32% ± 0.22%) compared with healthy control (0.83% ± 0.65%) and CP group (alcoholic and idiopathic CP; 0.52% ± 0.40%, P < 0.05). In untreated AIP patients, the number of CD4+CD25high Tregs and IgG4 are correlated (R = 0.53, P < 0.05). Conclusions: Increased numbers of CD4+CD25 high Tregs may influence IgG4 production in AIP, whereas decreased numbers of naïve Tregs may be involved in the pathogenesis of AIP.

Recent advances in autoimmune pancreatitis: concept, diagnosis, and pathogenesis

Recent advances support the concept of autoimmune pancreatitis (AIP) as a unique systemic disease, because it shows occasional extrapancreatic lesions such as sclerosing cholangitis, sclerosing sialoadenitis, and retroperitoneal fibrosis, pathological features similar to those of fibrosis, and abundant infiltration of IgG4-positive plasma cells, and it is steroid responsive. Based on these findings, several diagnostic criteria have been proposed. Although AIP is accepted worldwide as a unique clinical entity, its pathogenetic mechanism remains unclear. To clarify its pathogenesis, its genetic background, humoral immunity, candidate target antigens including self-antigens and molecular mimicry by microbes, and cellular immunity including regulatory T cells, the complement system, and experimental models are reviewed. On the basis of this review, we hypothesize that the pathogenesis of AIP involves a biphasic mechanism consisting of “induction” and “progression.” In the early stage, the initial response to self-antigens [lactoferrin, carbonic anhydrase (CA)-II, CA-IV, pancreatic secretory trypsin inhibitor, and α-fodrin] and molecular mimicry (Helicobacter pylori) are induced by decreased naïve regulatory T cells (Tregs), and T-helper (Th) 1 cells release proinflammatory cytokines [interferon-γ, interleukin (IL)-1β, IL-2, and tumor necrosis factor α]. In the chronic stage, progression is supported by increased memory Tregs and Th2 immune responses. The classical complement system pathway may be activated by the IgG1 immune complex. As Tregs seem to play an important role in progression as well as in induction of the disease, further studies are necessary to clarify the pathogenesis of AIP.

Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study

Background Characteristic pancreatic duct changes on endoscopic retrograde pancreatography (ERP) have been described in autoimmune pancreatitis (AIP). The performance characteristics of ERP to diagnose AIP were determined. Methods The study was done in two phases. In phase I, 21 physicians from four centres in Asia, Europe and the USA, unaware of the clinical data or diagnoses, reviewed 40 preselected ERPs of patients with AIP (n=20), chronic pancreatitis (n=10) and pancreatic cancer (n=10). Physicians noted the presence or absence of key pancreatographic features and ranked the diagnostic possibilities. For phase II, a teaching module was created based on features found most useful in the diagnosis of AIP by the four best performing physicians in phase I. After a washout period of 3 months, all physicians reviewed the teaching module and reanalysed the same set of ERPs, unaware of their performance in phase I. Results In phase I the sensitivity, specificity and interobserver agreement of ERP alone to diagnose AIP were 44, 92 and 0.23, respectively. The four key features of AIP identified in phase I were (i) long (>1/3 the length of the pancreatic duct) stricture; (ii) lack of upstream dilatation from the stricture (<5 mm); (iii) multiple strictures; and (iv) side branches arising from a strictured segment. In phase II the sensitivity (71%) of ERP significantly improved (p<0.05) without a significant decline in specificity (83%) (p>0.05); the interobserver agreement was fair (0.40). Conclusions The ability to diagnose AIP based on ERP features alone is limited but can be improved with knowledge of some key features.

Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis.

OBJECTIVE IgG4-related disease is a recently recognized entity affecting multiple organs, including the pancreas, biliary tracts, and salivary glands. Although IgG4-related disease is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells, the innate immune responses leading to adaptive IgG4 antibody responses are poorly understood. The aim of this study was to clarify the innate immune responses leading to IgG4 antibody production. METHODS IgG4 and cytokine responses to various nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) and Toll-like receptor (TLR) ligands were examined using peripheral blood mononuclear cells (PBMCs) from healthy control subjects and patients with IgG4-related autoimmune pancreatitis. RESULTS Activation of NOD-2 in monocytes from healthy control subjects induced IgG4 production by B cells in a BAFF-dependent and T cell-independent manner. In addition, PBMCs from patients with IgG4-related disease produced a large amount of IgG4 upon stimulation with NLR and TLR ligands; this enhanced IgG4 production was associated with the induction of BAFF by NLR and TLR ligands. Monocytes from patients with IgG4-related disease induced IgG4 production by B cells from healthy control subjects upon stimulation with NLR and TLR ligands. CONCLUSION The results of these studies suggest that abnormal innate immune responses against microbial antigens may underlie the immunopathogenesis of IgG4-related disease.

How to diagnose autoimmune pancreatitis by the revised Japanese clinical criteria.

When diagnosing autoimmune pancreatitis (AIP), it is most important to differentiate it from neoplastic lesions such as pancreatic or biliary cancers. The revised diagnostic criteria are based on the minimum consensus of AIP in order to avoid misdiagnosing pancreas or biliary cancer as far as possible, but not for screening AIP. Therefore, it is recommended that facile therapeutic diagnosis by steroidal administration should be avoided. These criteria contain three approaches: pancreatic imaging, laboratory data, and histopathology. (i) Pancreatic image examinations show the narrowing of the main pancreatic duct and enlargement of the pancreas, which are characteristic of the disease. (ii) Laboratory data show the presence of autoantibodies or elevated levels of serum gammaglobulin, IgG, or IgG4. (iii) Histopathologial examinations of the pancreas show fibrosis and pronounced infiltration of cells, mainly lymphocytes and plasmacytes, which is called lymphoplasmacytic sclerosing cholangitis (LPSP). For a diagnosis of AIP, criterion (i) must be present, together with criterion (ii) and/or (iii). However, it is necessary to exclude malignant diseases such as pancreatic or biliary cancers.

Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases

ObjectivesPatients with autoimmune pancreatitis (AIP) characteristically show elevated serum levels of immunoglobulin G4 (IgG4) and abundant infiltration of IgG4-positive plasmacytes in the involved organs. The most common involved organ showing extrapancreatic lesions is the bile duct, which exhibits sclerosing cholangitis (SC). However, the role of IgG4 in the development of IgG4-related SC (IgG4-SC) remains unclear. To clarify the role of IgG4 in IgG4-SC, we have performed an immunohistochemical analysis of the bile duct.MethodsLaboratory and immunohistochemical findings of liver biopsy specimens obtained from patients with IgG4-SC, primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and primary biliary cirrhosis (PBC) were compared. The biopsy specimens were first stained with anti-IgG1, anti-IgG4, and anti-Foxp3 (forkhead box P3) antibodies, and the ratio of IgG4-, IgG1-, and Foxp3-positive cells, respectively, to infiltrated mononuclear cells (IgG4/Mono, IgG1/Mono, Foxp3/Mono) was assessed.ResultsThe ratio of IgG4/IgG1-positive plasma cells was significantly higher in specimens obtained from patients with IgG4-SC than in those from patients with PSC, AIH, and PBC. The Foxp3/Mono ratio in patients with PBC was significantly higher than that in patients with IgG4-SC and PSC. In patients with IgG4-SC, the number of Foxp3-positive cells was significantly correlated with the number of IgG4-positive cells; in the other patient groups, there was no correlation.ConclusionsThe IgG4/IgG1 ratio in the liver may be a useful marker for differential diagnosis of IgG4-SC and PSC. In IgG4-SC, abundant infiltration of regulatory T cells (Tregs) may affect the switching of B cells to IgG4-producing plasmacytes, and there is a possibility that the function of Tregs is different in IgG4-SC and other liver diseases (PSC, AIH, and PBC).

Prevalence of IgG4-Related Disease in Japan Based on Nationwide Survey in 2009

The number of patients with autoimmune pancreatitis who visited hospitals in Japan in 2007 was approximately 2709 (95% confidence interval; range 2540–3040). Because IgG4-related disease is a new clinical entity, there are no data with regard to its prevalence. To estimate the number of patients with IgG4-related disease in Japan, we randomly selected hospitals using stratification and asked them how many patients they had with IgG4-related disease in 2009. The number of patients with Mikuliczs disease, IgG4-related retroperitoneal fibrosis, IgG4-related renal disease, IgG4-related pulmonary disease, and IgG4-related lymphadenopathy who visited hospitals in Japan in 2009 was approximately 4304 (95% confidence interval; range 3360–5048), 272 (95% confidence interval; range 264–306), 57 (95% confidence interval; range 47–66), 354 (95% confidence interval; range 283–424), and 203 (95% confidence interval; range 187–240), respectively. The total number of patients with IgG4-related disease without autoimmune pancreatitis in Japan was approximately 5190 (95% confidence interval; range 4141–6084). The male : female ratio was 1 : 0.77, and the average of age of disease onset was 58.8 years. The total number of patients with IgG4-related disease in Japan in 2009, including autoimmune pancreatitis, was approximately 8000.

Recent Concepts of Autoimmune Pancreatitis and IgG4-Related Disease

Recent studies suggested the existence of two subtypes of autoimmune pancreatitis (AIP): type 1 related with IgG4 (lymphoplasmacytic sclerosing pancreatitis; LPSP) and type 2 related with a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis; IDCP). Apart from type 2 AIP, the pathological features of type 1 AIP with increased serum IgG4/IgE levels, abundant infiltration of IgG4+ plasmacytes and lymphocytes, fibrosis, and steroid responsiveness are suggestive of abnormal immunity such as allergy or autoimmunity. Moreover, the patients with type 1 AIP often have extrapancreatic lesions such as sclerosing cholangitis, sclerosing sialadenitis, or retroperitoneal fibrosis showing similar pathological features. Based on these findings, many synonyms have been proposed for these conditions, such as “multifocal idiopathic fibrosclerosis”, “IgG4-related autoimmune disease”, “IgG4-related sclerosing disease”, “IgG4-related plasmacytic disease”, 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 fibrosclerosis in 2009, in which the term “IgG4-related disease” was appointed as a minimal consensus on 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 disease. The concept and diagnostic criteria of “IgG4-related disease” will be changed in accordance with future studies.

Toll-like receptor activation in basophils contributes to the development of IgG4-related disease

BackgroundIgG4-related disease (IRD) is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells into the affected organs. Although T helper type 2 (Th2) cytokines are implicated in enhanced IgG4 responses, molecular mechanisms accounting for the development of IgG4 antibody responses are poorly defined. Since basophils function as antigen-presenting cells for Th2 responses, we tried to clarify the role of basophils in the development of IgG4 responses in this study.MethodsIgG4 and cytokine responses to various nucleotide-binding oligomerization domain-like receptor and Toll-like receptor (TLR) ligands were examined by using basophils isolated from healthy controls and from patients with IgG4-related disease.ResultsActivation of TLRs in basophils from healthy controls induced IgG4 production by B cells, which effect was associated with enhanced production of B cell activating factor (BAFF) and IL-13. In addition, activation of TLRs in basophils from patients with IRD induced a large amount of IgG4 by B cells from healthy controls. This enhancement of IgG4 production was again associated with BAFF and IL-13.ConclusionsThese data suggest that innate immune responses mediated through TLRs may play a role in the development of IgG4-related disease, in part by production of BAFF from basophils.