Immunohistochemical study of autoimmune pancreatitis using anti-IgG4 antibody and patients' sera

AIMS: Autoimmune pancreatitis (AIP), characterized by raised serum IgG4 levels, is frequently complicated by disorders of extrapancreatic organs. The aim of the present study was to examine immunohistochemically which extrapancreatic organs are affected, and whether an autoantibody to such organs is present in the serum of AIP patients. METHODS: Various tissues/organs obtained from AIP patients were studied immunohistochemically with an anti-IgG4 antibody. To examine the presence of an autoantibody in the serum of AIP patients, sera were incubated with various normal organs/tissues extracted for other diseases, followed by detection with an anti-IgG4 antibody. Sera were also examined before and after glucocorticoid therapy. RESULTS: Marked infiltration of IgG4+ plasma cells was observed in the pancreas, liver, bile duct and salivary gland of many of the AIP patients examined. The normal epithelia of the pancreatic ducts, bile ducts, gallbladder and salivary gland ducts reacting with the patients' sera were detectable by the anti-IgG4 antibody. Following glucocorticoid therapy the IgG4 antibody from the patients' sera showed decreased reactivity with these tissues. CONCLUSIONS: AIP may also affect extrapancreatic organs, the serum of AIP patients may contain an IgG4 autoantibody to various organs and glucocorticoid therapy may improve such disorders.     

Biliary tumors with pancreatic counterparts

Some biliary diseases mimic pancreatic diseases pathologically as well as pathogenetically. Such diseases can be called “biliary diseases with pancreatic counterparts”. Biliary intraepithelial neoplasm (BilIN), intraductal papillary neoplasm of bile ducts (IPNB), hepatobiliary mucinous cystic neoplasm (hMCN), and IgG4-inflammatory pseudotumor represent the biliary counterparts of pancreatic intraepithelial neoplasm (PanIN), intraductal papillary mucinous neoplasm of pancreas (IPMN), pancreatic MCN, and mass forming type 1 autoimmune pancreatitis (AIP), respectively. BilIN and PanIN represent pre-invasive intraepithelial stages of nodular sclerosing cholangiocarcinoma and pancreatic ductal adenocarcinoma, respectively. IPNB and IPMN are grossly visible, predominant papillary, intraductal neoplasms that may progress to invasive carcinoma. Morphologically similar MCNs with subepithelial ovarian-like stroma occur in both the hepatobiliary system as well as the pancreas. IgG4-inflammatory pseudotumor, usually of the lymphoplasmacytic type, and mass forming type 1 AIP represent IgG4-related disease in the biliary tree and pancreas respectively. The biliary tract, which is associated with the peribiliary glands, including the pancreatic acini, can be regarded as an incomplete pancreas, so several diseases mimicking pancreatic diseases may be expected to occur in the biliary tract (biliary diseases with pancreatic counterparts).     

Distinct clinicopathological entity 'autoimmune pancreatitis-associated sclerosing cholangitis'

Autoimmune pancreatitis (AIP) is a recently proposed disease entity, in which an elevated serum IgG4 is characteristic. This disease is sometimes associated with other inflammatory diseases: Sjögren's disease, or sclerosing cholangitis. The aim of the present paper was to examine the difference in pathophysiology between AIP‐associated sclerosing cholangitis (AIP‐SC) and primary sclerosing cholangitis (PSC). The clinicopathological findings and the immunohistochemical expressions of IgG subclasses (IgG1, IgG2, IgG3, and IgG4) were evaluated for the two aforementioned diseases (six patients with each disease). Radiologically, the extrahepatic bile duct was involved in AIP‐SC, whereas both extrahepatic and intrahepatic bile ducts were involved in PSC. Clinically, bile duct lesions in the former responded well to steroid therapy. Histologically, various degrees of mononuclear cell infiltration and fibrosis around bile ducts and portal tracts were found in all patients. Immunohistochemically, the IgG4‐positive plasma cell/mononuclear cell ratio was significantly higher in AIP‐SC than in PSC (P < 0.05). The IgG4‐positive plasma cell/mononuclear cell ratio is a useful index to help distinguish AIP‐SC from PSC. A mechanism similar to that involved in AIP may be involved in AIP‐SC. The latter is a distinct clinicopathological entity that should be distinguished from PSC because it responds well to steroid therapy.     

Comparison of histopathological features of pancreatic carcinoma and type 1 autoimmune pancreatitis

Type 1 autoimmune pancreatitis (AIP‐1) is an immunoglobulin G (IgG)‐4‐related disease (IgG4‐RD), characterized by elevated serum immunoglobulin G4 (IgG4) and infiltration by IgG4⁺ plasma cells. Pancreatic carcinoma (PC) sometimes shows infiltration by IgG4⁺ plasma cells, but details have been unclear. We compared pathological findings and expression of IgG4 and IgG in fibroses in 18 PC patients to those from 9 AIP‐1 patients. Fibroses were divided into areas of ductal adenocarcinoma (DA) and obstructive pancreatitis (OP). Serum IgG4 levels were lower than the cut‐off value in all PC patients with no IgG4‐RD. Diffuse lymphoplasmacytic infiltration and eosinophil infiltration were characteristic of fibroses in PC. Though AIP‐1 samples often had storiform fibrosis even in biopsies, PC did not show storiform fibrosis. Ratios of IgG4⁺ plasma cells/IgG⁺ plasma cells (IgG4/IgG ratios) in DA and OP were significantly lower than in AIP‐1. However, high‐density IgG4⁺ plasma cell foci were detected in PC fibroses, particularly around peripheral nerves, vessels, and lymphoid follicles; between lobules and invasion fronts; and within neutrophilic abscesses. In conclusion, the IgG4/IgG ratio is useful in distinguishing PC from AIP‐1, and should be evaluated in three or more areas, as PC can show localized high‐density IgG4⁺ plasma cell areas.     

Follicular cholangitis and pancreatitis - clinicopathological features and differential diagnosis of an under-recognized entity

Zen Y, Ishikawa A, Ogiso S, Heaton N & Portmann B
(2012) Histopathology  60, 261–269
Follicular cholangitis and pancreatitis – clinicopathological features and differential diagnosis of an under‐recognized entity Aims: Biliary and pancreatic ductal systems can be involved in several lymphoplasmacytic inflammatory conditions, including primary sclerosing cholangitis, immunoglobulin G (IgG) 4‐related cholangitis and autoimmune pancreatitis. Here in we describe an unusual pancreatocholangitis whose features suggest a distinct disease entity. Methods and results: The study group consists of five adult patients, three with predominantly hilar bile duct stricture and two with a bulky pancreatic head. Four patients were treated surgically for suspected malignancy and one patient underwent liver transplantation with a clinical diagnosis of primary sclerosing cholangitis. Histological examination revealed extensive lymphoplasmacytic inflammation centred on large biliary or pancreatic ducts. Many lymphoid follicles with germinal centres were noted around the affected ducts. Whipple specimens from two patients with a pancreatic head mass showed similar follicular inflammation histologically around bile ducts. In contrast to autoimmune pancreatitis, diffuse infiltration of IgG4⁺ plasma cells, granulocytic epithelial lesions and obliterative phlebitis were not identified. The postoperative course was uneventful, without evidence of recurrence (follow‐up period 17–65 months). Conclusions: This study suggests that a disease entity which can be named follicular cholangitis and pancreatitis exists and may be under‐recognized. The disease mainly affects the hilar bile ducts and pancreatic head in adults.     

Abnormal binding of negatively charged serum proteins to diabetic basement membranes is largely a systemic phenomenon

Summary Direct immunofluorescence employing goat anti-human IgG, IgA, IgM, C₃ component of complement, fibrinogen, albumin, and polyvalent immunoglobulins was performed on postmortem samples of gingiva, parotid gland, thyroid, kidney, and pancreas tissue of 15 diabetic and 15 control patients.Basement membrane thickness quantification of kidney tubules, gingival capillaries, and parotid gland ducts and acini was also done utilizing a calibrated magnifier on uniformly enlarged photomicrographs which had been specially stained to highlight basement membranes.Results revealed binding of IgG, albumin, and polyvalent immunoglobulin to kidney glomerular and tubular basement membranes and parotid ductal and acinar basement membranes in all diabetic subjects. Thyroid follicular basement membranes were positive in 8 of 15 diabetic patients for the same antisera. All gingival and pancreatic tissue from diabetic and control patients was negative for binding of all serum proteins tested.Basement membrane thickening in kidney tubules and gingival capillaries was observed in diabetic subjects; however, there was no apparent difference between diabetic and control patients in thickness of ductal or acinar basement membranes of the parotid gland.     

Sialadenitis in a patient with ulcerative colitis and autoimmune pancreatitis type 2

Autoimmune pancreatitis (AIP) is a distinct form of chronic pancreatitis that has been increasingly recognised over the last decades and shows a good response to corticosteroid treatment. Two different forms of AIP have been characterized. Type 1 AIP is the pancreatic manifestation of IgG4-related disease and often affects multiple organ systems. In contrast, type 2 AIP is confined to the pancreas and involvement of extra-pancreatic organs has previously only very rarely been reported, except for an association with inflammatory bowel disease. The hallmark lesion of type 2 AIP is the granulocyte epithelial lesion (GEL), showing infiltration of neutrophilic granulocytes in the epithelium of pancreatic ducts and their accumulation in the duct lumen. We present a 61-year-old female patient who underwent pancreaticoduodenectomy with a postoperative histological diagnosis of type 2 AIP. Three months later, she underwent colectomy and was diagnosed with ulcerative colitis. One year later, she presented with swelling and pain of the right-sided submandibular salivary gland which was resected. Sialadenitis with lymphoplasmacytic inflammation, obliterative phlebitis, fibrosis and frequent accumulation of neutrophilic granulocytes in ducts, reminiscent of GELs, without IgG4-positivity or epitheloid cell granulomas, was found. Later, she presented with swelling and pain related to the left-sided submandibular gland, which resolved after steroid treatment. We describe the clinical, histological and immunohistochemical findings in this patient. It may be hypothesized that the sialadenitis may represent a rare extrapancreatic manifestation of, alternatively a rare association with, type 2 AIP or ulcerative colitis.     

Utility of serum IgG,IgG4 and carbonic anhydrase II antibodies in distinguishing autoimmune pancreatitis from pancreatic cancer and chronic pancreatitis

PurposeAutoimmune pancreatitis (AIP) can mimic pancreatic cancer in its clinical presentation, imaging features and laboratory parameters. The aim of our study was to compare IgG, IgG4 and anti-CAIIAb serum levels in patients with AIP, pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP) and to assess their clinical significance and utility in differential diagnosis of pancreatic diseases.Patient/methodsThe study included 124 patients: 45 with PA, 24 with AIP and 55 with CP. Peripheral venous blood samples were obtained from all analyzed patients at the time of hospital admission and total IgG, IgG4 and anti-CAIIAB serum levels were measured using ELISA tests.ResultsSerum levels of IgG, IgG4 and anti-CAIIAb were significantly higher in patients with AIP compared to PA and CP patients (p < 0.001). In AIP patients the median IgG levels were 19.7 g/l, IgG4 levels – 301.9 mg/dl and anti-CAIIAb – 81.82 ng/ml, compared to 10.61 g/l, 123.2 mg/dl and 28.6 ng/ml, respectively, in PA patients. IgG4 for the cut-off 210 mg/dl showed the best sensitivity and specificity (83.8% and 89.5%) in AIP diagnosis compared to IgG (69.3% and 87.3%, respectively) and anti-CAIIAb (45.3% and 74.3%). However, 16 (35.5%) patients with PA and 14 (25.4%) patients with CP had IgG4 levels greater than 140 mg/dl. Moreover, in 3 (6.67%) patients with pancreatic cancer those values were greater than 280 mg/dl. No patients with CP had IgG4 more than 280 mg/dl.ConclusionsIgG4 at cut-off 210 mg/dl showed the best sensitivity and specificity in AIP diagnosis compared to IgG and anti-CAIIAb, however elevations of serum IgG4 may be seen in subjects without AIP, including pancreatic cancer.     

Differential and mutually exclusive expression of CD95 and CD95 ligand in epithelia of normal pancreas and chronic pancreatitis

Acinar regression in chronic pancreatitis may be due to immune attack in parenchymal areas neoexpressing HLA-DR molecules. CD4+Th1 cytotoxic T cells induce apoptosis of their targets via oligomerizing CD95 (APO-1/Fas) death receptors on target cells by their CD95 ligand (CD95L). We determined the expression of CD95 and CD95L in epithelia of normal and chronically inflamed pancreatic tissues. We applied RT-PCR and Western blotting for CD95L expression profiles, serial frozen section immunohistochemistry to detect CD95, CD95L, and HLA-DR molecules, CD3, CD4, CD11c, and S-100 protein (S100p). Normal pancreases and chronic pancreatitis contain CD95L message and protein. Immunohistochemistry revealed a mutually exclusive expression of CD95 and CD95L. Physiologically, acini were CD95-/CD95L+, ducts were CD95-/CD95L-, and islets were CD95-/CD95L+. In areas of lymphohistiocytic infiltration, mainly consisting of CD3+CD4+ T cells and CD11c+, CD4+/-, S100p+ interstitial dendritic cells, and in areas of initial fibrosis, acini and ducts were HLA-DR+, acini CD95+/CD95L-, and ducts CD95+/CD95L-. Islet cells were CD95-/CD95L+ in both conditions. IFNgamma levels in protein lysates, as measured by an immunoassay, were significantly higher in chronic pancreatitis than in normal pancreas (p < 0.0003). In vitro, IFNgamma down-modulated CD95L message and protein in ASPC1 and BxPc3 pancreatic carcinoma cells. In conclusion, pancreatic epithelia differentially express CD95 and CD95L in a mutually exclusive manner. In chronic pancreatitis the CD95-/CD95L+ status is conserved in islet cells even in the vicinity of lymphohistiocytic infiltrates, whereas it is lost in acini coexpressing HLA-DR. As a potential consequence, and possibly triggered by local release of IFNgamma, CD4-Th1 cells may cognately interact with and successfully attack exocrine cells by triggering CD95 on their target without being killed by epithelial, CD95L-mediated, counterattack.     

Glomerular lesions induced in the rabbit by physicochemically altered homologous IgG.

Immunization of rabbits with physicochemically altered homologous or even autologous IgG induces formation of antibodies combining with IgG of rabbit and of foreign species. Cardiac but not renal lesions were reported in such animals. This study examined the nephritogenic potential of the immune response to cationized or heat-aggregated homologous IgG of b9 or b4 allotype in rabbits of the b4 allotype. Rabbits injected with either b9 or b4 cationized IgG produced antibodies reactive with rabbit and human IgG and with histones; they also developed abnormal glomerular deposits of IgG b4 and C3 corresponding to alterations of the glomerular basement membranes (GBM). Rabbits injected with either b9 or b4 aggregated IgG developed antibodies reactive with rabbit and human IgG and abnormal glomerular deposits of IgG b4 and C3 in the GBM and in the mesangium with subendothelial and mesangial electron-dense deposits. Some rabbits in both groups had proliferative and exudative glomerulonephritis and proteinuria. The results showed that immunization of rabbits with physicochemically altered homologous IgG induces an immune response to rabbit and human IgG and to histones as well as glomerular deposits of autologous IgG and C3 and other glomerular lesions.     

Duct‐obstructive pancreatitis with granulocytic epithelial lesion in a patient with ulcerative colitis: An atypical manifestation of type 2 autoimmune pancreatitis?

Type 2 autoimmune pancreatitis (AIP) typically presents with diffuse or focal enlargement of the pancreas; however, its diverse clinical presentation has not yet been clarified. We herein described a 46‐year‐old man with a 1‐month history of ulcerative colitis who presented with imaging features of a mass‐like lesion in the pancreatic body with upstream duct dilatation and serum CA19‐9 elevation. He underwent laparoscopic distal pancreatectomy with splenectomy for suspected malignancy. Histologically, the area radiologically suspected to be duct dilatation consisted of necrotic tissue, in which the disrupted main pancreatic duct was involved. The area radiologically suspected to be the mass lesion showed features of pancreatitis without discrete mass. In addition, several ducts showed neutrophilic duct injury similar to granulocytic epithelial lesions observed in type 2 AIP. Immunohistochemistry revealed the aberrant expression of IL‐8 in the pancreatic ductules and infiltrating CD3‐positive T‐lymphocytes, findings recently identified in type 2 AIP. The present case is not typical for either type 2 AIP or other known conditions, but extreme examples of type 2 AIP may present with ductal obstruction because of severe neutrophilic duct injury. IL‐8 immunostaining may also assist in establishing a diagnosis of type 2 AIP with an atypical presentation.     

Inflammation of colon adenoma in the setting of type 1 autoimmune pancreatitis

Although immunoglobulin G4‐related diseases (IgG4‐RD) have been found to affect many organs, little is known about their effects on the colonic mucosae. Pathological examination of colon adenomas has shown inflammatory cell infiltration into the stroma. We therefore assessed the clinicopathological characteristics of colon adenomas in patients with type 1 autoimmune pancreatitis (AIP‐1), a representative IgG4‐RD. Both colon adenomas from patients with (IgG4 adenomas) and without (Non‐IgG4 adenomas) IgG4‐RD were characterized by moderate to severe lymphoplasmacytic and eosinophilic inflammation without fibrosis or phlebitis. The ratio of IgG4‐positive to IgG‐positive plasma cells (IgG4/IgG ratio) and the numbers of IgG4‐positive plasma cells were significantly higher in IgG4 adenomas than in Non‐IgG4 adenomas. IgG4‐positive plasma cells tended to be distributed diffusely in lower areas of the mucosae in IgG4 adenomas. We were unable to confirm whether IgG4 adenomas constituted an IgG4‐RD. However, IgG4 adenomas in the setting of IgG4‐RD may provide useful pathological information, supplementing a diagnosis of IgG4‐RD outside the colon, or may facilitate examination for IgG4‐RD, especially AIP‐1. IgG4 adenomas warrant further investigation.     

Monoclonal antibodies to heparan sulfate proteoglycan: development and application to the study of normal tissue and pathologic human kidney biopsies

Monoclonal antibodies (mAbs) (4F2 and 7E12) were prepared against heparan sulfate proteoglycan (HSPG) isolated from bovine glomeruli. Enzyme linked immunosorbent assays (ELISA) and immunoblotting demonstrated that the mABs reacted with HSPG. Indirect immunofluorescence (IF) showed that the mAbs stained renal basement membranes (BMs) and BMs in other organs of normal bovine and human tissues in patterns typical of HSPG. Immunoinhibition studies, and immunoblotting of heparan lyase digested HSPG, indicated that the mAbs recognize HSPG core protein. In kidney biopsies from patients with acute poststreptococcal GN, intact linear glomerular BM (GBM) staining for HSPG was noted despite markedly widened capillary loops. In membranous and in diffuse proliferative lupus GN, loss of HSPG staining was demonstrated at sites of immunodeposition of IgG or C3, while increased staining for HSPG was noted in areas of newly formed GBM. Extensive loss of HSPG was seen in areas of glomerular sclerosis and necrosis. In biopsies from patients with minimal change glomerulonephritis (GN) and mesangioproliferative lupus GN, a normal linear GBM distribution of HSPG was noted. The findings are discussed in the context of current knowledge regarding the pathogenesis of glomerular injury. MAbs to BM HSPG should prove useful for future immunochemical studies, and for the study of diseases of the basement membrane.     

Diagnosis and classification of autoimmune pancreatitis

Recent studies suggested the existence of two subtypes of autoimmune pancreatitis (AIP): type 1 related with IgG4 as the pancreatic manifestation of IgG4-related disease (IgG4-RD), and type 2 related with a granulocytic epithelial lesion. Apart from type 2 AIP, the characteristic features of type 1 AIP are increased serum IgG4 levels, lymphoplasmacytic sclerosing pancreatitis (abundant infiltration of IgG4 + plasmacytes and lymphocytes, storiform fibrosis, and obliterative phlebitis), extra-pancreatic manifestations of IgG4-RD (e.g. sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis), and steroid responsiveness. Although the way how to diagnose IgG4-RD has not been established yet, the Comprehensive Diagnostic Criteria (CDC) for IgG4-RD for general use, and several organ specific criteria for AIP have been proposed; the International Consensus Diagnostic Criteria (ICDC) and the revised clinical diagnostic criteria in 2011 by Japan Pancreas Society (JPS-2011) for type1 AIP. In cases of probable or possible IgG4-RD diagnosed by the CDC, organ specific diagnostic criteria should be concurrently used according to an algorithm of diagnosis for IgG4-RD with reference to the specialist.     

Antibodies to Type IV Collagen Induce Type 1 Autoimmune Pancreatitis

Type 1 autoimmune pancreatitis (AIP) is prototypic autoantibody-mediated diseases. Sclerosis accompanied by fiber deposition is generally regarded as the primary lesion in the development of obliterative vasculitis. However, why collagens or their antibodies play a crucial role in the pathogenesis of AIP has not been demonstrated. This study was performed to investigate if anti-collagen type IV antibodies (ACIVAbs) are the key factor of fiber deposition and recruit leukocytes, resulting in obliterative vasculitis in pancreas. Enzyme-linked immunosorbent analyses (ELISA) were used to measure the expression of Col IV and ACIVAbs in serum of patients with and without AIP. In vitro, adhesion and proliferation were determined by human lymphocytes incubated with Col IV and ACIVAbs. In vivo, C57BL0/6 mice were immunized with IgG-ACIVAbs, followed by analysis of clinical phenotype. IgG-ACIVAbs were recognized by the serum specimens from 12 of 22 patients with type 1 AIP, 3 of 9 patients with Crohn’s disease, and 2 of 18 patients with pancreatic cancer, but not in healthy controls and acute pancreatitis. In patient’s biopsy, ACIVAb staining increased and co-localized with subepithelial IgG4 deposits along the capillary walls and surrounding nerve fibers. In vitro, recombinant IgG-ACIVAbs increased leukocyte adhesion and proliferation. What is more, AIP could be induced in mice by immunization with IgG-ACIVAbs into adult mice.     

Systemic inflammation in acute intermittent porphyria: a case–control study

This study aimed to examine whether acute intermittent porphyria (AIP) is associated with systemic inflammation and whether the inflammation correlates with disease activity. A case–control study with 50 AIP cases and age‐, sex‐ and place of residence‐matched controls was performed. Plasma cytokines, insulin and C‐peptide were analysed after an overnight fast using multiplex assay. Long pentraxin‐3 (PTX3) and complement activation products (C3bc and TCC) were analysed using enzyme‐linked immunosorbent assay (ELISA). Urine porphobilinogen ratio (U‐PBG, µmol/mmol creatinine), haematological and biochemical tests were performed using routine methods. Questionnaires were used to register AIP symptoms, medication and other diseases. All 27 cytokines, chemokines and growth factors investigated were increased significantly in symptomatic AIP cases compared with controls (P < 0·0004). Hierarchical cluster analyses revealed a cluster with high visfatin levels and several highly expressed cytokines including interleukin (IL)‐17, suggesting a T helper type 17 (Th17) inflammatory response in a group of AIP cases. C3bc (P = 0·002) and serum immunoglobulin (Ig)G levels (P = 0·03) were increased significantly in cases with AIP. The U‐PBG ratio correlated positively with PTX3 (r = 0·38, P = 0·006), and with terminal complement complex (TCC) levels (r = 0·33, P = 0·02). PTX3 was a significant predictor of the biochemical disease activity marker U‐PBG in AIP cases after adjustment for potential confounders in multiple linear regression analyses (P = 0·032). Prealbumin, C‐peptide, insulin and kidney function were all decreased in the symptomatic AIP cases, but not in the asymptomatic cases. These results indicate that AIP is associated with systemic inflammation. Decreased C‐peptide levels in symptomatic AIP cases indicate that reduced insulin release is associated with enhanced disease activity and reduced kidney function.     

IgG4‐related disease: Historical overview and pathology of hematological disorders

IgG4‐related diseases comprise a recently recognized systemic syndrome characterized by mass‐forming lesions in mainly exocrine tissue that consist of lymphoplasmacytic infiltrates and sclerosis. There are numerous IgG4‐positive plasma cells in the affected tissues, and the serum IgG4 level is increased in these patients. The present study describes the history, autoimmune pancreatitis (AIP), IgG4‐related lymphadenopathy and lymphomagenesis based upon ocular adnexal IgG4‐related disease. Lymphoplasmacytic sclerosing pancreatitis, a prototypal histological type of AIP, is now recognized as a systemic IgG4‐related disease. Lymph node lesions can be subdivided into at least five histological subtypes, and systemic IgG4‐related lymphadenopathy should be distinguished from multicentric Castleman's disease. Interleukin‐6 and CRP levels are abnormally high in multicentric Castleman's disease, but are normal in the majority of systemic IgG4‐related lymphadenopathy. Ocular adnexal IgG4‐related disease frequently involves bilateral lacrimal glands swelling, and obliterative phlebitis is rare. Moreover, some malignant lymphomas, especially mucosa‐associated lymphoid tissue lymphoma, arise from ocular adnexal IgG4‐related disease. In addition, IgG4‐producing lymphoma also exists.     

自身免疫性胰腺炎的临床和病理特征

自身免疫性胰腺炎(autoimmune pancreatitis,AIP)是一种罕见的具有独特的临床和组织形态学特点、以自身免疫性为病因的慢性胰腺炎.由于AIP患者的其他器官或部位常有相似的组织学改变,且都有免疫球蛋白G4(immunoglobin G4,IgG4)阳性浆细胞组织内浸润增多,以及对类固醇激素治疗有效,由...     

IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis.

Autoimmune pancreatitis typically produces an enlarged pancreas with narrowing of the pancreatic duct, and can mimic carcinoma. Autoimmune pancreatitis usually responds to corticosteroid treatment, making it important to differentiate from pancreatic ductal adenocarcinoma. Affected patients often have an elevated serum IgG4. It has been proposed that increased numbers of IgG4-positive plasma cells in tissue might be a marker for the condition. We investigated the role of IgG4 staining in the diagnosis of autoimmune pancreatitis, first in resected pancreas specimens (29 autoimmune pancreatitis, nine chronic alcoholic pancreatitis and 25 pancreatic cancer), then in pancreatic needle biopsies. Immunohistochemical stains for IgG4 were scored as none, mild, moderate or marked, according to published criteria. Moderate to marked numbers of IgG4-positive plasma cells were seen in 21/29 autoimmune pancreatitis patients, and were distributed in and around ducts, in interlobular fibrous tissue and in peripancreatic fat. In contrast, eight of nine examples of chronic alcoholic pancreatitis and 22/25 ductal adenocarcinomas had scores of none or mild. When we subdivided autoimmune pancreatitis into the histologic subtypes lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-destructive pancreatitis, 16/17 lymphoplasmacytic sclerosing pancreatitis had moderate to marked staining, compared to five to 12 idiopathic duct-destructive pancreatitis. Needle biopsies from nine patients suspected of having autoimmune pancreatitis had increased numbers of IgG4 cells. We conclude that pancreatic tissue from patients with autoimmune pancreatitis often shows moderate or marked infiltration by IgG4-positive plasma cells (>10/HPF). This is particularly so in the subtype we have designated lymphoplasmacytic sclerosing pancreatitis. We rarely see IgG4 staining in patients with chronic alcoholic pancreatitis and pancreatic ductal adenocarcinoma. IgG4-positive plasma cells are a useful marker for the tissue diagnosis of autoimmune pancreatitis.     

Immunology of membranous nephropathy: from animal models to humans

Membranous nephropathy (MN), the leading cause of nephrotic syndrome in adults, is characterized by the deposition of subepithelial immune deposits that consist mainly of immunoglobulin (Ig)G and complement. Most of the cases are primary or idiopathic (iMN), while only approximately 25% of the cases are secondary to some known disease such as systemic lupus erythematosus, hepatitis B, drugs and malignancies. Most of our knowledge on the pathogenesis of iMN has relied upon old experimental models (i.e. Heymann nephritis) that have shown that immune deposits are formed in situ by the reaction of autoantibodies against the respective podocyte antigen. Recent findings indicate that podocyte proteins also act as an autoantigen in human iMN. The M‐type phospholipase A2 receptor (PLA2R) has been identified as the main target antigen, as it can be found in approximately 70% of iMN patients but only rarely in other glomerulonephritides. Podocytes damage in the experimental model of Heymann nephritis is complement‐mediated. In humans, the presence of complement within the subepithelial deposits is well established, but IgG4, which does not activate complement by classical or alternative pathways, represents the predominant subclass of IgG anti‐PLA2R. Some evidence suggests that IgG4 anti‐PLA2R autoantibodies can bind mannan‐binding lectin (MBL) and activate the lectin complement pathway. A genetic background for iMN has been demonstrated by genome‐wide association studies that have shown highly significant associations of the PLA2R1 and the human leucocyte antigen (HLA)‐DQA1 loci with iMN. In addition to their diagnostic value, anti‐PLA2R antibodies may be useful to monitor disease activity and predict response to treatment.