Pathogenesis Of Autoimmune Pancreatitis Research Articles

Autoimmune pancreatitis - role of intestinal microbiota in pathogenesis. Review of the literature

Introduction: Autoimmune pancreatitis is a type of chronic autoimmune inflammation that can be divided into two types. Type 1 is a clinical manifestation of IgG4-mediated disease, while type 2 may coexist with inflammatory bowel diseases. Objective: The aim of the study is to review the literature on the role of the intestinal microbiota in the pathogenesis of autoimmune pancreatitis. Methods: A literature review was conducted on databases such as PubMed and Google Scholar using the terms: ”autoimmune pancreatits”, “intestinal dysbiosis”, “intestinal microbiome”, and “pathogenesis”. Conclusions: The intestinal microbiota has an impact on the development of autoimmune pancreatitis, but it is not the main pathogenic factor, but rather a risk factor.

Increased SLAMF7+CD8+ T cells are associated with the pathogenesis of experimental autoimmune pancreatitis in mice

BackgroundIgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8+ T cells have only received brief mention, and have yet to be completely studied. The study aimed to investigate the expression of signaling lymphocytic activation molecule family 7 (SLAMF7) on CD8+ T cells and the features of SLAMF7+CD8+ T cells in MRL/Mp mice with AIP. MethodsA murine model of AIP was established by intraperitoneal injection with polyinosinic:polycytidylic acid (poly I:C) for 8 weeks. Dexamethasone treatment was daily administrated for the last 2 weeks during a 6-week course of poly I:C. SLAMF7 expression on CD8+ T cells in the spleen and pancreas was detected by flow cytometry. Granzyme B (GZMB) and cytokines including IFN-γ, TNF-α, and IL-2, were monitored in an in vitro T cell activation assay. Dexamethasone suppression assays were performed to downregulate SLAMF7 expression on T cells upon T cell receptor stimulation. ResultsAIP in MRL/Mp mice was induced by repeated intraperitoneal administration of poly I:C and CD8+ T cells were increased in the inflamed pancreas. SLAMF7+CD8+ T cells were elevated in the spleen and pancreas of AIP mice. SLAMF7+CD8+ T subsets produced more GZMB, IFN-γ, TNF-α and IL-2 than SLAMF7−CD8+ T subsets. Dexamethasone treatment ameliorated pancreatic inflammatory and fibrosis of AIP. Dexamethasone could downregulate SLAMF7+CD8+ T cells and reduce GZMB, IFN-γ and TNF-α levels both in vitro and in vivo. ConclusionsIncreased SLAMF7+CD8+ T cells exhibit enhanced cytotoxicity and cytokines secretion capacity, which may be involved in the pathogenesis of AIP.

Intestinal microbiota and pancreatic diseases

The article presents a detailed literature review on the role of intestinal dysbiosis, including bacterial overgrowth syndrome, as well as increasing intestinal permeability in the pathogenesis of the main pancreatic diseases: acute and chronic pancreatitis (AP and CP), autoimmune pancreatitis, pancreatic cancer.
 Thus, according to the results of meta-analysis, populations of Enterobacteriaceae and Enterococcus were larger in all patients with AP as compared with healthy. There was no difference between the groups with severe and mild AP. Number of Bifidobacterium was lower in all patients with AP as compared with healthy. In severe AP, level of endotoxin and cytokines in blood was higher than in mild AP and in healthy.
 Participation of Helicobacter pylori in pathogenesis of autoimmune pancreatitis via molecular mimicry is assumed. In addition, Helicobacter pylori may have significance in development of pancreatic adenocarcinoma.
 In CP, rate of syndrome of bacterial overgrowth has been studied in numerous studies, since dysbiosis halts the effect of enzyme preparations, causes worsening of clinical manifestations. According to the results of meta-analysis, patients with CP are characterized by quantitative and qualitative changes in the composition of intestinal microbiome: decrease of Bifidobacterium and Lactobacillus, and increase of Enterobacteriaceae. The authors also preseented their own data.
 Recent data suggest a connection between the oral microbiota, tongue plaque and pancreatic adenocarcinoma. Pancreatic cancer is characterized by decrease of Neisseria elongate, Streptococcus mitis, and increase of Porphyromonas gingivalis and Granulicatella adiacens. Recent reports have found that oral microbiota may be important in increasing the risk of pancreatic cancer. The conclusion is drawn on the prospects of studying the intestinal microbiota in pancreatic diseases and the need for its participation in the pathogenesis of this disease.

Unique properties of IgG4 antibody and its clinical application in autoimmune pancreatitis

Background: Autoimmune pancreatitis (AIP) is defined as a unique form of chronic pancreatitis characterized by clinical presentation with obstructive jaundice, a dense lymphoplasmacytic infiltrate and fibrosis histologically, and a dramatic response to steroids therapeutically. The possible role of IgG4 in driving the pathology of AIP is a controversial subject that has not been addressed satisfactorily. Objective: The purpose of this review is to discuss the unique biology of IgG4 that are important for its role and the clinical applications for serologic detection.Methods: Review of current literature about IgG4 antibody in the clinical application in AIP.Results: High serum levels of IgG4 are an important biomarker and broadly used for diagnosis, differentiation from diseases especially pancreatic cancer, and as a parameter to indicate disease activity, extra-pancreatic lesions, and treatment monitoring. However, some controversial studies show it has a limited specificity and sensitivity in these conditions. Conclusion: Although increasing studies have promoted our understanding of the structure and function of IgG4, there is still dilemma between the beneficial and the adverse aspect of IgG4 in the pathogenesis of AIP.

Potential role of bacterial components in the pathogenesis of autoimmune pancreatitis

Potential role of bacterial components in the pathogenesis of autoimmune pancreatitis

Promoter hypomethylation of SKI in autoimmune pancreatitis

The relationship between methylation abnormality and autoimmune pancreatitis (AIP)—a representative IgG4-related disease—has not yet been elucidated. We identified SKI might have a significant methylation abnormality in AIP through methylation array analysis using the Illumina Infinium Human Methylation 450K BeadChip array, and investigated the relationship of SKI with AIP clinicopathological features. The methylation rate of SKI was assessed by quantitative SYBR green methylation-specific PCR, and the degree of SKI expression in tissue specimens was assessed by immunohistochemistry in 10 AIP cases, 14 cases of obstructive pancreatitis area in pancreatic ductal adenocarcinoma (PDA) without a history of AIP, and 9 normal pancreas (NP) cases. The SKI methylation ratio was significantly lower in AIP than in PDA and NP. Additionally, the immunohistochemical staining-index (SI) score for SKI was significantly higher in AIP than NP, although there was no significant difference between AIP and PDA. There was a strong negative correlation between SI score and SKI methylation ratio, and between the serum concentrations of IgG4 and the SKI methylation ratio. There was a moderate positive correlation between the serum concentrations of IgG4 and SI. SKI is thought to be an oncogene indicating that SKI hypomethylation and carcinogenesis might be linked to AIP. Furthermore, the correlation between serum concentrations of IgG4 and SKI methylation levels suggest SKI might be involved in the pathogenesis of AIP. However, the role of SKI has not been clearly elucidated. Further studies are needed to understand further the function of SKI.

Adoptive transfer of CD3+ T cells and CD4+ CD44high memory T cells induces autoimmune pancreatitis in MRL/MpJ mice.

The immunopathogenesis of autoimmune pancreatitis (AIP) is poorly understood. Here, we have used MRL/MpJ mice, a model of spontaneous AIP, to address the role of cellular autoimmune processes in the initiation and progression of the disease. Therefore, different T cell subpopulations were adoptively transferred from sick to still healthy (but susceptible) MRL/MpJ mice. Unpurified splenocytes and CD3+ T cells both efficiently induced AIP, while CD4+ and CD8+ T cells alone, as well as splenocytes from healthy mice, were insufficient to trigger the disease. Strikingly, CD4+ CD44high memory T cells, although transferred at lower numbers than other T cells, also induced AIP in recipient mice. Employing a modified experimental design, we also evaluated the effects of regulatory T cells (T regs) on the progression of AIP in already diseased mice. Under the given experimental conditions, there was no significant suppressive effect of adoptively transferred T regs on pancreatic histopathology. The results of our studies suggest a key role of T cell‐mediated processes in murine AIP. The effects of CD4+ CD44high memory T cells are in accordance with genetic studies of our group, which had previously implicated this cell type into the pathogenesis of AIP. In follow‐up studies, we will focus on the interplay of cellular and humoral autoimmunity in the context of AIP.

Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells.

In previous studies, we found that human IgG4-related autoimmune pancreatitis (AIP) and murine AIP are driven by activation of plasmacytoid dendritic cells (pDCs) producing IFN-α. In the present studies we examined additional roles of pDC-related mechanisms in AIP pathogenesis, particularly those responsible for induction of fibrosis. We found that in murine AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid) not only the pancreatic infiltration of immune cells but also the development of fibrosis were markedly reduced by the depletion of pDCs or blockade of type I IFN signaling; moreover, such treatment was accompanied by a marked reduction of pancreatic expression of IL-33. Conversely, polyinosinic-polycytidylic acid-induced inflamed pancreatic tissue in murine AIP exhibited increased expression of type I IFNs and IL-33 (and downstream IL-33 cytokines such as IL-13 and TGF-β1). pDCs stimulated by type I IFN were the source of the IL-33 because purified populations of these cells isolated from the inflamed pancreas produced a large amount of IL-33 upon activation by TLR9 ligands, and such production was abrogated by the neutralization of type I IFN. The role of IL-33 in murine AIP pathogenesis was surprisingly important because blockade of IL-33 signaling by anti-ST2 Ab attenuated both pancreatic inflammation and accompanying fibrosis. Finally, whereas patients with both conventional pancreatitis and IgG4-related AIP exhibited increased numbers of acinar cells expressing IL-33, only the latter also exhibited pDCs producing this cytokine. These data thus suggest that pDCs producing IFN-α and IL-33 play a pivotal role in the chronic fibro-inflammatory responses underlying murine AIP and human IgG4-related AIP.

Autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is a rare, distinct and increasingly recognized form of pancreatitis which has autoimmune features. The international consensus diagnostic criteria (ICDC) for AIP recently described two subtypes; type 1[lymphoplasmacytic sclerosing pancreatitis (LPSP)] and type 2 [idiopathic duct-centric pancreatitis (IDCP) or AIP with granulocytic epithelial lesion (GEL)]. Type 1 is the more common form of the disease worldwide and current understanding suggests that it is a pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). In contrast, type 2 AIP is a pancreas-specific disease not associated with IgG4 and mostly without the overt extra-pancreatic organ involvement seen in type 1. The pathogenesis of AIP is not completely understood and its clinical presentation is non-specific. It shares overlapping features with more sinister pathologies such as cancer of the pancreas, which continues to pose a diagnostic challenge for clinicians. The diagnostic criteria requires a variable combination of histopathological, imaging and serological features in the presence of typical extrapancreatic lesions and a predictable response to steroids.

A high-throughput sequence analysis of Japanese patients revealed 11 candidate genes associated with type 1 autoimmune pancreatitis susceptibility

The pathogenesis of autoimmune pancreatitis is unknown. In the present study we used high-throughput sequencing with next generation sequencing to identify the candidate genes associated with AIP. A total of 27 type 1 AIP patients and 30 healthy blood donors were recruited, and DNA samples were isolated from their mononuclear cells. A high-throughput sequencer with an original custom panel of 1031 genes was used to detect the genetic variants in each sample. Polymorphisms of CACNA1S (c.4642C>T), rs41554316, rs2231119, rs1042131, rs2838171, P2RX3 (c.195delG), rs75639061, SMAD7 (c.624delC) and TOP1 (c.2007delG), were identified as candidate genetic variants in patients with type 1 AIP. P2RX3 and TOP1 were significantly associated with AIP, even after adjusting bay means of Bonferroni's correction. In addition, we also identified eight candidate genetic variants that were associated with the relapse of type 1 AIP, namely: rs1143146, rs1050716, HLA-C (c.759_763delCCCCCinsTCCCG), rs1050451, rs4154112, rs1049069, CACNA1C (c.5996delC) and CXCR3 (c.630_631delGC). Finally polymorphisms of rs1050716 and rs111493987 were identified as candidate genetic variants associated with extra-pancreatic lesions in patients with type 1 AIP. These candidates might be used as markers of AIP susceptibility and could contribute to the pathogenesis of type 1 AIP.

The Immunobiology of Immunoglobulin G4 and Complement Activation Pathways in IgG4-Related Disease.

High serum immunoglobulin (Ig) G4 concentration and abundant IgG4-bearing plasma cell infiltration are characteristic features in autoimmune pancreatitis (AIP). AIP is also complicated with a variety of other organ involvements that commonly share marked IgG4-bearing plasma cell infiltration, suggesting the existence of a systemic disease associated with IgG4 currently recognized as IgG4-related disease (IgG4-RD). However, it is controversial whether IgG4 plays a role in the pathogenesis of AIP or IgG4-RD through such characteristic attributes as Fab-arm exchange and rheumatoid factor (RF)-like activity. Hypocomplementemia has been observed in AIP and several other IgG4-RDs. Muraki et al. reported that complements C3 and C4 were decreased in 36% of patients with AIP, which implicated the complement activation system in disease pathogenesis. AIP patients with a high level of immune complexes showed serum elevation of IgG4-type immune complexes in an active disease stage, elevated serum IgG1 concentration, and decreased C3 and C4 values. This inferred that while IgG4 may have had little contribution to complement activation, IgG1 played a prominent role via the classical pathway. On the other hand, Sugimoto et al. observed that polyethylene glycol-precipitated immune complexes from patients with IgG4-RD and hypocomplementemia had the ability to activate the complement system through both the classical and the mannose-binding lectin pathways and that IgG4 might participate in the complement activation system. Thus, debate continues on which complement activation systems are working in AIP and IgG4-RD and whether they are associated with the pathogenesis of these conditions.

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.

Potential role of Th17 cells in the pathogenesis of type 2 autoimmune pancreatitis.

Th17 cells have been shown to play an important role in the pathogenesis of a variety of autoimmune diseases. The aim of this study was to investigate the potential role of Th17 cells in autoimmune pancreatitis (AIP). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine gene expression of the signature cytokines of Th17 cells IL-17A and IL-21 and of the Th17 lineage-specific transcription factor retinoic acid receptor-related orphan receptor C (RORC) in human tissue specimens of AIP, classical chronic pancreatitis (CP), and normal pancreas (NP). Infiltrating immune cells were characterized by immunohistochemistry (IHC). Gene expression of IL-17A, IL-21, and RORC were found to be significantly increased in AIP. Accordingly, the number of Th17 cells was significantly increased in AIP compared to NP or CP. Both gene expression analysis and IHC revealed a clear difference between type 1 and 2 AIP. In the periductal compartment of type 2 AIP, which is characterized by granulocytic epithelial lesions (GELs), the number of infiltrating Th17 cells and neutrophilic granulocytes was significantly increased compared to type 1 AIP. Our data suggest that Th17 cells play a role in the pathogenesis of AIP, in particular of type 2 AIP. Cross-talk between Th17 cells and neutrophilic granulocytes mediated via IL-17A may be a potential mechanism by which neutrophils are recruited to the duct and acinar cells with subsequent destruction, a process that is pathognomonic for type 2 AIP.

Quantitative Trait Locus Analysis Implicates CD4+/CD44high Memory T Cells in the Pathogenesis of Murine Autoimmune Pancreatitis

The mouse strain MRL/MpJ is prone to spontaneously develop autoimmune pancreatitis (AIP). To elucidate the genetic control towards the development of the phenotype and to characterize contributions of immunocompetent cell types, MRL/MpJ mice were interbred with three additional strains (BXD2/TYJ, NZM2410/J, CAST/EIJ) for four generations in an advanced intercross line. Cellular phenotypes were determined by flow cytometric quantification of splenic leukocytes and complemented by the histopathological evaluation of pancreatic lesions. An Illumina SNP array was used for genotyping. QTL analyses were performed with the R implementation of HAPPY. Out of 41 leukocyte subpopulations (B cells, T cells and dendritic cells), only three were significantly associated with AIP: While CD4+/CD44high memory T cells and CD4+/CD69+ T helper (Th) cells correlated positively with the disease, the cytotoxic T cell phenotype CD8+/CD44low showed a negative correlation. A QTL for AIP on chromosome 2 overlapped with QTLs for CD4+/CD44high and CD8+/CD44high memory T cells, FoxP3+/CD4+ and FoxP3+/CD8+ regulatory T cells (Tregs), and CD8+/CD69+ cytotoxic T cells. On chromosome 6, overlapping QTLs for AIP and CD4+/IL17+ Th17 cells and again FoxP3+/CD8+ Tregs were observed. In conclusion, CD4+/CD44high memory T cells are the only leukocyte subtype that could be linked to AIP both by correlation studies and from observed overlapping QTL. The potential role of this cell type in the pathogenesis of AIP warrants further investigations.

Identification of a Novel Frame-Shift Mutation in PRSS1 Gene in Han Patients with Autoimmune Pancreatitis

To detect mutations of trypsinogen gene (PRSS1) in patients with autoimmune pancreatitis (AIP) and to determine the underlying pathogenesis. DNA sequencing was used to detect full-length of PRSS1, cystic fibrosis transmembrane conductance regulator (CFTR), and pancreatic secretory trypsin inhibitor (SPINK1) genes mutations in an AIP family and a sporadic case and 520 normal controls. Furthermore, a mutant-expressing system was constructed for functional confirmation. For the first time, we report a deletion mutation at exon 2 of PRSS1 gene (IVS 2 +56_60 del CCCAG) which encoded a truncated PRSS1 protein without trypsinogen activation peptide (TAP). Vitro functional study suggested the identified mutation would result in loss of PRSS1 activity. Mutant trypsinogen activated at a faster rate than wild-type trypsinogen in the autoactivation experiment. Histopathologic examination revealed the ratio of IgG4/IgG-positive plasma cells exceeded 0.455 in pancreas, and the patients responded to glucocorticoids. PRSS1: IVS 2 +56_60 del CCCAG is a noval mutant which may contribute to AIP pathogenesis.

Periductal Induction of High Endothelial Venule-Like Vessels in Type 1 Autoimmune Pancreatitis

Type 1 autoimmune pancreatitis (AIP) is histologically characterized by dense lymphoplasmacytic infiltration and marked storiform fibrosis, manifestations associated with pancreatic ducts. Such periductal lymphocyte recruitment is thought to be elicited by dysregulation of mechanisms governing physiological lymphocyte homing. The present study was undertaken to determine whether vascular addressins including peripheral lymph node addressin and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) play a role in type 1 AIP histogenesis. Tissue sections of type 1 AIP and tumor-associated non-AIP chronic pancreatitis, as well as normal pancreas, were subjected to immunohistochemical analysis using vascular addressin-related antibodies. The number of periductal mouse endothelial cell antigen 79-positive high endothelial venule (HEV)-like vessels was increased in type 1 AIP relative to that seen in non-AIP chronic pancreatitis, whereas the number of MAdCAM-1-positive HEV-like vessels did not differ between the 2 conditions. Mouse endothelial cell antigen 79 antigens are expressed on duct-forming epithelial cells not only in pancreas but also in salivary glands, which often harbor extrapancreatic lesions in type 1 AIP. Type 1 AIP can be characterized by periductal induction of MECA-79-positive HEV-like vessels. MECA-79-positive 6-sulfo sialyl Lewis X-related carbohydrate antigens expressed on duct-forming epithelial cells could be associated with type 1 AIP pathogenesis.

Covering the Cover

Covering the Cover

Commensal Flora, is it an Unwelcomed Companion as a Triggering Factor of Autoimmune Pancreatitis?

The etiopathogenesis of many autoimmune disorders has not been identified. The aim of this paper is to focus on the involvement of bacterial exposure, as an environmental factor, in the pathogenesis of autoimmune pancreatitis (AIP), which is broadly categorized as autoimmune disorders involving pancreatic lesions. Avirulent and/or commensal bacteria, which may have an important role(s) as initiating/progressing factors in the pathogenesis of autoimmune disorder AIP, will be emphasized.

Autoantibodies in Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) was first used to describe cases of pancreatitis with narrowing of the pancreatic duct, enlargement of the pancreas, hyper-γ-globulinaemia, and antinuclear antibody (ANA) positivity serologically. The main differential diagnosis, is pancreatic cancer, which can be ruled out through radiological, serological, and histological investigations. The targets of ANA in patients with autoimmune pancreatitis do not appear to be similar to those found in other rheumatological diseases, as dsDNA, SS-A, and SS-B are not frequently recognized by AIP-related ANA. Other disease-specific autoantibodies, such as, antimitochondrial, antineutrophil cytoplasmic antibodies or diabetes-specific autoantibodies are virtually absent. Further studies have focused on the identification of pancreas-specific autoantigens and reported significant reactivity to lactoferrin, carbonic anhydrase, pancreas secretory trypsin inhibitor, amylase-alpha, heat-shock protein, and plasminogen-binding protein. This paper discusses the findings of these investigations and their relevance to the diagnosis, management, and pathogenesis of autoimmune pancreatitis.

Autoimmune Pancreatitis: An Autoimmune or Immunoinflammatory Disease?

Autoimmune pancreatitis (AIP) has been widely presumed to be an autoimmune disease that is characterized by elevated IgG and/or IgG4, the presence of autoantibodies, and an infiltration of lymphocytes and plasma cells with fi- brosis. However, no detailed immunological studies have been published. To define immunological changes in AIP in de- tail, and to review evidence for autoimmunity which may be antigen specific and may play a role in the pathogenesis of AIP, and therefore, to determine whether AIP is an autoimmune disease. A detailed immunological investigation for both innate and adaptive immune responses was performed in a patient with AIP. Review of literature was performed from Pub med, and Medline search. Immunological analysis of patient with AIP revealed increased production of proinflammatory IL-6, and IL-17, and increased NK cell activity. No organ-specific or non-specific antibodies were detected. There was no correlation between serum IgG4 with disease activity or response to steroid therapy. Review of literature revealed lack of auto-antigen-specific T and B cell responses in AIP, and autoantibodies are present only in a subset of patients, and are not specific to pancreatic tissue antigens. Therefore, we propose the term Immunoinflammatory pancreatitis rather than an autoimmune pancreatitis. Autoimmune pancreatitis is typically characterized by a diffuse or segmental narrowing of the main pancreatic duct on imaging, elevated IgG and/or IgG4, the presence of autoantibodies, an infiltration of lymphocytes and plasma cells, and presence of fibrosis. The autoantibodies that have been examined include ANA, anti-microsomal antibodies, anti-thyroglobulin antibodies, and antibodies against pancre- atic secretory trypsin inhibitor, lactoferrin, and carbonic an- hydrase (2-5). However, the presence of these autoantibodies has been only sporadically documented in limited numbers of cases. In addition, many of these autoantibodies are di- rected against antigens that are also present in the salivary gland, biliary duct, and distal renal tubules. The detection of IgG, IgG4, antinuclear antibodies, and rheumatoid factor