Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recently defined emerging entity characterized by a diffuse or mass forming inflammatory reaction rich in IgG4-positive plasma cells associated with fibrosclerosis and obliterative phlebitis. IgG4-RSD usually affects middle aged and elderly patients, with a male predominance. It is associated with an elevated serum titer of IgG4, which acts as a marker for this recently characterized entity. The prototype is IgG4-related sclerosing pancreatitis or autoimmune pancreatitis (AIP). Other common sites of involvement are the hepatobiliary tract, salivary gland, orbit, and lymph node, however practically any organ can be involved, including upper aerodigestive tract, lung, aorta, mediastinum, retroperitoneum, soft tissue, skin, central nervous system, breast, kidney, and prostate. Fever or constitutional symptoms usually do not comprise part of the clinical picture. Laboratory findings detected include raised serum globulin, IgG and IgG4. An association with autoantibody detection (such as antinuclear antibodies and rheumatoid factor) is seen in some cases. Steroid therapy comprises the mainstay of treatment. Disease progression with involvement of multiple organ-sites may be encountered in a subset of cases and may follow a relapsing-remitting course. The principal histopathologic findings in several extranodal sites include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosis and obliterative phlebitis, along with atrophy and destruction of tissues. Immunohistochemical staining shows increased IgG4+ cells in the involved tissues (>50 per high-power field, with IgG4/IgG ratio >40%). IgG4-RSD may potentially be rarely associated with the development of lymphoma and carcinoma. However, the nature and pathogenesis of IgG4-RSD are yet to be fully elucidated and provide immense scope for further studies.
Autoimmune Diseases/*immunology ; Cholangitis, Sclerosing/*immunology ; Humans ; Immunoglobulin G/*immunology ; Lacrimal Apparatus/immunology ; Lymphatic Diseases/*immunology ; Pancreatitis, Chronic/*immunology ; Salivary Glands/immunology ; Sclerosis/immunology

Reactive oxygen species (ROS), generated by infiltrating neutrophils, are considered as an important regulator in the pathogenesis and deveolpment of pancreatitis. A hallmark of the inflammatory response is the induction of cytokine gene expression, which may be regulated by oxidant-sensitive transcription factor, nuclear factor-kappaB (NF-KB). Present study aims to investigate whether neutrophils primed by 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA) affect the productions of H2O2 and lipid peroxide (LPO), NF-kappaB activation and cytokine production in pancreatic acinar cells, and whether these alterations were inhibited by N-acetylcysteine (NAC) and superoxide dismutase (SOD). ROS generation in neutrophils increased by PMA, which was inhibited by NAC and SOD. The productions of H2O2, LPO and TNF-alpha were increased with the amounts of PMA-primed neutrophils added to acinar cells while the productions of H2O2, LPO and cytokines increased with time. PMA-primed neutrophils resulted in the activation of two species of NF-kappaB dimers (a p50/p65 heterodimer and a p50 homodimer). Both NAC and SOD inhibited neutrophil-induced alterations in acinar cells. In conclusion, ROS, generated by neutrophils, activates NF-kappaB, resulting in upregulation of inflammatory cytokines in acinar cells. Antioxidants such as NAC might be clinically useful antiinflammatory agents by inhibiting oxidant-mediated activation of NF-KB and decreasing cytokine production.
Acute Disease ; Chronic Disease ; Cytokines/immunology* ; Human ; NF-kappa B/metabolism* ; Pancreas/metabolism* ; Pancreas/immunology* ; Pancreas/cytology ; Pancreatitis/metabolism ; Pancreatitis/immunology ; Support, U.S. Gov't, Non-P.H.S.

Autoimmune Diseases ; diagnostic imaging ; immunology ; Female ; Humans ; Immunoglobulin G ; immunology ; Middle Aged ; Pancreatic Neoplasms ; diagnostic imaging ; immunology ; Pancreatitis ; diagnostic imaging ; immunology ; Tomography, X-Ray Computed

Recent studies have proposed nomenclatures of type 1 autoimmune pancreatitis (AIP) (IgG4-related pancreatitis), IgG4-related sclerosing cholangitis (IgG4-SC), IgG4-related cholecystitis, and IgG4-related hepatopathy as IgG4-related disease (IgG4-RD) in the hepato-bilio-pancreatic system. In IgG4-related hepatopathy, a novel concept of IgG4-related autoimmune hepatitis (AIH) with the same histopathological features as AIH has been proposed. Among organs involved in IgG4-RD, associations with pancreatic and biliary lesions are most frequently observed, supporting the novel concept of "biliary diseases with pancreatic counterparts." Targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts. Based on genetic backgrounds, innate and acquired immunity, Th2-dominant immune status, regulatory T (Treg) or B cells, and complement activation via a classical pathway may be involved in the development of IgG4-RD. Although the role of IgG4 remains unclear in IgG4-RD, IgG4-production is upregulated by interleukin 10 from Treg cells and by B cell activating factor from monocytes/basophils with stimulation of toll-like receptors/nucleotide-binding oligomerization domain-like receptors. Based on these findings, we have proposed a hypothesis for the development of IgG4-RD in the hepato-bilio-pancreatic system. Further studies are necessary to clarify the pathogenic mechanism of IgG4-RD.
Adaptive Immunity ; Autoimmune Diseases/*immunology ; B-Cell Activating Factor/metabolism ; Cholangitis, Sclerosing/*immunology ; Cholecystitis/*immunology ; Humans ; Immunoglobulin G/*immunology ; Interleukin-10/metabolism ; Liver Diseases/*immunology ; Pancreatitis/*immunology ; T-Lymphocytes, Regulatory/immunology

The cholinergic anti-inflammatory pathway (CAP) is a neurophysiological mechanism that regulates the immune system. The CAP inhibits inflammation by suppressing cytokine synthesis via release of acetylcholine in organs of the reticuloendothelial system, including the lungs, spleen, liver, kidneys and gastrointestinal tract. Acetylcholine can interact with alpha7 nicotinic acetylcholine receptors (alpha7 nAchR) expressed by macrophages and other cytokine producing cells, down-regulate pro-inflammatory cytokine synthesis and prevent tissue damage. Herein is a review of the neurophysiological mechanism in which the CAP regulates inflammatory response, as well as its potential interventional strategy for inflammatory diseases.
Acetylcholine ; pharmacology ; Animals ; Humans ; Inflammation ; immunology ; prevention & control ; Myocardial Infarction ; immunology ; Pancreatitis ; immunology ; Receptors, Muscarinic ; physiology ; Receptors, Nicotinic ; physiology ; Reperfusion Injury ; immunology ; Sepsis ; immunology ; Shock, Hemorrhagic ; immunology ; Spleen ; immunology ; innervation ; Vagus Nerve ; physiology ; alpha7 Nicotinic Acetylcholine Receptor

No abstract availble.
Autoimmune Diseases/*drug therapy ; Glucocorticoids/*therapeutic use ; Humans ; Pancreatitis, Chronic/*drug therapy/immunology

Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic disease characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration in various organs. We described the imaging findings of an IgG4-related inflammatory pseudotumor in the urethra. The urethral mass showed isoattenuation on unenhanced CT images, delayed enhancement on enhanced CT images, iso- to slight hyper-intensity on T1 and T2 weighted magnetic resonance images, diffusion restriction on diffusion weighted images, and heterogeneously low echogeneity on ultrasonography.
Aged ; Autoimmune Diseases/diagnosis ; Female ; Granuloma, Plasma Cell/*diagnosis ; Humans ; Immunoglobulin G/*immunology ; Pancreatitis/diagnosis/immunology ; Sclerosis ; Urethral Diseases/*diagnosis/immunology

BACKGROUND/AIMS: Autoimmune pancreatitis is a distinctive type of chronic pancreatitis with reversibility. We analyzed the largest number of patients with autoimmune pancreatitis among the studies carried out at a single institution in Korea. METHODS: We retrospectively analyzed the clinical, radiologic, laboratory and histologic features in 17 patients who were diagnosed as autoimmune pancreatitis. RESULTS: The patients were predominately elderly men who presented with jaundice or nonspecific gastrointestinal symptoms. In most of the patients, serum pancreatic enzymes were normal or mildly elevated with an accompanying cholestatic biochemical profile. Elevated IgG levels and detection of autoantibodies were observed in 47% (8/17) and 35% (6/17), respectively. Thirteen patients showed histologic findings of lymphoplasmacytic infiltration and fibrosis, and one patient showed predominant infiltration of eosinophils. Fifteen patients revealed radiologic images of diffuse swelling of pancreas and the sclerosing pattern on direct pancreatogram. All of the features improved in response to oral steroid therapy. Two cases showed focal narrowing with upstream duct dilatation and thus, they were diagnosed as focal type. Diabetes mellitus concurred in 13 cases and primary sclerosing cholangitis and Sjogren's syndrome were present in 1 case, respectively. CONCLUSIONS: The recognition of autoimmune pancreatitis allows patients to avoid unnecessary surgery and recover with the administration of oral steroid.
Aged ; Autoimmune Diseases/*diagnosis/pathology ; Chronic Disease ; English Abstract ; Humans ; Male ; Middle Aged ; Pancreas/pathology ; Pancreatitis/*diagnosis/immunology/pathology

No abstract availble.
Autoimmune Diseases/*diagnosis ; Bile Duct Diseases/*diagnosis ; Cholangitis, Sclerosing/*diagnosis ; Diagnosis, Differential ; Female ; Humans ; Male ; Pancreatitis/*diagnosis/immunology

BACKGROUND/AIMS: To diagnose autoimmune pancreatitis (AIP), serum IgG and IgG4 concentration are significant serologic markers. The purpose of this study was to assess the utility of serum IgG and IgG4 for the diagnosis of AIP. METHODS: We divided enrolled patients into 2 groups: autoimmune pancreatitis and other pancreatic disease. We measured serum IgG and IgG4 levels in patients including 12 AIP and 23 other pancreatic disease. RESULTS: Among AIP patients, 10 cases (83%) showed elevated IgG4 levels of more than 135 mg/dL and 4 cases (33%) showed elevated IgG levels of more than 1,800 mg/dL, the current cutoff value applied in Japan. Only one patient showed elevated serum IgG level, despite having normal IgG4 level. Sensitivity and specificity for AIP of elevated serum IgG4 (>135 mg/dL) were 91% and 92%, and for elevated serum IgG (>1,800 mg/dL) 67% and 92%, respectively. The optimal cut-off level of IgG4 using receiver operation characteristic (ROC) was 127 mg/dL, at which the sensitivity and specificity were 83% and 96%, respectively, for the diagnosis of AIP. Serum IgG at 1,520 mg/dL showed the sensitivity and specificity of 83% and 87%, respectively. CONCLUSONS: The measurement of serum IgG and IgG4 are helpful to diagnose AIP. Serum IgG and IgG4 are complementary to each other in the diagnosis of AIP.
Adult ; Aged ; Autoimmune Diseases/*diagnosis/immunology ; Biological Markers/blood ; Diagnosis, Differential ; Female ; Humans ; Immunoglobulin G/*blood ; Male ; Middle Aged ; Pancreatitis, Chronic/*diagnosis/etiology/immunology ; ROC Curve ; Sensitivity and Specificity