IgG4-related vascular disease

IgG4 関連疾患（IgG4-relared disease; IgG4-RD）は，血清の IgG4 高値，組織での多数の IgG4陽性の形質細胞浸潤と線維増生を特徴とする疾患群である . 発見から 10 年以上経過し，全身ほぼ全ての臓器に発生しうる事や免疫異常が病因に関わる事等など，病態の理解も進んできた．　腹部大動脈瘤の一亜型に，動脈壁肥厚や炎症細胞浸潤が特徴的な炎症性腹部大動脈瘤 がある．IgG4-RD が多中心性の繊維増殖性疾患の視点から， 我々は炎症性腹部大動脈瘤の約半数が IgG4-RD である事を解明し，臨床病理像をまとめてきた . その後，心血管領域での IgG4-RD の探索を進め，大血管のみならず中型血管，冠動脈，大腿動脈等の末梢血管にまで発生することや，その多くが炎症性動脈瘤或いは動脈周囲炎を呈することも解明し，現在では1gG4 関連血管病変の概念が確立してきた . 本稿では，頻度が高く，prototype となる IgG4 関連炎症性腹部大動脈瘤から説明し， 胸部大動脈，中型動脈，心病変などについても，疾患概念，診断，臨床像，病理像，治療等の概略を示す．IgG4-related disease （IgG4-RD） is a new disease entity characterized by serum IgG4 elevation, and pathological IgG4-positive plasma cell infiltration and fibrosis in the affected organs. It occurs in almost all organs of the whole body and its pathogenesis is associated with immune disorder.Inflammatory abdominal aortic aneurysm （IAAA） is a special subtype of abdominal aortic aneurysm characterized by arterial wall thickening and inflammatory cell infiltration. From the viewpoint of multicentric fibrous proliferative diseases, we focused on the histological similarity of idiopathic retroperitoneal fibrosis and IAAA, and about half of all cases of IAAA were clarified as IgG4-RD. We have estimated the clinicopathological characteristics of IgG4-RD occurring in the cardiovascular organs, not only in large vessels but also in peripheral blood vessels, such as medium-sized blood vessels, coronary artery, and femoral artery, etc. In addition, we showed that IgG4-RD occurred in the cardiovascular organs seen morphologically as inflammatory aneurysms or periarteritis, which were tumorous lesions surrounding the aorta or artery. This article first discusses IgG4-related IAAA, because of it was the just prototype of IgG4-RD in vascular organs, and then presents an outline of the disease concept, diagnosis, clinicopathological features, pathology, and treatment, in the thoracic aorta, middle-level arteries, cardiac lesions, etc

Androgen receptor and 5α-reductase immunohistochemical profiles in extramammary Paget disease

Background Extramammary Paget disease is an uncommon skin tumour occurring mostly in the genitoperineal region. Previous reports have shown frequent expression of androgen receptor, suggesting a tumour-proliferative effect of androgens on Paget cells. Androgen-converting enzymes such as 5α-reductase, which locally produces a bioactive androgen, have recently gained attention in studies of the intratumoral actions of androgens. Objectives We investigated correlations between the androgenic microenvironment and invasiveness in extramammary Paget disease, particularly in terms of sex differences. Methods We examined 58 cases of extramammary Paget disease (32 men, 26 women; 42 noninvasive, 16 invasive) using immunohistochemistry for androgen receptor and 5α-reductase. Results In all 58 cases, expression rates were 57% for androgen receptor and 55% for 5α-reductase, with 38% double-positivity for androgen receptor and 5α-reductase. Only 5α-reductase expression rate was significantly higher in invasive cases (81%) than in noninvasive cases (45%; P = 0·042). For invasive cases, numbers of double-positive results for androgen receptor and 5α-reductase were significantly higher in men (70%) than in women (17%; P = 0·039). Conclusions Double positivity for androgen receptor and 5α-reductase in Paget cells suggests autocrine synthesis of androgens in extramammary Paget disease. The different hormonal microenvironments in male and female cases and intratumoral androgen levels affect the invasiveness of extramammary Paget disease. © 2010 British Association of Dermatologists

Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis

Aim: Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic nonsuppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRa) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α-ERRa axis interrupts glycolytic metabolism through the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α and stimulates fatty acid oxidation. In this study, we investigated the PGC-1α-ERRa axis to clarify PDC dysfunction in CNSDC of PBC. Methods: The expression of PGC-1α, Bcl-3, ERRa, PDK4 and PDC-E1α was examined by immunohistochemistry in liver sections from patients with PBC and controls. The expression of these molecules, the activity of mitochondrial dehydrogenase and PDC, and their alterations by starvation, a treatment used to induce PGC-1α expression, were examined in cultured human biliary epithelial cells (BECs). Results: The nuclear expression of PGC-1α, Bcl-3 and ERRa was exclusively observed in CNSDC of PBC. Moreover, the expression of PDK4 and PDC-E1α was enhanced in CNSDC of PBC. In cultured BECs, the amplification of Bcl-3 and PDK4 mRNAs by reversetranscription-PCR and mitochondrial dehydrogenase activity were markedly increased but PDC activity was decreased according to the upregulation of PGC-1α. Conclusions: In CNSDC of PBC, the activation of the ERRa-PGC-1α axis was exclusively observed, suggesting the interference of PDC-related glycolytic function and the induction of the fatty acid degradation system. The switching of the cellular energy system is possibly associated with the pathogenesis of CNSDC in PBC

Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis

金沢大学医薬保健研究域医学系Aims: Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis. Methods: Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and α-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry. Results: All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1β, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying α-smooth muscle actin-positive activated HSCs. Conclusions: Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis. Copyright Article author (or their employer) 2011

Evaluation of a new histologic staging and grading system for primary biliary cirrhosis in comparison with classical systems

Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions. © 2013 Elsevier Inc. All rights reserved

Consensus Statement on the Pathology of IgG4-Related Disease

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum

Clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis: A retrospective multicenter study

金沢大学医薬保健研究域医学系Introduction: Immunoglobulin G4 (IgG4)-related aortitis/periaortitis and periarteritis are vascular manifestations of IgG4-related disease. In this disease, the affected aneurysmal lesion has been suspected to be at risk of rupture. In this study, we aimed to clarify the clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis.Methods: We retrospectively evaluated clinical features, including laboratory data, imaging findings and the course after corticosteroid therapy, in 40 patients diagnosed with IgG4-related aortitis/periaortitis and periarteritis on the basis of periaortic/periarterial radiological findings, satisfaction of the comprehensive diagnostic criteria or each organ-specific diagnostic criteria, and exclusion of other diseases. Results: The patients were mainly elderly, with an average age of 66.4 years and with a marked male predominance and extensive other organ involvement. Subjective symptoms were scanty, and only a small proportion had elevated serum C-reactive protein levels. The affected aorta/artery were the abdominal aortas or the iliac arteries in most cases. Thirty-six patients were treated with prednisolone, and the periaortic/periarterial lesions improved in most of them during the follow-up period. Two (50.0%) of four patients with luminal dilatation of the affected lesions before corticosteroid therapy had exacerbations of luminal dilatation after therapy, whereas none of the twenty-six patients without it had a new appearance of luminal dilatation after therapy. Conclusions: The results of this retrospective multicenter study highlight three important points: (1) the possibility of latent existence and progression of periaortic/periarterial lesions, (2) the efficacy of corticosteroid therapy in preventing new aneurysm formation in patients without luminal dilatation of periaortic/periarterial lesions and (3) the possibility that a small proportion of patients may actually develop luminal dilatation of periaortic/periarterial lesions in IgG4-related aortitis/periaortitis and periarteritis. A larger-scale prospective study is required to confirm the efficacy and safety of corticosteroid therapy in patients with versus those without luminal dilatation and to devise a more useful and safe treatment strategy, including administration of other immunosuppressants. © 2014 Mizushima et al.; licensee BioMed Central Ltd