Recent Concepts of Autoimmune Pancreatitis and IgG4-Related Disease

Abstract

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.

IgG4 plasma cell myeloma: new insights into the pathogenesis of IgG4-related disease

“…Two recently proposed classifications are based on elevated levels of serum IgG4 (4135 mg/dl or 41.5 times the normal upper limit); enlargement, mass lesions, or dysfunction in one or more characteristic organs; typical radiographic features; and the histologic presence of a prominent lymphoplasmacytic infiltrate, abundant IgG4-positive plasma cells, storiform swirling fibrosis, and obliterative phlebitis. 2,24,25 Patients with IgG4-related disease have a 3.5 times higher risk of cancer than the general population. 26 Reported cases consist predominantly of extranodal marginal zone lymphoma (MALT lymphoma), which may either arise in the background of a preexisting non-clonal IgG4-related chronic sclerosing lesion or have evidence of plasmacytic differentiation with IgG4-positive monoclonal plasma cells.…”

Autoimmune pancreatitis characterized by predominant CD8+ T lymphocyte infiltration

“…T helper imbalance (Th1 vs Th2) is believed to be associated with the initiation of AIP [17] and elevated Th1 responses were reported in both pancreatic and extra-pancreatic lesions in AIP patients [18,19] . CD4+CD25+ regulatory T lymphocytes have also been demonstrated to contribute significantly to the pathology of AIP-associated lesions compared to lesions resulting from other pancreatic disorders [6,19] . In animal AIP disease models, administration of amylase-sensitized CD4+ T lymphocytes elicited autoimmune pancreatitis, suggesting that CD4+ T lymphocytes may be the most important components in mediating disease pathogenesis [20] .…”

“…To date, the pathogenesis and pathology of AIP remain undefined. Previously, CD4+ T lymphocytes were thought to be critical (relative to CD8+ T lymphocytes) in mediating AIP pathogenesis [5][6][7] . However, the case of AIP described herein demonstrated a significant CD8+ infiltration and an absence of CD4+ T lymphocytes in the pancreas and surrounding organs, including the duodenum.…”

IgG4-Related Cardiovascular Disorders

“…Vol 55 No 4 IGG4-RELATED CARDIOVASCULAR DISORDERS ers, such as white blood cell count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), 66) elevation of IgG, IgG4, IgE, 93,95) and soluble IL-2 receptor (sIL2R); 60) and decreased albumin-globulin (A/G) ratio. CRP and ESR are useful markers for the inflammatory activity of IgG4-related disease.…”