Autoimmune pancreatitis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]
Overview
Th1-type CD4+ T cells are thought to play an important role in the pathogenesis of autoimmune pancreatitis (AIP) via autoimmune reaction against carbonic anhydrase type II or lactoferrin. Autoimmune pancreatitis may involve fibrosis of peripancreatic vessels leading to obliterative vasculitis and phlebitis similar to that occuring in pancreatic cancer. Autoimmune pancreatitis may be associated with systemic autoimmune conditions such as IgG4-associated cholangitis, chronic sclerosing sialadenitis (Küttner's tumor), Mikulicz's disease (IgG4-related plasmacytic exocrinopathy), mediastinal fibrosis, adenopathy, chronic periaortitis, idiopathic retroperitoneal fibrosis, tubulointerstitial nephritis, IgG4-associated pseudolymphoma, ulcerative colitis and hypergammaglobulinemia. Diffuse pancreatic gland enlargement may be seen on gross examination. Microscopic findings suggestive of autoimmune pancreatitis may include Interlobular ducts surrounded by the infiltration of inflammatory cells and fibrosis. Immunohistochemistry stains may show CD4+ T cells (mainly), some CD8+ T cells, B cells and HLA-DR antigen expression on pancreatic duct or acinar cells.
Pathophysiology
Pathogenesis:
Role of Th1-type CD4+ T cells:
- In the normal pancreatic gland, carbonic anhydrase type II and lactoferrin are located in the ductal cells and pancreatic acini respectively.
- Th1-type CD4+ T cells are thought to play an important role in the pathogenesis of autoimmune pancreatitis (AIP) via autoimmune reaction against carbonic anhydrase type II or lactoferrin.[1][2][3]
Autoimmune exocrinopathy:
- Autoimmune exocrinopathy is usually defined as an autoimmune disease affecting more than one exocrine organs.[4]
- It can be explained based on the fact that carbonic anhydrase type II and lactoferrin (that act as target antigens) are found not only in pancreatic gland but also in others such as salivary gland, lacrimal gland, and bile duct.[4]
- Autoimmune pancreatitis may also be found coexisting with other autoimmune conditions such as Primary sclerosing cholangitis (PSC) and Sjögren's syndrome.[5]
Peripancreatic vascular and lymphatic involvement:
- Autoimmune pancreatitis may involve fibrosis of peripancreatic vessels leading to obliterative vasculitis and phlebitis similar to that occurs in pancreatic cancer.[6][7][8][9]
- Follicular hyperplasia may also be seen due to peripancreatic lymph nodes enlargement.
Genetics
- Autoimmune pancreatitis may be associated with polymorphisms in antigen gene 4 of cytotoxic T lymphocytes (CTLA-4, CD152).[10]
Associated Conditions
- Autoimmune pancreatitis may be associated with systemic autoimmune conditions such as:[11][12][13][14][15][16][17][18][19]
- IgG4-associated cholangitis
- Chronic sclerosing sialadenitis (Küttner's tumor)
- Mikulicz's disease (IgG4-related plasmacytic exocrinopathy)
- Mediastinal fibrosis, adenopathy
- Chronic periaortitis
- Idiopathic retroperitoneal fibrosis
- Tubulointerstitial nephritis
- IgG4-associated pseudolymphoma
- Ulcerative colitis
- Hypergammaglobulinemia
Gross Pathology
- On gross pathology, findings suggestive of autoimmune pancreatitis may include
- Diffuse pancreatic gland enlargement
- Autoimmune pancreatitis mostly involves the head of pancreas manifesting as mass-forming pancreatitis[9][7]
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Microscopic Pathology
- Microscopic findings suggestive of autoimmune pancreatitis may include:[20]
- Interlobular ducts surrounded by the infiltration of inflammatory cells
- Lymphocytes
- Plasma cells
- Eosinophils and neutrophils (occasionally)[7][21]
- Fibrosis[8][7]
- Patchy inflammatory infiltrates
- Interlobular ducts surrounded by the infiltration of inflammatory cells
- Immunohistochemistry stains may show:[7][22]
- CD4+ T cells (mainly)
- Some CD8+ T cells and B cells
- HLA-DR antigen expression on pancreatic duct or acinar cells
Type 1 AIP:
- A lymphoplasmacytic sclerosing pancreatitis
- >10 IgG4-positive cells with at least two of the following
Type 2 AIP or Idiopathic duct-centric pancreatitis (IDCP):
- Pancreatic duct: Granulocytic epithelial lesion
- Pancreatic parenchyma: Minimal IgG4-positive cells
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References
- ↑ Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, Matsushima Y, Katamura K, Ohmori K, Chiba T (2000). "Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response". Gastroenterology. 118 (3): 573–81. PMID 10702209.
- ↑ Vallance BA, Hewlett BR, Snider DP, Collins SM (1998). "T cell-mediated exocrine pancreatic damage in major histocompatibility complex class II-deficient mice". Gastroenterology. 115 (4): 978–87. PMID 9753501.
- ↑ Uchida K, Okazaki K, Nishi T, Uose S, Nakase H, Ohana M, Matsushima Y, Omori K, Chiba T (2002). "Experimental immune-mediated pancreatitis in neonatally thymectomized mice immunized with carbonic anhydrase II and lactoferrin". Lab. Invest. 82 (4): 411–24. PMID 11950899.
- ↑ 4.0 4.1 Strand V, Talal N (1979). "Advances in the diagnosis and concept of Sjögren's syndrome (autoimmune exocrinopathy)". Bull Rheum Dis. 30 (9): 1046–52. PMID 398729.
- ↑ Montefusco PP, Geiss AC, Bronzo RL, Randall S, Kahn E, McKinley MJ (1984). "Sclerosing cholangitis, chronic pancreatitis, and Sjogren's syndrome: a syndrome complex". Am. J. Surg. 147 (6): 822–6. PMID 6731702.
- ↑ Notohara K, Burgart LJ, Yadav D, Chari S, Smyrk TC (2003). "Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases". Am. J. Surg. Pathol. 27 (8): 1119–27. PMID 12883244.
- ↑ 7.0 7.1 7.2 7.3 7.4 Klöppel G, Lüttges J, Löhr M, Zamboni G, Longnecker D (2003). "Autoimmune pancreatitis: pathological, clinical, and immunological features". Pancreas. 27 (1): 14–9. PMID 12826900.
- ↑ 8.0 8.1 Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita N (1991). "Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas". Hum. Pathol. 22 (4): 387–95. PMID 2050373.
- ↑ 9.0 9.1 Wreesmann V, van Eijck CH, Naus DC, van Velthuysen ML, Jeekel J, Mooi WJ (2001). "Inflammatory pseudotumour (inflammatory myofibroblastic tumour) of the pancreas: a report of six cases associated with obliterative phlebitis". Histopathology. 38 (2): 105–10. PMID 11207823.
- ↑ Chang MC, Chang YT, Tien YW, Liang PC, Jan IS, Wei SC, Wong JM (2007). "T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis". Clin. Chem. 53 (9): 1700–5. doi:10.1373/clinchem.2007.085951. PMID 17712006.
- ↑ Hirano K, Shiratori Y, Komatsu Y, Yamamoto N, Sasahira N, Toda N, Isayama H, Tada M, Tsujino T, Nakata R, Kawase T, Katamoto T, Kawabe T, Omata M (2003). "Involvement of the biliary system in autoimmune pancreatitis: a follow-up study". Clin. Gastroenterol. Hepatol. 1 (6): 453–64. PMID 15017645.
- ↑ Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, Topazian MD, Clain JE, Pearson RK, Petersen BT, Vege SS, Lindor K, Farnell MB (2008). "Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy". Gastroenterology. 134 (3): 706–15. doi:10.1053/j.gastro.2007.12.009. PMID 18222442.
- ↑ Raina A, Yadav D, Krasinskas AM, McGrath KM, Khalid A, Sanders M, Whitcomb DC, Slivka A (2009). "Evaluation and management of autoimmune pancreatitis: experience at a large US center". Am. J. Gastroenterol. 104 (9): 2295–306. doi:10.1038/ajg.2009.325. PMID 19532132.
- ↑ Tabata M, Kitayama J, Kanemoto H, Fukasawa T, Goto H, Taniwaka K (2003). "Autoimmune pancreatitis presenting as a mass in the head of the pancreas: a diagnosis to differentiate from cancer". Am Surg. 69 (5): 363–6. PMID 12769204.
- ↑ Erkelens GW, Vleggaar FP, Lesterhuis W, van Buuren HR, van der Werf SD (1999). "Sclerosing pancreato-cholangitis responsive to steroid therapy". Lancet. 354 (9172): 43–4. PMID 10406367.
- ↑ Kojima E, Kimura K, Noda Y, Kobayashi G, Itoh K, Fujita N (2003). "Autoimmune pancreatitis and multiple bile duct strictures treated effectively with steroid". J. Gastroenterol. 38 (6): 603–7. PMID 12856677.
- ↑ Horiuchi A, Kaneko T, Yamamura N, Nagata A, Nakamura T, Akamatsu T, Mukawa K, Kawa S, Kiyosawa K (1996). "Autoimmune chronic pancreatitis simulating pancreatic lymphoma". Am. J. Gastroenterol. 91 (12): 2607–9. PMID 8946997.
- ↑ Hamano H, Kawa S, Uehara T, Ochi Y, Takayama M, Komatsu K, Muraki T, Umino J, Kiyosawa K, Miyagawa S (2005). "Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of a spectrum of autoimmune pancreatitis?". Gastrointest. Endosc. 62 (1): 152–7. PMID 15990840.
- ↑ Church NI, Pereira SP, Deheragoda MG, Sandanayake N, Amin Z, Lees WR, Gillams A, Rodriguez-Justo M, Novelli M, Seward EW, Hatfield AR, Webster GJ (2007). "Autoimmune pancreatitis: clinical and radiological features and objective response to steroid therapy in a UK series". Am. J. Gastroenterol. 102 (11): 2417–25. doi:10.1111/j.1572-0241.2007.01531.x. PMID 17894845.
- ↑ Chari ST, Takahashi N, Levy MJ, Smyrk TC, Clain JE, Pearson RK, Petersen BT, Topazian MA, Vege SS (2009). "A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer". Clin. Gastroenterol. Hepatol. 7 (10): 1097–103. doi:10.1016/j.cgh.2009.04.020. PMID 19410017.
- ↑ Abraham SC, Leach S, Yeo CJ, Cameron JL, Murakata LA, Boitnott JK, Albores-Saavedra J, Hruban RH (2003). "Eosinophilic pancreatitis and increased eosinophils in the pancreas". Am. J. Surg. Pathol. 27 (3): 334–42. PMID 12604889.
- ↑ Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K, Egawa N, Nakajima H (2003). "Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis". Gut. 52 (5): 683–7. PMC 1773660. PMID 12692053.