Pathogenetic role of an autoimmune susceptibility locus derived from MRL/MpJ strain chromosome 1 in chronic pancreas inflammation

Abstract

We examined the role of Mag, an autoimmune susceptibility locus encoded by the telomeric region of MRL/MpJ mouse chromosome 1, in the pathogenesis of autoimmune exocrinopathy. At nine to 12 months of age, strain-specific differences were observed in the pancreas of the animals. B- and T-cell-containing periductal/perivascular cell infiltrations in the pancreases of MRL/MpJ and B6.MRLc1 congenic C57BL/6-background Mag-carrying strains were more severe than were those of C57BL/6. Pancreatic periductal/perivascular cell infiltration was observed frequently in A/J, AKR/N, B6.MRLc1, C57BL/6, and MRL/MpJ, moderately in DBA/1 and DBA/2, and rarely in BALB/c and C3H/He strains. Females tended to have greater pancreatic periductal/perivascular cell infiltration than males. C57BL/6 mice possessed defined borders between cell infiltrations and acini, but borders were indistinct in MRL/MpJ and B6.MRLc1 mice. We attributed this to the invasion of inflammatory cells between each acinus and the disruption of acinar cells around cell infiltrations in the latter strains. No strain-specific differences were observed in the appearance of fibrotic lesions and high endothelial venules in the cell infiltrates. The levels of serum anti-dsDNA antibodies and amylase, and mRNA expression of tumor necrosis factor-α and Fc gamma receptor III (encoded on Mag) in the pancreases, were elevated in MRL/MpJ- and B6.MRLc1-strain mice relative to C57BL/6. These results emphasized the crucial roles of Mag in the molecular and genetic pathogenesis of autoimmune-mediated pancreatitis.

Keywords

Telomeric region of chromosome 1 MRL/MpJ mouse inflammatory exocrinopathy pancreas

Get full access to this article

View all access options for this article.

References

Hatchette

Mahony

Chong

LeBlanc

. Difficulty with mumps diagnosis: What is the contribution of mumps mimickers? J Clin Virol 2009; 46: 381–383.

Irié

Maeda

Aida

Sumitani

Nagumo

Tachikawa

. Multiple granulomatous inflammation in the minor salivary glands: A proposed new entity, allergic granulomatous sialadenitis. Pathol Int 2004; 54: 850–853.

Okazaki

Uchida

Koyabu

Miyoshi

Takaoka

. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol 2011; 46: 277–288.

Kosenda

Ichii

Otsuka

Hashimoto

Kon

. BXSB/MpJ-Yaa mice develop autoimmune dacryoadenitis with the appearance of inflammatory cell marker messenger RNAs in the lacrimal fluid. Clin Experiment Ophthalmol 2013; 41: 788–797.

Fox

Stern

. Sjögren’s syndrome: Mechanisms of pathogenesis involve interaction of immune and neurosecretry systems. Scand J Rheumatol Suppl 2002; 116: 3–13.

Mahajan

Mattoo

Deshpande

Pillai

Stone

. IgG4-related disease. Annu Rev Pathol 2014; 9: 315–347.

Jabs

Gérard

Wei

. Inflammatory mediators in autoimmune lacrimal gland disease in MRL/Mpj mice. Invest Ophthalmol Vis Sci 2004; 45: 2293–2298.

Kanno

Nose

Itoh

Taniguchi

Kyogoku

. Spontaneous development of pancreatitis in the MRL/Mp strain of mice in autoimmune mechanism. Clin Exp Immunol 1992; 89: 68–73.

Kamao

Miyazaki

Soga

. Genetic dissociation of dacryoadenitis and sialadenitis in a Sjögren’s syndrome mouse model with common and different susceptibility gene loci. Invest Ophthalmol Vis Sci 2009; 50: 3257–3265.

10.

Theofilopoulos

Dixon

. Murine models of systemic lupus erythematosus. Adv Immunol 1985; 37: 269–390.

11.

Nguyen

Cornelius

Cooper

. Identification of possible candidate genes regulation Sjögren’s syndrome-associated autoimmunity: A potential role for TNFSF4 in autoimmune exocrinopathy. Arthritis Res Ther 2008; 10: R137–R137.

12.

Santiago-Raber

Laporte

Reininger

Izui

. Genetic basis of murine lupus. Autoimmun Rev 2004; 3: 33–39.

13.

Ichii

Konno

Sasaki

Endoh

Hashimoto

Kon

. Autoimmune glomerulonephritis induced in congenic mouse strain carrying telomeric region of chromosome 1 derived from MRL/MpJ. Histol Histopathol 2008; 23: 411–422.

14.

Ichii

Konno

Sasaki

Endoh

Hashimoto

Kon

. Altered balance of inhibitory and active Fc gamma receptors in murine autoimmune glomerulonephritis. Kidney Int 2008; 74: 339–347.

15.

Cantor

Yuan

Napier

. Systemic lupus erythematosus genome scan: Support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23. Arthritis Rheum 2004; 50: 3203–3210.

16.

Kong

Ogawa

Nakabayashi

. Fas and Fas ligand expression in the salivary glands of patients with primary Sjögren’s syndrome. Arthritis Rheum 1997; 40: 87–97.

17.

Pezzilli

Corsi

Barassi

. Serum adhesion molecules in acute pancreatitis: Time course and early assessment of disease severity. Pancreas 2008; 37: 36–41.

18.

Niederer

Willcocks

Rayner

. Copy number, linkage disequilibrium and disease association in the FCGR locus. Hum Mol Genet 2010; 19: 3282–3294.

19.

Huang

Liu

Daniluk

. Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology 2013; 144: 202–210.

20.

Afanasyeva

Wang

Kaya

. Experimental autoimmune myocarditis in A/J mice is an interleukin-4-dependent disease with a Th2 phenotype. Am J Pathol 2001; 159: 193–203.

21.

Holdsworth

Kitching

Tipping

. Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis. Kidney Int 1999; 55: 1198–1216.

22.

Hopfer

Maron

Butzmann

Helmchen

Weiner

Kalluri

. The importance of cell-mediated immunity in the course and severity of autoimmune anti-glomerular basement membrane disease in mice. FASEB J 2003; 17: 860–868.

23.

Zhang

Goldschmidt

Salter

. Possible allelic structure of IgG2a and IgG2c in mice. Mol Immunol 2012; 50: 169–171.

24.

Choi

Park

Kim

Lim

Kim

. Analysis of age-related changes in the functional morphologies of salivary glands in mice. Arch Oral Biol 2013; 58: 1635–1642.

25.

Whitacre

. Sex differences in autoimmune disease. Nat Immunol 2001; 2: 777–780.

26.

Fox

Michelson

. Approaches to the treatment of Sjögren’s syndrome. J Rheumatol Suppl 2000; 61: 15–21.

27.

Okazaki

Uchida

Fukui

Takaoka

Nishio

. Autoimmune pancreatitis—a new evolving pancreatic disease? Langenbecks Arch Surg 2010; 395: 989–1000.

28.

Andonopoulos

Skopouli

Dimou

Drosos

Moutsopoulos

. SjÖ;gren’s syndrome in systemic lupus erythematosus. J Rheumatol 1990; 17: 201–204.

29.

Ice

Adrianto

. Genetics of Sjögren’s syndrome in the genome-wide association era. J Autoimmun 2012; 39: 57–63.

30.

Choubey

Panchanathan

. Interferon-inducible Ifi200-family genes in systemic lupus erythematosus. Immunol Lett 2008; 119: 32–41.

31.

Ichii

Kamikawa

Otsuka

. Overexpression of interferon-activated gene 202 (Ifi202) correlates with the progression of autoimmune glomerulonephritis associated with the MRL chromosome 1. Lupus 2010; 19: 897–905.

32.

Maruyama

Kobayashi

Sakai

. Periductal induction of high endothelial venule-like vessels in type 1 autoimmune pancreatitis. Pancreas 2013; 42: 53–59.

33.

Cravedi

Abbate

Gagliardini

. Membranous nephropathy associated with IgG4-related disease. Am J Kidney Dis 2011; 58: 272–275.

34.

Naitoh

Nakazawa

Ohara

. Autoimmune pancreatitis associated with various extrapancreatic lesions during a long-term clinical course successfully treated with azathioprine and corticosteroid maintenance therapy. Intern Med 2009; 48: 2003–2007.

35.

Durand

Lamour

Devauchelle

Youinou

Jamin

. Fc-gamma receptor reactivity in nonorgan-specific autoimmune diseases. Clin Rev Allergy Immunol 2000; 18: 11–26.

36.

Pastor

Frossard

. Are genetically modified mice useful for the understanding of acute pancreatitis? FASEB J 2001; 15: 893–897.

37.

Chouchakova

Skokowa

Baumann

. Fc gamma RIII-mediated production of TNF-alpha induces immune complex alveolitis independently of CXC chemokine generation. J Immunol 2001; 166: 5193–5200.