nach oben

Erschienen in:

01.02.2009 | Original Article

Deficiency in EBV-induced gene 3 (EBI3) in MRL/lpr mice results in pathological alteration of autoimmune glomerulonephritis and sialadenitis

verfasst von: Takashi Igawa, Hitoshi Nakashima, Atsushi Sadanaga, Kohsuke Masutani, Katsuhisa Miyake, Sakiko Shimizu, Atsunobu Takeda, Shinjiro Hamano, Hiroki Yoshida

Erschienen in: Modern Rheumatology | Ausgabe 1/2009

Einloggen, um Zugang zu erhalten

Abstract

MRL/lpr mice develop a systemic autoimmune disease that is reminiscent of systemic lupus erythematosus (SLE) and Sjögren’s syndrome in humans. To investigate the role of IL-27 in the development of autoimmune disorders in MRL/lpr mice, we disrupted the EBV-induced gene 3 (EBI3), which is a subunit of IL-27. Consequently, the pathophysiology of glomerulonephritis and sialadenitis, which develops in MRL/lpr mice, was drastically changed. EBI3^−/− MRL/lpr mice developed disease that resembles human membranous glomerulonephritis (MGN), not diffuse proliferative glomerulonephritis (DPGN), with a predominance of IgG1 in glomerular deposits, and different type sialadenitis from Sjögren’s syndrome, with IgG1 producing plasma cell infiltration in salivary glands, accompanied by increased IgG1 and IgE in the sera. T cells in these mice displayed significantly reduced IFN-γ production along with elevated IL-4 expression. Loss of EBI3 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of phenotypes of human autoimmune diseases.

Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity. 2002;16:779–90.PubMedCrossRef

Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, et al. A novel interleukin-12 p40-related protein induced by latent Epstein–Barr virus infection in B lymphocytes. J Virol. 1996;70:1143–53.PubMed

Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E, Bazan JF, et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol. 2004;172:2225–31.PubMed

Artis D, Villarino A, Silverman M, He W, Thornton EM, Mu S, et al. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J Immunol. 2004;173:5626–34.PubMed

Hibbert L, Pflanz S, De Waal Malefyt R, Kastelein RA. IL-27 and IFN-alpha signal via Stat1 and Stat3 and induce T-Bet and IL-12Rbeta2 in naive T cells. J Interferon Cytokine Res. 2003;23:513–22.PubMedCrossRef

Takeda A, Hamano S, Yamanaka A, Hanada T, Ishibashi T, Mak TW, et al. Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J Immunol. 2003;170:4886–90.PubMed

Chen Q, Ghilardi N, Wang H, Baker T, Xie MH, Gurney A, et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature. 2000;407:916–20.PubMedCrossRef

Takeda A, Hamano S, Shiraishi H, Yoshimura T, Ogata H, Ishii K, et al. WSX-1 over-expression in CD4(+) T cells leads to hyperproliferation and cytokine hyperproduction in response to TCR stimulation. Int Immunol. 2005;17:889–97.PubMedCrossRef

Yoshida H, Hamano S, Senaldi G, Covey T, Faggioni R, Mu S, et al. WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. Immunity. 2001;15:569–78.PubMedCrossRef

10.

Lucas S, Ghilardi N, Li J, de Sauvage FJ. IL-27 regulates IL-12 responsiveness of naive CD4⁺ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci USA. 2003;100:15047–52.PubMedCrossRef

11.

Miyazaki Y, Inoue H, Matsumura M, Matsumoto K, Nakano T, Tsuda M, et al. Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice. J Immunol. 2005;175:2401–7.PubMed

12.

Villarino A, Hibbert L, Lieberman L, Wilson E, Mak T, Yoshida H, et al. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity. 2003;19:645–55.PubMedCrossRef

13.

Dixon FJ. The pathogenesis of glomerulonephritis. Am J Med. 1968;44:493–8.PubMedCrossRef

14.

Churg J BJ, Glassock RJ. Renal disease: Classification and atlas of glomerular disease. In: Churg J, Bernstein J, Glassock RJ, editors. Tokyo: Igaku-Shoin; 1995. p. 151–6.

15.

Masutani K, Akahoshi M, Tsuruya K, Tokumoto M, Ninomiya T, Kohsaka T, et al. Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum. 2001;44:2097–106.PubMedCrossRef

16.

Akahoshi M, Nakashima H, Tanaka Y, Kohsaka T, Nagano S, Ohgami E, et al. Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis Rheum. 1999;42:1644–8.PubMedCrossRef

17.

Van Parijs L, Abbas AK. Role of Fas-mediated cell death in the regulation of immune responses. Curr Opin Immunol. 1996;8:355–61.PubMedCrossRef

18.

Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol. 1985;37:269–390.PubMedCrossRef

19.

Shimizu S, Sugiyama N, Masutani K, Sadanaga A, Miyazaki Y, Inoue Y, et al. Membranous glomerulonephritis development with Th2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1). J Immunol. 2005;175:7185–92.PubMed

20.

Sugiyama N, Nakashima H, Yoshimura T, Sadanaga A, Shimizu S, Masutani K, et al. Amelioration of human lupus-like phenotypes in MRL/lpr mice by overexpression of IL-27R{alpha} (WSX-1). Ann Rheum Dis. 2007. (Epub ahead of print).

21.

Woodrow DF, Shore I, Moss J, Gower P, Phillips M. Immunoelectron microscopic studies of immune complex deposits and basement membrane components in IgA nephropathy. J Pathol. 1989;157:47–57.PubMedCrossRef

22.

Cohen PL, Eisenberg RA. Lpr and gld: single-gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–69.PubMedCrossRef

23.

Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol. 2007;37:3021–9.PubMedCrossRef

24.

Hoffman RW, Alspaugh MA, Waggie KS, Durham JB, Walker SE. Sjögren’s syndrome in MRL/l and MRL/n mice. Arthritis Rheum. 1984;27:157–65.PubMedCrossRef

25.

Jonsson R, Tarkowski A, Backman K, Holmdahl R, Klareskog L. Sialadenitis in the MRL-l mouse: morphological and immunohistochemical characterization of resident and infiltrating cells. Immunology. 1987;60:611–6.PubMed

26.

Hasegawa H, Inoue A, Kohno M, Muraoka M, Miyazaki T, Terada M, et al. Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice. Arthritis Rheum. 2006;54:1174–83.PubMedCrossRef

27.

Yanagi K, Haneji N, Hamano H, Takahashi M, Higashiyama H, Hayashi Y. In vivo role of IL-10 and -12 during development of Sjögren’s syndrome in MRL/lpr mice. Cell Immunol. 1996;168:243–50.PubMedCrossRef

28.

Fox RI, Kang HI, Ando D, Abrams J, Pisa E. Cytokine mRNA expression in salivary gland biopsies of Sjögren’s syndrome. J Immunol. 1994;152:5532–9.PubMed

29.

Ohyama Y, Nakamura S, Matsuzaki G, Shinohara M, Hiroki A, Fujimura T, et al. Cytokine messenger RNA expression in the labial salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum. 1996;39:1376–84.PubMedCrossRef

30.

Konttinen YT, Kemppinen P, Koski H, Li TF, Jumppanen M, Hietanen J, et al. T(H)1 cytokines are produced in labial salivary glands in Sjögren’s syndrome, but also in healthy individuals. Scand J Rheumatol. 1999;28:106–12.PubMedCrossRef

31.

Price EJ, Venables PJ. The etiopathogenesis of Sjögren’s syndrome. Semin Arthritis Rheum. 1995;25:117–33.PubMedCrossRef

32.

Ozaki Y, Amakawa R, Ito T, Iwai H, Tajima K, Uehira K, et al. Alteration of peripheral blood dendritic cells in patients with primary Sjögren’s syndrome. Arthritis Rheum. 2001;44:419–31.PubMedCrossRef

33.

Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–8.PubMedCrossRef

34.

Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut. 2003;52:683–7.PubMedCrossRef

35.

Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982–4.PubMedCrossRef

36.

Kamisawa T, Chen PY, Tu Y, Nakajima H, Egawa N. Autoimmune pancreatitis metachronously associated with retroperitoneal fibrosis with IgG4-positive plasma cell infiltration. World J Gastroenterol. 2006;12:2955–7.PubMed

37.

Kitagawa S, Zen Y, Harada K, Sasaki M, Sato Y, Minato H, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner’s tumor). Am J Surg Pathol. 2005;29:783–91.PubMedCrossRef

38.

Zen Y, Kasahara Y, Horita K, Miyayama S, Miura S, Kitagawa S, et al. Inflammatory pseudotumor of the breast in a patient with a high serum IgG4 level: histologic similarity to sclerosing pancreatitis. Am J Surg Pathol. 2005;29:275–8.PubMedCrossRef

39.

Zen Y, Sawazaki A, Miyayama S, Notsumata K, Tanaka N, Nakanuma Y. A case of retroperitoneal and mediastinal fibrosis exhibiting elevated levels of IgG4 in the absence of sclerosing pancreatitis (autoimmune pancreatitis). Hum Pathol. 2006;37:239–43.PubMedCrossRef

40.

Yamamoto M, Harada S, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. Clinical and pathological differences between Mikulicz’s disease and Sjogren’s syndrome. Rheumatology (Oxford). 2005;44:227–34.CrossRef

41.

Morgan WS, Castleman B. A clinicopathologic study of Mikulicz’s disease. Am J Pathol. 1953;29:471–503.PubMed

42.

Zhang K, Mills FC, Saxon A. Switch circles from IL-4-directed epsilon class switching from human B lymphocytes. Evidence for direct, sequential, and multiple step sequential switch from mu to epsilon Ig heavy chain gene. J Immunol. 1994;152:3427–35.PubMed

43.

Agresti A, Vercelli D. Analysis of gamma4 germline transcription in human B cells. Int Arch Allergy Immunol. 1999;118:279–81.PubMedCrossRef

44.

Miyake K, Moriyama M, Aizawa K, Nagano S, Inoue Y, Sadanaga A, et al. Peripheral CD4⁺ T cells showing a Th2 phenotype in a patient with Mikulicz’s disease associated with lymphadenopathy and pleural effusion. Mod Rheumatol. 2008;18:86–90.PubMedCrossRef

Titel: Deficiency in EBV-induced gene 3 (EBI3) in MRL/lpr mice results in pathological alteration of autoimmune glomerulonephritis and sialadenitis
verfasst von: Takashi Igawa
Hitoshi Nakashima
Atsushi Sadanaga
Kohsuke Masutani
Katsuhisa Miyake
Sakiko Shimizu
Atsunobu Takeda
Shinjiro Hamano
Hiroki Yoshida
Publikationsdatum: 01.02.2009
Verlag: Springer Japan
Erschienen in: Modern Rheumatology / Ausgabe 1/2009
Print ISSN: 1439-7595
Elektronische ISSN: 1439-7609
DOI: https://doi.org/10.1007/s10165-008-0117-1

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

SGLT2-Inhibitoren und GLP-1-Rezeptoragonisten im Schlagabtausch

16.05.2024 DDG-Jahrestagung 2024 Kongressbericht

Wer hat die Nase vorn – SGLT2-Inhibitoren oder GLP-1-Rezeptoragonisten? Diese Frage diskutierten zwei Experten in einer Session auf dem diesjährigen Diabetes-Kongress.

Betalaktam-Allergie: praxisnahes Vorgehen beim Delabeling

16.05.2024 Pädiatrische Allergologie Nachrichten

Die große Mehrheit der vermeintlichen Penicillinallergien sind keine. Da das „Etikett“ Betalaktam-Allergie oft schon in der Kindheit erworben wird, kann ein frühzeitiges Delabeling lebenslange Vorteile bringen. Ein Team von Pädiaterinnen und Pädiatern aus Kanada stellt vor, wie sie dabei vorgehen.

Alphablocker schützt vor Miktionsproblemen nach der Biopsie

16.05.2024 alpha-1-Rezeptorantagonisten Nachrichten

Nach einer Prostatabiopsie treten häufig Probleme beim Wasserlassen auf. Ob sich das durch den periinterventionellen Einsatz von Alphablockern verhindern lässt, haben australische Mediziner im Zuge einer Metaanalyse untersucht.

Delir bei kritisch Kranken – Antipsychotika versus Placebo

16.05.2024 Delir nicht substanzbedingt Nachrichten

Um die Langzeitfolgen eines Delirs bei kritisch Kranken zu mildern, wird vielerorts auf eine Akuttherapie mit Antipsychotika gesetzt. Eine US-amerikanische Forschungsgruppe äußert jetzt erhebliche Vorbehalte gegen dieses Vorgehen. Denn es gibt neue Daten zum Langzeiteffekt von Haloperidol bzw. Ziprasidon versus Placebo.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2009

Response of early active rheumatoid arthritis to tumor necrosis factor inhibitors: evaluation by magnetic resonance imaging

An adult case of Henoch-Schönlein purpura complicating common peroneal nerve mononeuropathy

Improvement in diagnosis and management of musculoskeletal conditions with one-stop clinic-based ultrasonography

Sjogren’s syndrome: promising, new treatment options besides nizatidine

Treatment of refractory retrobulbar granuloma with rituximab in a patient with ANCA-negative Wegener’s granulomatosis: a case report