Die funktionellen Besonderheiten von IgG4 und die IgG4-assoziierten Krankheiten aus Sicht des Immunologen

Zusammenfassung

Obwohl IgG4 nur einen geringen Anteil der Serum Immunglobuline ausmacht und die immunologischen Effektormechanismen wie Komplementaktivierung und Bindung an Fc-Rezeptoren nur unzureichend vermittelt, mehren sich derzeit die Berichte über IgG4-vermittelte Erkrankungen (IgG4-related diseases; IgG4-RD). Diese stellen eine erst kürzlich neu definierte Krankheitsentität dar, die durch eine diffuse oder noduläre lympho-plasmazelluläre (IgG4+) Gewebsinfiltration mit chronisch-fibrosierender Entzündungsreaktion in verschiedensten Organen gekennzeichnet ist. Serum IgG4 kann, muss aber nicht erhöht sein, häufig lassen sich diverse IgG4-positive Autoantikörper im Serum nachweisen. Wir fassen die Faktoren, die einen Klassenwechsel zum IgG4 begünstigen, sowie die strukturellen Besonderheiten des IgG4 Moleküls zusammen und diskutieren Mechanismen, wie der Fab-Armaustausch die periphere B-Zelltoleranz beeinflusst und die chronische Immunpathologie bei IgG4-RD unterhalten könnte.

Abstract

The IgG4 subclass accounts only for a small amount of total IgG (3–5%) and exhibits poor effector properties with regard to complement and FcRgamma activation. Yet since 10 years an increasing number of reports has defined a new set of IgG4-related diseases (IgG4-RD) characterised by elevated serum IgG4 levels and diffuse or nodular lympho-plasmocytic infiltrates (>40% IgG4+ plasma cells) in various, mainly exocrine organs. The infiltrates are typically associated with a chronic-fibrosing inflammation. While the serum IgG4+ fraction is not always increased it contains an increased proportion of various autoantibodies. Here we review the structural properties of the IgG4 molecule and the factors regulating class-switch to IgG4 and we discuss how the unique property of IgG4 to undergo Fab-arm exchange may influence the peripheral B cell tolerance and impact on the immunopathology of IgG4-RD.

Schlüsselwörter

IgG4-Eigenschaften - IgG4-assoziierten Krankheiten - Lymphoproliferation

Key words

biology of IgG4 - IgG4-related diseases - lymphoproliferation

• Literatur

• 1 Murphy KM, Travers P, Walport M. Janeways’s Immunobiology. Garland Science; 2011
• 2 Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008; 8 (01) 34-47
• 3 Xiang Z, Cutler AJ, Brownlie RJ et al. FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis. Nat Immunol 2007; 8 (04) 419-429
• 4 Nirula A, Glaser SM, Kalled SL et al. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr Opin Rheumatol 2011; 23 (01) 119-124
• 5 Bruhns P, Iannascoli B, England P et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 2009; 113 (16) 3716-3725
• 6 Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol 2010; 10 (05) 301-316
• 7 Tao MH, Smith RI, Morrison SL. Structural features of human immunoglobulin G that determine isotype-specific differences in complement activation. J Exp Med 1993; 178 (02) 661-667
• 8 Brekke OH, Michaelsen TE, Aase A et al. Human IgG isotype-specific amino acid residues affecting complement-mediated cell lysis and phagocytosis. Eur J Immunol 1994; 24 (10) 2542-2547
• 9 Canfield SM, Morrison SL. The binding affinity of human IgG for its high affinity Fc receptor is determined by multiple amino acids in the CH2 domain and is modulated by the hinge region. J Exp Med 1991; 173 (06) 1483-1491
• 10 van der Neut Kolfschoten M, Schuurman J, Losen M et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 2007; 317 (5844) 1554-1557
• 11 Schuurman J, Van Ree R, Perdok GJ et al. Normal human immunoglobulin G4 is bispecific: it has two different antigen-combining sites. Immunology 1999; 97 (04) 693-698
• 12 Aalberse RC, Stapel SO, Schuurman J et al. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009; 39 (04) 469-477
• 13 Rock B, Martins CR, Teofilopoulos AN et al. The pathogeneic effect of IgG4 autoantibodies in endemic pemphigus foliaceus. N Engl J Med 1989; 320: 1463-1469
• 14 Sitaru C, Mihai S, Zillikens D. The relevance of the IgG subclass of autoantibodies for blister induction in autoimmune bullous skin diseases. Arch Dermatol Res 2007; 299 (01) 1-8
• 15 Parkes AB, McLachlan SM, Bird P et al. The distribution of microsomal and thyro-globulin antibody activity among the IgG subclasses. Clin Exp Immunol 1984; 57 (01) 239-243
• 16 Engelmann R, Brandt J, Eggert M et al. IgG1 and IgG4 are the predominant subclasses among auto-antibodies against two citrullinated antigens in RA. Rheumatology (Oxford) 2008; 47 (10) 1489-1492
• 17 Blanco F, Kalsi J, Ravirajan CT et al. IgG subclasses in systemic lupus erythematosus and other autoimmune rheumatic diseases. Lupus 1992; 1 (06) 391-399
• 18 Brouwer E, Tervaert JW, Horst G et al. Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic autoantibodies (ANCA) in patients with Wegener’s granulomatosis and clinically related disorders. Clin Exp Immunol 1991; 83 (03) 379-386
• 19 Punnonen J, Aversa G, Cocks BG et al. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 1993; 90 (08) 3730-3734
• 20 Ettinger R, Kuchen S, Lipsky PE. The role of IL-21 in regulating B-cell function in health and disease. Immunol Rev 2008; 223: 60-86
• 21 Jeannin P, Lecoanet S, Delneste Y et al. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol 1998; 160 (07) 3555-3561
• 22 Mauri C, Blair PA. Regulatory B cells in autoimmunity: developments and controversies. Nat Rev Rheumatol 2010; 6 (11) 636-643
• 23 Satoguina JS, Adjobimey T, Arndts K et al. Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR-L interaction, IL-10 and TGF-beta. Eur J Immunol 2008; 38 (11) 3101-3113
• 24 Cao D, Malmstrom V, Baecher-Allan C et al. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 2003; 33 (01) 215-223
• 25 Masaki Y, Kurose N, Umehara H. IgG4-related disease: A novel lymphoproliferative disorder discovered and established in Japan in the 21^th century. J Clin Exp Haematol 2011; 51: 13-20
• 26 Divatia M, Mim SA, Ro JY. IgG4-related sclerosing disease, an emerging entity: a review of amulti-system disease. Yonsei Med J 2012; 53: 15-34
• 27 Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; 366: 539-551
• 28 Hamano H, Kawa S, Horiuchi A et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001; 344: 732-738
• 29 Kamisawa T, Nakajima H, Egawa N et al. IgG4-relatedsclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology 2006; 6: 132-137
• 30 Masaki Y, Dong L, Kurose N et al. Proposal for a new clinical entity, IgG4 positive multi-organ lymphoproliferative syndrome: Analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 2009; 68: 1310-1315
• 31 Takahashi H, Yamamoto M, Suzuki C et al. The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity. Autoimmun Rev 2010; 9 (09) 591-594
• 32 Umehara H, Okazaki K, Masaki Y et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012 22. 21-30
• 33 Ferrari S, Mudde GC, Rieger M et al. IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytpenic purpura. J Thromb Haemost 2009; 7: 1703-1710
• 34 Raissian Y, Nasr SH, Larsen CP et al. Diagnosis of IgG4-related tubulo-interstitiell nephritis. J Am Soc Nephrol 2011; 22: 1343-1352
• 35 Saeki T, Nishi S, Ito T et al. Renal lesions in IgG4-related systemic disease. Intern Med 2007; 46: 1365-1371
• 36 Strehl DJ, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol 2011; 64 (03) 237-243
• 37 Engelmann R, Bier A, Voirchow J et al. Immune complex-mediated plamsa cell apoptosis is abrogated by IgG4 – an in vitro study. Minerva Medica 2011; 102 (Suppl. 01) 1-206
• 38 Warnatz K, Keskin AG, Uhl M et al. Immunosuppressive therapy of chronic periaortitis – A retrospective study of 20 patients with chronic periaortitis and a review of the literature. Ann Rheum Dis 2005; 64: 828-833
• 39 Khosroshahi A, Bloc h DM, Deschpande V et al. Rituximab therapy lead to rapid decline of serum IgG-levels and prompt clinical improvement in IgG4-related systemic disorders. Arthritis Rheum 2010; 62: 1755-1762
• 40 Khan ML, Colby TV, Viffiano RW et al. Treatment woth bortezomib of a patient having hyper-IgG4 disease. Clin Lymphoma Myeloma Leuk 2010; 10: 217-219
• 41 Koyabu M, Uchida K, Fukata N et al. Primary sclerosing cholangitis with elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells. J Gastroenterol 2010; 45: 122-129
• 42 Takuma K, Kamisawa T, Igarashi Y. Autoimmune pancreatitis and IgG4-related sclerosing cholangitis. Curr Opinion Rheum 2011; 23 (01) 80-87
• 43 Wang WL, Farris AB, Lauwers GY et al. Autoimmune pancreatitis-related cholecystitis: a morphologically and immunologically distinctive form of lymphoplasmacytic sclerosing cholecystitis. Histopathology 2009; 54: 829-836
• 44 Zen Y, Harada K, Sasaki M et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?. Am J Surg Pathol 2004; 28: 1193-1203
• 45 Kitagawa S, Zen Y, Harada K et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner’s tumor). Am J Surg Pathol 2005; 29: 783-791
• 46 Yamamoto M, Takahashi H, Sugai S et al. Clinical and pathological characteristics of Mikulicz’s disease (IgG4-related plasmacytic exocrinopathy). Autoimmun Rev 2005; 4: 195-200
• 47 Tanaka A, Moriyama M, Nakashima H et al. Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease. Arthritis Rheum 2012; 64: 254-263
• 48 Masaki Y, Sugai S, Umehara H. IgG4-related diseases including Mikulicz’s disease and sclerosing pancreatitis: diagnostic insights. J Rheumatol 2010; 37: 1380-1385
• 49 Kasashima S, Zen Y, Kawashima A et al. Inflammatory abdominal aortic aneurysm: close relationship to IgG4-related periaortitis. Am J Surg Pathol 2008; 32: 197-204
• 50 Stone JR. Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease. Curr Opin Rheumatol 2011; 23: 88-94
• 51 Ishizaka N, Sakamoto A, Imai Y et al. Multifocal fibrosclerosis and IgG4-related disease involving the cardiovascular system. J Cardiol 2012; 59: 132-138
• 52 Sugimoto T, Morita Y, Isshiki K et al. Constrictive pericarditis as an emerging manifestation of hyper-IgG4 disease. Int J Cardiol 2008; 130: e100-e101
• 53 Saeki T, Nishi S, Imai N et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int 2010; 78: 1016-1023
• 54 Li Y, Nishihara E, Hirokawa M et al. Distinct clinical, serological, and sonographic characteristics of hashimoto’s thyroiditis based with and without IgG4-positive plasma cells. J Clin Endocrinol Metab 2010; 95: 1309-1317
• 55 Cheuk W, Chan AC, Lam WL et al. IgG4-related sclerosing mastitis: description of a new member of the IgG4-related sclerosing diseases. Am J Surg Pathol 2009; 33: 1058-1064
• 56 Zen Y, Inoue D, Kitao A et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 2009; 33: 1886-1893
• 57 Yamashita K, Haga H, Kobashi Y et al. Lung involvement in IgG4-related lymphoplasmacytic vasculitis and interstitial fibrosis: report of 3 cases and review of the literature. Am J Surg Pathol 2008; 32: 1620-1626
• 58 Uehara T, Hamano H, Kawakami M et al. Autoimmune pancreatitis-associated prostatitis: distinct clinicopathological entity. Pathol Int 2008; 58: 118-125
• 59 Sato Y, Notohara K, Kojima M et al. IgG4-related disease: historical overview and pathology of hematological disorders. Pathol Int 2010; 60: 247-258
• 60 Cheuk W, Yuen HK, Chu SY et al. Lymphadenopathy of IgG4-related sclerosing disease. Am J Surg Pathol 2008; 32: 671-681
• 61 Grimm KE, Barry TS, Chizhevsky V et al. Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells. Mod Pathol 2012; 25: 480-491
• 62 Hori M, Makita N, Andoh T et al. Long-term clinical course of IgG4-related systemic disease accompanied by hypophysitis. Endocr J 2010; 57: 485-492
• 63 Shimatsu A, Oki Y, Fujisawa I et al. Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J 2009; 56: 1033-1041
• 64 Hamaguchi Y, Fujimoto M, Matsushita Y et al. IgG4-Related Skin Disease, a Mimic of Angiolymphoid Hyperplasia with Eosinophilia. Dermatology 2011; 223: 301-305
• 65 Futei Y, Amagai M, Ishii K et al. Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus. J Dermatol Sci 2001; 26: 55-61