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Published in: BMC Musculoskeletal Disorders 1/2015

Open Access 01-12-2015 | Research article

Screening for IgG4-type anti-nuclear antibodies in IgG4-related disease

Authors: Kazuhiro Kiyama, Hajime Yoshifuji, Tsugumitsu Kandou, Yuji Hosono, Koji Kitagori, Ran Nakashima, Yoshitaka Imura, Naoichiro Yukawa, Koichiro Ohmura, Takao Fujii, Daisuke Kawabata, Tsuneyo Mimori

Published in: BMC Musculoskeletal Disorders | Issue 1/2015

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Abstract

Background

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and infiltration of IgG4+ plasma cells into multiple organs. It is not known whether serum IgG4 is autoreactive in IgG4-RD.

Methods

We measured anti-nuclear antibody (ANA) in 19 IgG4-RD cases, determined IgG subclasses of the ANA, and compared them with those of other systemic autoimmune diseases (systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, and polymyositis), using subclass-based ANA test (indirect immunofluorescence).

Results

58 % of IgG4-RD cases were ANA-positive (cut-off: 1:40). Whereas their subclass of ANA was predominantly IgG2, we observed no IgG4-type ANA. In systemic autoimmune diseases, subclasses of ANA were mostly IgG1, 2, or 3, but IgG4-type ANA was very rarely detected. We also found several patients in whose serum ANA patterns differed among IgG subclasses, probably due to the difference of corresponding autoantigens.

Conclusions

Although IgG4 is highly elevated in sera of IgG4-RD patients, their ANA do not include IgG4 subclass. These results offer new insight into the role of IgG4 and the pathogenesis of IgG4-RD, implying that each IgG subclass tends to cover its own spectrum of antigens, and IgG4 is not preferentially used to make ANA.
Literature
1.
go back to reference Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2009;68(8):1310–5.CrossRefPubMed Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2009;68(8):1310–5.CrossRefPubMed
2.
go back to reference Okazaki K, Uchida K, Miyoshi H, Ikeura T, Takaoka M, Nishio A. Recent concepts of autoimmune pancreatitis and IgG4-related disease. Clin Rev Allergy Immunol. 2011;41(2):126–38.CrossRefPubMed Okazaki K, Uchida K, Miyoshi H, Ikeura T, Takaoka M, Nishio A. Recent concepts of autoimmune pancreatitis and IgG4-related disease. Clin Rev Allergy Immunol. 2011;41(2):126–38.CrossRefPubMed
3.
go back to reference Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22(1):1–14.CrossRefPubMed Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22(1):1–14.CrossRefPubMed
4.
go back to reference Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30.CrossRefPubMed Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30.CrossRefPubMed
5.
go back to reference Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology. 2000;118(3):573–81.CrossRefPubMed Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology. 2000;118(3):573–81.CrossRefPubMed
6.
go back to reference Nishi H, Tojo A, Onozato ML, Jimbo R, Nangaku M, Uozaki H, et al. Anti-carbonic anhydrase II antibody in autoimmune pancreatitis and tubulointerstitial nephritis. Nephrol Dial Transplant. 2007;22(4):1273–5.CrossRefPubMed Nishi H, Tojo A, Onozato ML, Jimbo R, Nangaku M, Uozaki H, et al. Anti-carbonic anhydrase II antibody in autoimmune pancreatitis and tubulointerstitial nephritis. Nephrol Dial Transplant. 2007;22(4):1273–5.CrossRefPubMed
7.
go back to reference Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.CrossRefPubMed Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.CrossRefPubMed
8.
go back to reference Fujibayashi T, Sugai S, Miyasaka N, Hayashi Y, K T: Revised Japanese criteria for Sjögren’s syndrome (1999): availability and validity. Mod Rheumatol 2004(14):425–434. Fujibayashi T, Sugai S, Miyasaka N, Hayashi Y, K T: Revised Japanese criteria for Sjögren’s syndrome (1999): availability and validity. Mod Rheumatol 2004(14):425–434.
9.
go back to reference Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980, 23(5):581–590. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980, 23(5):581–590.
10.
go back to reference Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344–7.CrossRefPubMed Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344–7.CrossRefPubMed
11.
go back to reference Zouali M, Jefferis R, Eyquem A. IgG subclass distribution of autoantibodies to DNA and to nuclear ribonucleoproteins in autoimmune diseases. Immunology. 1984;51(3):595–600.PubMedPubMedCentral Zouali M, Jefferis R, Eyquem A. IgG subclass distribution of autoantibodies to DNA and to nuclear ribonucleoproteins in autoimmune diseases. Immunology. 1984;51(3):595–600.PubMedPubMedCentral
12.
go back to reference Eisenberg RA, Dyer K, Craven SY, Fuller CR, Yount WJ. Subclass restriction and polyclonality of the systemic lupus erythematosus marker antibody anti-Sm. J Clin Invest. 1985;75(4):1270–7.CrossRefPubMedPubMedCentral Eisenberg RA, Dyer K, Craven SY, Fuller CR, Yount WJ. Subclass restriction and polyclonality of the systemic lupus erythematosus marker antibody anti-Sm. J Clin Invest. 1985;75(4):1270–7.CrossRefPubMedPubMedCentral
13.
go back to reference Maran R, Dueymes M, Pennec YL, Casburn-Budd R, Shoenfeld Y, Youinou P. Predominance of IgG1 subclass of anti-Ro/SSA, but not anti-La/SSB antibodies in primary Sjogren's syndrome. J Autoimmun. 1993;6(3):379–87.CrossRefPubMed Maran R, Dueymes M, Pennec YL, Casburn-Budd R, Shoenfeld Y, Youinou P. Predominance of IgG1 subclass of anti-Ro/SSA, but not anti-La/SSB antibodies in primary Sjogren's syndrome. J Autoimmun. 1993;6(3):379–87.CrossRefPubMed
14.
go back to reference Vazquez-Abad D, Monteon V, Senecal JL, Walsh S, Rothfield N. Analysis of IgG subclasses of human antitopoisomerase I autoantibodies suggests chronic B cell stimulation. Clin Immunol Immunopathol. 1997;84(1):65–72.CrossRefPubMed Vazquez-Abad D, Monteon V, Senecal JL, Walsh S, Rothfield N. Analysis of IgG subclasses of human antitopoisomerase I autoantibodies suggests chronic B cell stimulation. Clin Immunol Immunopathol. 1997;84(1):65–72.CrossRefPubMed
15.
go back to reference Rigopoulou EI, Davies ET, Pares A, Zachou K, Liaskos C, Bogdanos DP, et al. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis. Gut. 2005;54(4):528–32.CrossRefPubMedPubMedCentral Rigopoulou EI, Davies ET, Pares A, Zachou K, Liaskos C, Bogdanos DP, et al. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis. Gut. 2005;54(4):528–32.CrossRefPubMedPubMedCentral
16.
go back to reference Asada M, Nishio A, Uchida K, Kido M, Ueno S, Uza N, et al. Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas. 2006;33(1):20–6.CrossRefPubMed Asada M, Nishio A, Uchida K, Kido M, Ueno S, Uza N, et al. Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas. 2006;33(1):20–6.CrossRefPubMed
17.
go back to reference Kiyama K, Kawabata D, Hosono Y, Kitagori K, Yukawa N, Yoshifuji H, et al. Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance. Arthritis Res Ther. 2012;14(2):R86.CrossRefPubMedPubMedCentral Kiyama K, Kawabata D, Hosono Y, Kitagori K, Yukawa N, Yoshifuji H, et al. Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance. Arthritis Res Ther. 2012;14(2):R86.CrossRefPubMedPubMedCentral
18.
go back to reference Rock B, Martins CR, Theofilopoulos AN, Balderas RS, Anhalt GJ, Labib RS, et al. The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem). N Engl J Med. 1989;320(22):1463–9.CrossRefPubMed Rock B, Martins CR, Theofilopoulos AN, Balderas RS, Anhalt GJ, Labib RS, et al. The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem). N Engl J Med. 1989;320(22):1463–9.CrossRefPubMed
19.
go back to reference Ding X, Aoki V, Mascaro Jr JM, Lopez-Swiderski A, Diaz LA, Fairley JA. Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles. J Invest Dermatol. 1997;109(4):592–6.CrossRefPubMed Ding X, Aoki V, Mascaro Jr JM, Lopez-Swiderski A, Diaz LA, Fairley JA. Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles. J Invest Dermatol. 1997;109(4):592–6.CrossRefPubMed
20.
go back to reference Beck Jr LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11–21.CrossRefPubMedPubMedCentral Beck Jr LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11–21.CrossRefPubMedPubMedCentral
21.
go back to reference Brouwer E, Tervaert JW, Horst G, Huitema MG, van der Giessen M, Limburg PC, 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(3):379–86.CrossRefPubMedPubMedCentral Brouwer E, Tervaert JW, Horst G, Huitema MG, van der Giessen M, Limburg PC, 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(3):379–86.CrossRefPubMedPubMedCentral
22.
go back to reference Gao Y, Ye H, Yu F, Guo XH, Zhao MH. Anti-myeloperoxidase IgG subclass distribution and avidity in sera from patients with propylthiouracil-induced antineutrophil cytoplasmic antibodies associated vasculitis. Clin Immunol. 2005;117(1):87–93.CrossRefPubMed Gao Y, Ye H, Yu F, Guo XH, Zhao MH. Anti-myeloperoxidase IgG subclass distribution and avidity in sera from patients with propylthiouracil-induced antineutrophil cytoplasmic antibodies associated vasculitis. Clin Immunol. 2005;117(1):87–93.CrossRefPubMed
23.
go back to reference Mellbye OJ, Mollnes TE, Steen LS. IgG subclass distribution and complement activation ability of autoantibodies to neutrophil cytoplasmic antigens (ANCA). Clin Immunol Immunopathol. 1994;70(1):32–9.CrossRefPubMed Mellbye OJ, Mollnes TE, Steen LS. IgG subclass distribution and complement activation ability of autoantibodies to neutrophil cytoplasmic antigens (ANCA). Clin Immunol Immunopathol. 1994;70(1):32–9.CrossRefPubMed
24.
go back to reference Liu LJ, Chen M, Yu F, Zhao MH, Wang HY. IgG subclass distribution, affinity of anti-myeloperoxidase antibodies in sera from patients with Wegener's granulomatosis and microscopic polyangiitis. Nephrology. 2008;13(7):629–35.CrossRefPubMed Liu LJ, Chen M, Yu F, Zhao MH, Wang HY. IgG subclass distribution, affinity of anti-myeloperoxidase antibodies in sera from patients with Wegener's granulomatosis and microscopic polyangiitis. Nephrology. 2008;13(7):629–35.CrossRefPubMed
25.
go back to reference Engelmann R, Brandt J, Eggert M, Karberg K, Krause A, Neeck G, et al. IgG1 and IgG4 are the predominant subclasses among auto-antibodies against two citrullinated antigens in RA. Rheumatology (Oxford). 2008;47(10):1489–92.CrossRef Engelmann R, Brandt J, Eggert M, Karberg K, Krause A, Neeck G, et al. IgG1 and IgG4 are the predominant subclasses among auto-antibodies against two citrullinated antigens in RA. Rheumatology (Oxford). 2008;47(10):1489–92.CrossRef
26.
go back to reference Holland M, Hewins P, Goodall M, Adu D, Jefferis R, Savage CO. Anti-neutrophil cytoplasm antibody IgG subclasses in Wegener's granulomatosis: a possible pathogenic role for the IgG4 subclass. Clin Exp Immunol. 2004;138(1):183–92.CrossRefPubMedPubMedCentral Holland M, Hewins P, Goodall M, Adu D, Jefferis R, Savage CO. Anti-neutrophil cytoplasm antibody IgG subclasses in Wegener's granulomatosis: a possible pathogenic role for the IgG4 subclass. Clin Exp Immunol. 2004;138(1):183–92.CrossRefPubMedPubMedCentral
27.
go back to reference Hussain A, Pankhurst T, Goodall M, Colman R, Jefferis R, Savage CO, et al. Chimeric IgG4 PR3-ANCA induces selective inflammatory responses from neutrophils through engagement of Fcgamma receptors. Immunology. 2009;128(2):236–44.CrossRefPubMedPubMedCentral Hussain A, Pankhurst T, Goodall M, Colman R, Jefferis R, Savage CO, et al. Chimeric IgG4 PR3-ANCA induces selective inflammatory responses from neutrophils through engagement of Fcgamma receptors. Immunology. 2009;128(2):236–44.CrossRefPubMedPubMedCentral
28.
go back to reference Engelmann R, Eggert M, Neeck G, Mueller-Hilke B. The impact of HLA-DRB alleles on the subclass titres of antibodies against citrullinated peptides. Rheumatology (Oxford). 2010;49(10):1862–6.CrossRef Engelmann R, Eggert M, Neeck G, Mueller-Hilke B. The impact of HLA-DRB alleles on the subclass titres of antibodies against citrullinated peptides. Rheumatology (Oxford). 2010;49(10):1862–6.CrossRef
29.
go back to reference van der Zee JS, van Swieten P, Aalberse RC. Inhibition of complement activation by IgG4 antibodies. Clin Exp Immunol. 1986;64(2):415–22.PubMedPubMedCentral van der Zee JS, van Swieten P, Aalberse RC. Inhibition of complement activation by IgG4 antibodies. Clin Exp Immunol. 1986;64(2):415–22.PubMedPubMedCentral
30.
go back to reference Jefferis R, Reimer CB, Skvaril F, de Lange G, Ling NR, Lowe J, et al. Evaluation of monoclonal antibodies having specificity for human IgG sub-classes: results of an IUIS/WHO collaborative study. Immunol Lett. 1985;10(3–4):223–52.CrossRefPubMed Jefferis R, Reimer CB, Skvaril F, de Lange G, Ling NR, Lowe J, et al. Evaluation of monoclonal antibodies having specificity for human IgG sub-classes: results of an IUIS/WHO collaborative study. Immunol Lett. 1985;10(3–4):223–52.CrossRefPubMed
31.
go back to reference van der Neut KM, Schuurman J, Losen M, Bleeker WK, Martinez-Martinez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317(5844):1554–7.CrossRef van der Neut KM, Schuurman J, Losen M, Bleeker WK, Martinez-Martinez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317(5844):1554–7.CrossRef
33.
go back to reference Hammarstrom L, Smith CI. IgG subclasses in bacterial infections. Monogr Allergy. 1986;19:122–33.PubMed Hammarstrom L, Smith CI. IgG subclasses in bacterial infections. Monogr Allergy. 1986;19:122–33.PubMed
34.
go back to reference Escobar-Perez X, Dorta-Contreras AJ, Interian-Morales MT, Noris-Garcia E, Ferra-Valdes M. IgG2 immunodeficiency: association to pediatric patients with bacterial meningoencephalitis. Arq Neuropsiquiatr. 2000;58(1):141–5.CrossRefPubMed Escobar-Perez X, Dorta-Contreras AJ, Interian-Morales MT, Noris-Garcia E, Ferra-Valdes M. IgG2 immunodeficiency: association to pediatric patients with bacterial meningoencephalitis. Arq Neuropsiquiatr. 2000;58(1):141–5.CrossRefPubMed
Metadata
Title
Screening for IgG4-type anti-nuclear antibodies in IgG4-related disease
Authors
Kazuhiro Kiyama
Hajime Yoshifuji
Tsugumitsu Kandou
Yuji Hosono
Koji Kitagori
Ran Nakashima
Yoshitaka Imura
Naoichiro Yukawa
Koichiro Ohmura
Takao Fujii
Daisuke Kawabata
Tsuneyo Mimori
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2015
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-015-0584-4

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