Anti-Sitoplazmik ve Anti-Mitotik Otoantikorlar; Bu Antikorların Hastalıklarla İlişkisi Var Mı?

Öz

Sistemik otoimmün hastalıkların tanısında antinükleer antikor (ANA) incelemesi yapılır ve HEp-2 hücrelerini kullanan indirekt immünfloresan (IIF) test altın standart yöntemdir. HEp-2, çok sayıda hedef antijene yönelmiş otoantikorların saptanmasına imkân verir. “Antinükleer Antikor (ANA) Paterninde Uluslararası Uzlaşı” rehberi, paternleri üç gruba ayırır: nükleer, sitoplazmik ve mitotik. Bunların çoğu otoimmün hastalıklarla ilişkilidir, ancak bazıları otoimmün hastalıklarda nadiren görülür veya otoimmün hastalık dışındaki durumlarla ilişkili olabilir. Sitoplazmik ve mitotik paternlerin nasıl raporlanacağı konusunda- negatif veya pozitif- bir fikir birliği yoktur. IIF ile ANA değerlendirmesinde sitoplazmik veya mitotik boyanma olan hastaların özelliklerini incelemeyi amaçladık. Tıbbi Mikrobiyoloji Laboratuvarımızda 01.01.2015-31.12.2019 tarihleri arasında 16940 hastaya ait 18985 ANA testi çalışılmıştır. 385 hastaya ait 393 (%2.07) testte sitoplazmik veya mitotik patern tespit edildi. Anti-mitokondriyal antikor (AMA), anti-düz kas antikoru (ASMA), anti-Jo-1 ve anti-ribozomal P-proteini düşündüren sitoplazmik paternler çalışmaya dahil edilmedi. En sık görülen paternler anti-midbody (hücreler arası köprü), anti-spindle fibers (iğsi iplikçikler) ve anti-vimentin paternleriydi. Altmış altı romatoloji hastasında ANA negatifti ancak sitoplazmik veya mitotik boyanma saptandı. Bu hastaların tanı ve paternleri arasında istatistiksel olarak anlamlı bir fark bulunamadı. Anti-hücre antikoru terimi kullanılmadıkça, sitoplazmik veya mitotik patern olması durumunda ANA'nın “negatif” olarak rapor edilmesini öneriyoruz. Bu boyanma, önemli sitoplazmik paternleri ayırt etmek ve bazı spesifik durumlar hakkında fikir vermek için raporun açıklama kısmında belirtilmelidir

Anahtar Kelimeler

• Anti-nükleer antikor
• anti-sitoplazmik patern
• anti-mitotik patern
• otoantikor
• indirekt immünfloresan test

The Anti-Cytoplasmic and Anti-Mitotic Autoantibodies; Are These Antibodies Associated with Diseases?

Öz

Examination of antinuclear antibody (ANA) is used in diagnosis of systemic autoimmune diseases, and the indirect immunofluorescence (IIF) assay using HEp-2 cells is the gold standard method. HEp-2 allows the detection of multiple target antigen-directed autoantibodies. The guide “The International Consensus on ANA Patterns (ICAP)”, characterizes the patterns into three groups: nuclear, cytoplasmic, and mitotic. The majority of these are associated with autoimmune diseases, but some are rarely seen in autoimmune diseases or may be associated with conditions other than autoimmune disease. There is no consensus on how to report cytoplasmic and mitotic patterns-negative or positive. We aimed to examine the characteristics of patients that had cytoplasmic or mitotic staining in ANA evaluation by IIF. In our Medical Microbiology Laboratory, 18985 ANA tests of 16940 patients were studied between 01.01.2015-31.12.2019. Cytoplasmic or mitotic pattern was detected in 393 (2.07%) tests belonging to 385 patients. Cytoplasmic patterns suggestive of anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA), anti-Jo-1 and anti-ribosomal P-protein were not included. The most common patterns were anti-midbody, anti-spindle fibers, and anti-vimentin patterns. There were 66 rheumatology patients that were negative for ANA but had cytoplasmic or mitotic staining. There was no statistically significant difference between the diagnosis and patterns of these patients. We suggest that the ANA should be reported as “negative” in case of cytoplasmic or mitotic pattern unless the term anti-cell antibody is used. It should be noted in the description part of the report in order to distinguish significant cytoplasmic patterns and give an idea for some specific conditions.

Anahtar Kelimeler

• Anti-nuclear antibody
• anti-cytoplasmic pattern
• anti-mitotic pattern
• autoantibody
• indirect immunofluorescence assay

Kaynakça

1. Meroni PL, Schur PH. ANA screening: an old test with new recommendations. Ann Rheum Dis 2010;69:1420-2.
2. Chan EKL, de Melo Cruvinel W, Andrade LEC. The International Consensus on Standardized Nomenclature of Antinuclear Antibody HEp-2 Cell Patterns (ICAP) initiative - Current state and perspectives. In: Conrad K, Chan EKL, Andrade LEC, Steiner G, Pruijn GJM, Shoenfeld Y, editors. From Autoantibody Research to Standardized Diagnostic Assays in the Management of Human Diseases series. Report on the 12th Dresden Symposium on Autoantibodies. Germany. 2015. p. 282-288.
3. Damoiseaux J, von Mühlen CA, Garcia-De La Torre I, Carballo OG, de Melo Cruvinel W, Francescantonio PL, et al. International consensus on ANA patterns (ICAP): the bumpy road towards a consensus on reporting ANA results. Auto Immun Highlights 2016;7:1.
4. Agmon-Levin N, Damoiseaux J, Kallenberg C, Sack U, Witte T, Herold M, et al. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis 2014;73:17-23.
5. Chan EKL, Damoiseaux J, Carballo OG, Conrad K, de Melo Cruvinel W, Francescantonio PLC, et al. Report of the First International Consensus on Standardized Nomenclature of Antinuclear Antibody HEp-2 Cell Patterns 2014-2015. Front Immunol 2015;6:412.
6. Andrade LEC, Klotz W, Herold M, Conrad K, Rönnelid J, Fritzler MJ, von Mühlen CA, Satoh M, Damoiseaux J, Cruvinel WM, Chan EKL; Executive Committee of ICAP. International consensus on antinuclear antibody patterns: definition of the AC-29 pattern associated with antibodies to DNA topoisomerase I. Clin Chem Lab Med 2018. pii: /j/cclm.ahead-of-print/cclm-2018-0188/cclm-2018-0188.xml.
7. Chan EKL, Damoiseaux J, de Melo Cruvinel W, Carballo OG, Conrad K, Francescantonio PL, et al. Report on the second International Consensus on ANA Pattern (ICAP) workshop in Dresden 2015. Lupus 2016;25:797-804.
8. Hughes GRV, Asherson RA. Atypical lupus with special reference to ANA negative lupus and lupus subsets. Adv Nephrol 1985;14:333-46.

9. Reichlin M. ANA negative systemic lupus erythematosus sera revisited serologically. Lupus 2000; 9:116-9.
10. Dellavance A, Junior AG, Cintra AFU, Ximenes AC, Nuccitelli B, Taliberti BH, et al. II Brazilian consensus on antinuclear antibodies in HEp-2 cells. Definitions for standardization of autoantibody testing against the nucleus (ANA HEP-2), nucleolus, cytoplasm and mitotic apparatus, as well as its clinical associations. Rev Bras Reumatol 2003;43:129-40.
11. von Mühlen CA, Garcia-De La Torre I, Infantino M, Damoiseaux J, Andrade LEC, Carballo OG, Conrad K, Francescantonio PLC, Fritzler MJ, Herold M, Klotz W, de Melo Cruvinel W, Mimori T, Satoh M, Musset L, Chan EKL. How to report the antinuclear antibodies (anti-cell antibodies) test on HEp-2 cells: guidelines from the ICAP initiative. Immunol Res 2021 Dec;69(6):594-608.
12. Francescantonio P, Cruvinel W, Dellavance A, et al. IV Brazilian Guidelines for autoantibodies on HEp-2 cells. Rev Bras Reumatol 2014;54(1):44–50.
13. Infantino M, Palterer B, Biagiotti R, Almerigogna F, Benucci M, Damiani A, et al. Reflex testing of speckled cytoplasmic patterns observed in routine ANA HEp-2 indirect immunofluorescence with a multiplex anti-synthetase dot-blot assay: a multicentric pilot study. Immunol Res 2018;66:74‐8.
14. Stinton LM, Eystathioy T, Selak S, Chan EKL, Fritzler MJ. Autoantibodies to protein transport and messenger RNA processing pathways: endosomes, lysosomes, Golgi complex, proteasomes, assemblyosomes, exosomes, and GW bodies. Clin Immunol 2004;110:30-44.
15. Koh WH, Dunphy J, Whyte J, Dixey J, McHugh NJ. Characterization of anticytoplasmic antibodies and their clinical associations. Ann Rheum Dis 1995;54:269-73.
16. Craig WY, Ledue TB, Collins MF, Meggison WE, Leavitt LF, Ritchie RF. Serologic associations of anti-cytoplasmic antibodies identified during anti-nuclear antibody testing. Clin Chem Lab Med 2006;44:1283-6.
17. Satoh M, Chan EKL, Ho LA, Rose KM, Parks CG, Cohn RD, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum 2012;64:2319-27.
18. Betancur JF, Londoño A, Estrada VE, Puerta SL, Osorno SM, Loazia A, et al. Uncommon patterns of antinuclear antibodies recognizing mitotic spindle apparatus antigens and clinical associations. Medicine (Baltimore) 2018;97:e11727.
19. Vermeersch P, Bossuyt X. Prevalence and clinical significance of rare antinuclear antibody patterns. Autoimmun Rev 2013;12:998-1003.
20. Senecal JL, Oliver JM, Rothfield N. Anticytoskeletal autoantibodies in the connective tissue diseases. Arthritis Rheum 1985;28:889-98.
21. Fritzler MJ, Ayer LM, Gohill J, O’Connor C, Laxer RM, Humbel RL. An antigen in metaphase chromatin and the midbody of mammalian cells binds to scleroderma sera. J Rheumatol 1987;14:291-4.
22. Bettoni L, Perini P, Milanesi B. Significato clinic degli anticorpi anti-midbody. (In Italian). Caso Clinico RIMeL / IJLaM 2009; 5.
23. Tausche AK, Conrad K, Seidel W, Roch B. Anti-midbody antibodies as a possible predictive factor for a special limited or abortive form of systemic sclerosis? Ann Rheum Dis 2005;64:1237-8.
24. Andrade LE, Chan EK, Peebles CL, Tan EM. Two major autoantigen-antibody systems of the mitotic spindle apparatus. Arthritis Rheum 1996;39:1643-53.
25. Whitehead CM, Winkfein RJ, Fritzler MJ, Rattner JB. The spindle kinesin-like protein HsEg5 is an autoantigen in systemic lupus erythematosus. Arthritis Rheum 1996;39:1635-42.
26. Mozo L, Gutiérrez C, Gómez J. Antibodies to mitotic spindle apparatus: clinical significance of NuMA and HsEg5 autoantibodies. J Clin Immunol 2008;28:285-90.
27. Szalat R, Ghillani-Dalbin P, Jallouli M, Amoura Z, Musset L, Cacoub P, Sene D. Anti-NuMA1 and anti-NuMA2 (anti-HsEg5) antibodies: Clinical and immunological features: A propos of 40 new cases and review of the literature. Autoimmun Rev 2010;9:652-6.
28. Rose ML. Role of anti-vimentin antibodies in allograft rejection. Hum Immunol 2013;74:1459-62.
29. Divanyan T, Acosta E, Patel D, Constantino D, Lopez-Soler RI. Anti-vimentin antibodies in transplant and disease. Hum Immunol 2019;80:602-7.
30. Alvarez-Márquez A, Aguilera I, Blanco RM, Pascual D, Encarnacion-Carrizosa M, Alvarez-Lopez MR, et al. Positive association of anticytoskeletal endothelial cell antibodies and cardiac allograft rejection. Hum Immunol 2008;69:143-8.
31. Lopez-Soler RI, Borgia JA, Kanangat S, Fhied CL, Conti DJ, Constantino D, et al. Anti-vimentin Antibodies Present at the Time of Transplantation May Predict Early Development of Interstitial Fibrosis/Tubular Atrophy. Transplant Proc 2016;48:2023-33.
32. Besarani D, Cerundolo L, Smith JD, Procter J, Barnardo MCN, Roberts ISD, et al. Role of anti-vimentin antibodies in renal transplantation. Transplantation 2014;98:72-8.
33. Mahesh B, Leong HS, McCormack A, Sarathchandra P, Holder A, Rose ML. Autoantibodies to vimentin cause accelerated rejection of cardiac allografts. Am J Pathol 2007;170:1415-27.
34. Li FJ, Surolia R, Li H, Wang Z, Kulkarni T, Liu G, et al. Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis. J Immunol 2017;199:1596-605.
35. Yang Y, Fujita J, Bandoh S, Ohtsuki Y, Yamadori I, Yoshinouchi T, Ishida T. Detection of antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. Clin Exp Immunol 2002;128:169-74.
36. Kotaska K, Petrak B, Kukacka J, Kraus J, Prusa R. Anti-vimentin antibodies and neuron-specific enolase in children with neurofibromatosis type-1. Neuro Endocrinol Lett 2007;28:761-4.
37. Bonaci-Nikolic B, Andrejevic S, Bukilica M, Urosevic I, Nikolic M. Autoantibodies to mitotic apparatus: association with other autoantibodies and their clinical significance. J Clin Immunol 2006;26:438-46.
38. Maniotis A, Schliwa M. Microsurgical removal of centrosomes blocks cell reproduction and centriole generation in BSC-1 cells. Cell 1991;67:495-504.
39. Brenner S, Pepper DA, Turner DS, Boyd AE, Brinkley BR. Autoantibodies in human serum selectively bind to the centriole region in cultured cells. J Cell Biol 1980;87:240a.
40. Takahashi T, Asano Y, Hirakawa M, Nakamura K, Saigusa R, Aozasa N, et al. Linear scleroderma with prominent multiple lymphadenopathy followed by the development of polymyositis: a case report and review of published work. J Dermatol 2016;43:1224-7.
41. Howng SL, Chou AK, Lin CC, Lin ZA, Wang CJ, Loh JK, et al. Autoimmunity against hNinein, a human centrosomal protein, in patients with rheumatoid arthritis and systemic lupus erythematosus. Mol Med Rep 2011;4:825-30.
42. Hamaguchi Y, Matsushita T, Hasegawa M, Ueda-Hayakawa I, Sato S, Takehara K, Fujimoto M. High incidence of pulmonary arterial hypertension in systemic sclerosis patients with anti-centriole autoantibodies. Mod Rheumatol 2015;25:798-801.
43. Gavanescu I, Vazquez-Abad D, McCauley J, Senecal JL, Doxsey S. Centrosome proteins: a major class of autoantigens in scleroderma. J Clin Immunol 1999;19:166-71.
44. Cimolai N, Mah D, Roland E. Anticentriolar autoantibodies in children with central nervous system manifestations of Mycoplasma pneumonia infection. J Neurol Neurosurg Psychiatry 1994;57:638-9.
45. Madrid FF, Maroun MC, Olivero OA, Long M, Stark A, Grossman LI, et al. Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis. BMC Cancer 2015;15:407.
46. Maroun MC, Olivero O, Lipovich L, Stark A, Tait L, Bandyopadhyay S, et al. Anti-centrosome antibodies in breast cancer are the expression of autoimmunity. Immunol Res 2014;60:339-47.
47. Alpini C, Lotzniker M, Valaperta S, Bottone MG, Malatesta M, Montanelli A, Merlini G. Characterization for anti-cytoplasmic antibodies specificity by morphological and molecular techniques. Auto Immun Highlights 2012;3:79-85.
48. Rossie KM, Piesco NP, Charley MR, Oddis CV, Steen VD, Fratto J, Deng JS. A monoclonal antibody recognizing Golgi apparatus produced using affinity purified material from a patient with connective tissue disease. Scand J Rheumatol 1992;21:109-15.
49. Wallis D, Greig A, Dunphy J, Owen P, McHugh N. Anti-Golgi autoantibodies: prevalence and disease associations in a rheumatic disease population. Int J Rheum Dis 2012;15:23-5.
50. Ma L, Zeng A, Chen Y, Chen B, Zhou R. Anti-golgi antibodies: Prevalence and disease association in Chinese population. Clin Chim Acta 2019;496:121-4.
51. Hong HS, Chung WH, Hung SI, Chen MJ, Lee SH, Yang LC. Clinical association of anti-Golgi autoantibodies and their autoantigens. Scand J Immunol 2004;59:79-87.
52. Vermeersch P, Van den Bergh K, Blockmans D, Westhovens R, Bossuyt X. Anti-Golgi autoantibodies are not clinically associated with systemic autoimmune diseases. Ann Rheum Dis 2011;70:234-5.
53. Rodriguez JL, Gelpi C, Thomson TM, Real FJ, Fernández J. Anti-golgi complex autoantibodies in a patient with Sjögren syndrome and lymphoma. Clin Exp Immunol 1982;49:579-86.
54. Fritzler MJ, Etherington J, Sokoluk C, Kinsella TD, Valencia DW. Antibodies from patients with autoimmune disease react with a cytoplasmic antigen in the Golgi apparatus. J Immunol 1984;132:2904-8.
55. Staub HL, Souza F, Chan EKL, von Mühlen CA. Anti-Golgi antibodies in adult Still's disease. Clin Exp Rheumatol 2003;21:275-6.
56. Bizzaro N, Pasini P, Ghirardello A, Finco B. High anti-golgi autoantibody levels: an early sign of autoimmune disease? Clin Rheumatol 1999;18:346-8.
57. Hong HS, Morshed SA, Tanaka S, Fujiwara T, Ikehara Y, Nishioka M. Anti-Golgi antibody in rheumatoid arthritis patients recognizes a novel antigen of 79kDa (doublet) by Western blot. Scand J Immunol 1992;36:785-92.
58. Yang Y, Fujita J, Tokuda M, Bandoh S, Ishida T, Murota M, et al. Clinical features of several connective tissue diseases with anti- Golgi antibody. Ann Rheum Dis 2001;60:986–7.
59. Taniai M, Isono E, Nakamura S, Kobayashi K, Matsushima S, Komatsu T, et al. A case of autoimmune hepatitis associated with rheumatoid arthritis presenting with anti-Golgi antibody (in Japanese). Kanzo 1994;37:428-33.
60. Cumming WJ, Weiser R, Teoh R, Hudgson P, Walton JN. Localised nodular myositis: a clinical and pathological variant of polymyositis. Q J Med 1977;46:531-46.
61. Marui K, Sahashi K, Ibi T, Ling J, Nakao N. Corticosteroid responsive inflammatory myopathy with autoantibody against Golgi apparatus. Rinsho Shinkeigaku 1995;35:379-83.
62. Sahashi K, Ibi T, Ohno K, Sahashi K, Nakao N, Kondo H. Progressive myopathy with circulating autoantibody against giantin in the Golgi apparatus. Neurology 2004;62:1891-3.
63. Hattori H, Nagata E, Ishihara T, Jinnouchi K, Ogawa Y, Nagai T, et al. Inflammatory myopathy with anti-Golgi antibody and anti-SS-A/Ro antibody. Intern Med 2007;46:1927-30.
64. Probst C, Radzimski C, Blöcker IM, Teegen B, Bogdanos DP, Stöcker W, Komorowski L. Development of a recombinant cell-based indirect immunofluorescence assay (RC-IFA) for the determination of autoantibodies against "rings and rods"-associated inosine-5'-monophosphate dehydrogenase 2 in viral hepatitis C. Clin Chim Acta 2013;418:91-6.
65. Covini G, Carcamo WC, Bredi E, von Mühlen CA, Colombo M, Chan EK. Cytoplasmic rods and rings autoantibodies developed during pegylated interferon and ribavirin therapy in patients with chronic hepatitis C. Antivir Ther 2012;17:805-11.
66. Climent J, Morandeira F, Castellote J, Xiol J, Niubo J, Calatayud L, et al. Clinical correlates of the "rods and rings" antinuclear antibody pattern. Autoimmunity 2016;49:102-8.
67. Calise SJ, Carcamo WC, Ceribelli A, Dominguez Y, Satoh M, Chan EKL. Antibodies to rods and rings. In: Meroni PL, Gershwin ME, editors. Autoantibodies, 3rd ed. San Diego, CA: Elsevier, 2014:161–8.
68. Keppeke GD, Prado MS, Nunes E, Perazzio SF, Rodriguez SH, Ferraz MLG, et al. Differential capacity of therapeutic drugs to induce Rods/Rings structures in vitro and in vivo and generation of anti-Rods/Rings autoantibodies. Clin Immunol 2016;173:149-56.
69. Ohta M, Ohta K, Itoh N, Kurobe M, Hayashi K, Nishitani H. Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-myosin, actomyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis. Clin Chim Acta 1990;187:255-64.
70. Fries W, Comunale S. Ulcerative colitis: pathogenesis. Curr Drug Targets 2011;12:1373-82.
71. Mayet WJ, Press AG, Hermann E, Moll R, Manns M, Ewe K, zum Büschenfelde KHM. Antibodies to cytoskeletal proteins in patients with Crohn's disease. Eur J Clin Invest 1990;20:516-24.
72. Blaschek M, Muller S, Youinou P. Anti-"dividing cell antigen" autoantibody: a novel antinuclear antibody pattern related to histones in systemic lupus erythematosus. J Clin Immunol 1993;13:329-38.
73. Rayzman VM, Sentry JW. MCA1 detection of histone H3 serine 10 phosphorylation, a novel biomarker for determination of mitotic indices. Hum Antibodies 2006;15:71-80.
74. Bhanji RA, Eystathioy T, Chan EKL, Bloch DB, Fritzler MJ. Clinical and serological features of patients with autoantibodies to GW/P bodies. Clin Immunol 2007;125:247-56.