mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2014-3-221-226mimmun-687Research ArticleОБЗОРЫREVIEWSНОВЫЕ ПОДХОДЫ К СТАНДАРТИЗАЦИИ ВЫЯВЛЕНИЯ АУТОАНТИТЕЛ В ЛАБОРАТОРНОЙ ДИАГНОСТИКЕ АУТОИММУННЫХ РЕВМАТИЧЕСКИХ ЗАБОЛЕВАНИЙNOVEL METHODS FOR AUTOANTIBODY DETECTION IN LABORATORY DIAGNOSTICS OF AUTOIMMUNE RHEUMATIC DISEASESРоггенбукД.RoggenbuckD.

д.м.н., профессор, факультет биотехнологии, Бранденбургский технический университет Коттбус-Зенфтенберг

PhD, MD (Medicine), Professor, Faculty of Science,Brandenburg Technical University Cottbus-Senftenberg

dirk.roggenbuck@hs-lausitz.deШиракП.SchieracP.

д.м.н., профессор, Факультет биотехнологии, Бранденбургский технический университет Коттбус-Зенфтенберг

PhD, MD (Medicine), Professor, Faculty of Science,Brandenburg Technical University Cottbus-Senftenberg

СакУ.SackU.

д.м.н., профессор, Институт трансляционной и регенеративной медицины, Университет Лейпцига

PhD, MD (Medicine), Professor, Institute of Translationaland Regenerative Medicine, University of Leipzig

ЛапинС. В.LapinS. V.

к.м.н., заведующий лабораторей диагностики аутоиммунных заболеваний, Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова

PhD (Medicine), Сhief, Laboratory of AutoimmuneDiagnostics, St. Petersburg Pavlov State Medical University

МазингА. В.MazingA. V.

к.м.н, старший научный сотрудник лаборатории диагностики аутоиммунных заболеваний, Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова

PhD (Medicine), Senior Research Associate,Laboratory of Autoimmune Diagnostics, St. Petersburg Pavlov State Medical University

ТотолянАрег А.TotolianAreg A.

д.м.н., член-корр. РАМН, заместитель директора по научной работе, Санкт-Петербургский НИИ эпидемиологии и микробиологии имени Пастера; заведующий НИЛ иммунологии, Федеральный медицинский исследовательский центр им. В.А. Алмазова Минздрава России

PhD, MD (Medicine), Professor, Corresponding Member of RAMS, Deputy Director, St. Petersburg Pasteur Institute ofEpidemiology and Microbiology; Head, Laboratory of Immunology, Almazov Federal Medical Research Centre

Бранденбургский технический университет Коттбус-Зенфтенберг, ГерманияРоссияBrandenburg Technical University Cottbus-Senftenberg, Senftenberg, GermanyRussian FederationИнститут трансляционной и регенеративной медицины, Университет Лейпцига, ГерманияРоссияInstitute of Translational and Regenerative Medicine, University of Leipzig, GermanyRussian FederationПервый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова, Санкт-ПетербургРоссияSt. Petersburg Pavlov State Medical University, St. PetersburgRussian FederationСанкт-Петербургский НИИ эпидемиологии и микробиологии имени Пастера, Санкт-Петербург Федеральный медицинский исследовательский центр им. В.А. Алмазова, Санкт-ПетербургРоссияSt. Petersburg Pasteur Institute of Epidemiology and Microbiology, St. Petersburg Almazov Federal Medical Research Centre, St. PetersburgRussian Federation201401082014163221226Copyright © Роггенбук Д., Ширак П., Сак У., Лапин С.В., Мазинг А.В., Тотолян А.А., 20142014Роггенбук Д., Ширак П., Сак У., Лапин С.В., Мазинг А.В., Тотолян А.А.Roggenbuck D., Schierac P., Sack U., Lapin S.V., Mazing A.V., Totolian A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/687

Основой объективизации диагноза аутоиммунных ревматических заболеваний (АРЗ) является определение аутоантител. Аутоантитела являются важными биомаркерами, выявление которых позволяет проводить раннюю диагностику и дифференциальную диагностику АРЗ. Для серологической диагностики АРЗ применяется традиционный поэтапный подход, использующий для скрининга высокочувствительные тесты, при положительном результате которых применяются высокоспецифические подтверждающие тесты. В связи с разнообразием тестов для выявления аутоантител, а также различных методических подходов для скрининга и подтверждения серологических реакций, результаты клинико-диагностических лабораторий могут отличаться между собой. Новейшие технические разработки в области цифровой иммунофлюоресценции дают возможность лучше согласовывать методы и обеспечивать более высокую сопоставимость данных от разных лабораторий. Кроме того, появляется возможность комбинации скрининговых и подтверждающих тестов в одной реактивной среде для эффективного мультипараметрического выявления аутоантител.

Autoantibodies are well-established biomarkers of autoimmune rheumatic diseases. Their detection in the routine clinical laboratory provides key information for early and differential diagnosis, prognosis, and monitoring of disease-activity. However, the currently existing variety of laboratory tests and methods as well as different diagnostic and clinical algorithms of autoimmune testing is the reason for lack of reproducibility and harmonization across immunological laboratories. Novel technical developments in the area of digital analysis of immunofluorescent images paved the way for the improvement of intra- and interlaboratory standardizationof test results. Additionally, digital immunofluorescence analysis enables the simultaneous multiparametric combination of cell- or tissue-based indirect immunofluorescence screening tests with confirmatory testing employing microparticles covered with purified autoantigens in one reaction environment.

аутоантителаревматические заболеваниястандартизациялабораторная диагностикаautoantibodyrheumatic diseasesstandardizationlaboratory diagnosticsReferencesLasareva N.M., Lapin S.V., Mazing A.V., Bulgakova T.V., Ilivanova E.P., Maslyanskiy A.L. Optimizatsiya kompleksa serologicheskikh metodov diagnostiki sistemnykh zabolevaniy soedinitel`noy tkani [Optimization of complex of serological methods for diagnosis of systemic connective tissue diseases]. Klinicheskaya laboratornaya diagnostika – Clinical Laboratory Diagnostics, 2011, vol. 12, pp. 12-17.Lasareva N.M., Lapin S.V., Mazing A.V., Bulgakova T.V., Ilivanova E.P., Maslyanskiy A.L. Optimizatsiya kompleksa serologicheskikh metodov diagnostiki sistemnykh zabolevaniy soedinitel`noy tkani [Optimization of complex of serological methods for diagnosis of systemic connective tissue diseases]. Klinicheskaya laboratornaya diagnostika – Clinical Laboratory Diagnostics, 2011, vol. 12, pp. 12-17.Lapin S.V., Totolian A.A. Antinuklearnye antitela: laboratornye testy i diagnosticheskoe znachenie [Antinuclear antibody: laboratory tests and clinical significance]. Meditsinskaya immunologiya – Medical Immunology, 2001, vol. 3, no. 1, pp. 35-50.Lapin S.V., Totolian A.A. Antinuklearnye antitela: laboratornye testy i diagnosticheskoe znachenie [Antinuclear antibody: laboratory tests and clinical significance]. Meditsinskaya immunologiya – Medical Immunology, 2001, vol. 3, no. 1, pp. 35-50.Lapin S.V., Totolian A.A. Diagnostika autoimmunnykh zabolevaniy s pomoshch`yu metoda nepryamoy immunoflyuorestsentsii [DIagnostics of autoimmune diseases with indirect immunofluorascence]. Meditsinskaya immunologiya – Medical Immunology, 2000, vol. 2, no. 2, pp. 174.Lapin S.V., Totolian A.A. Diagnostika autoimmunnykh zabolevaniy s pomoshch`yu metoda nepryamoy immunoflyuorestsentsii [DIagnostics of autoimmune diseases with indirect immunofluorascence]. Meditsinskaya immunologiya – Medical Immunology, 2000, vol. 2, no. 2, pp. 174.Lapin S.V., Totolian A.A. Immunologicheskaya diagnostika zabolevaniy pochek pri vaskulitakh [Immunolgical diagnostics of kidney involvment in vasculitis]. Nephrologia – Nephrology, 2003, vol. 16, no. 4, pp. 39-44.Lapin S.V., Totolian A.A. Immunologicheskaya diagnostika zabolevaniy pochek pri vaskulitakh [Immunolgical diagnostics of kidney involvment in vasculitis]. Nephrologia – Nephrology, 2003, vol. 16, no. 4, pp. 39-44.Sozina A.V., Neustroeva Yu.A., Tikhomirova T.A., Lapin S.V. Sochetannaya vstrechaemost` autoantitel u bol`nykh s diffuznymi boleznyami soedinitel`noy tkani [Сoincidence of autoantibodies among patients with diffuse connective tissue disorders]. Meditsinskaya immunologiya – Medical Immunology, 2007, vol. 9, no. 1, pp. 69-76.Sozina A.V., Neustroeva Yu.A., Tikhomirova T.A., Lapin S.V. Sochetannaya vstrechaemost` autoantitel u bol`nykh s diffuznymi boleznyami soedinitel`noy tkani [Сoincidence of autoantibodies among patients with diffuse connective tissue disorders]. Meditsinskaya immunologiya – Medical Immunology, 2007, vol. 9, no. 1, pp. 69-76.Agmon-Levin N., Damoiseaux J., Kallenberg C., Sack U., Witte T., Herold M., Bossuyt X., Musset L., Cervera R., Plaza-Lopez A., Dias C., Sousa M. J., Radice A., Eriksson C., Hultgren O., Viander M., Khamashta M., Regenass S., Andrade L.E., Wiik A., Tincani A., Ronnelid J., Bloch D.B., Fritzler M.J., Chan E.K., Garcia-De La Torre I., Konstantinov K.N., Lahita R., Wilson M., Vainio O., Fabien N., Sinico R.A., Meroni P., Shoenfeld Y. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann. Rheum. Dis., 2014, vol. 73, no. 1, pp. 17-23.Agmon-Levin N., Damoiseaux J., Kallenberg C., Sack U., Witte T., Herold M., Bossuyt X., Musset L., Cervera R., Plaza-Lopez A., Dias C., Sousa M. J., Radice A., Eriksson C., Hultgren O., Viander M., Khamashta M., Regenass S., Andrade L.E., Wiik A., Tincani A., Ronnelid J., Bloch D.B., Fritzler M.J., Chan E.K., Garcia-De La Torre I., Konstantinov K.N., Lahita R., Wilson M., Vainio O., Fabien N., Sinico R.A., Meroni P., Shoenfeld Y. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann. Rheum. Dis., 2014, vol. 73, no. 1, pp. 17-23.Bossuyt X., Cooreman S., De Baere H., Verschueren P., Westhovens R., Blockmans D., Marien G. Detection of antinuclear antibodies by automated indirect immunofluorescence analysis. Clin. Chim. Acta, 2013, vol. 415, pp. 101-106.Bossuyt X., Cooreman S., De Baere H., Verschueren P., Westhovens R., Blockmans D., Marien G. Detection of antinuclear antibodies by automated indirect immunofluorescence analysis. Clin. Chim. Acta, 2013, vol. 415, pp. 101-106.Conrad K., Roggenbuck D., Reinhold D., Sack U. Autoantibody diagnostics in clinical practice. Autoimmun. Rev., 2012, vol. 11, no. 3, pp. 207-211.Conrad K., Roggenbuck D., Reinhold D., Sack U. Autoantibody diagnostics in clinical practice. Autoimmun. Rev., 2012, vol. 11, no. 3, pp. 207-211.Conrad K., Sack U. Multiparametric analyses in diagnostics and monitoring of autoimmune diseases: current state and perspectives. Laboratoriumsmedizin – Journal of Laboratory Medicine, 2011, vol. 35, pp. 375-382.Conrad K., Sack U. Multiparametric analyses in diagnostics and monitoring of autoimmune diseases: current state and perspectives. Laboratoriumsmedizin – Journal of Laboratory Medicine, 2011, vol. 35, pp. 375-382.Czaja A.J., Freese D.K. Diagnosis and treatment of autoimmune hepatitis. Hepatology, 2002, vol. 36, no. 2, pp. 479-497.Czaja A.J., Freese D.K. Diagnosis and treatment of autoimmune hepatitis. Hepatology, 2002, vol. 36, no. 2, pp. 479-497.Damoiseaux J. Autoantibodies in the grocery shop: does quantity matter? Immunol. Res., 2013, vol. 56, no. 2-3, pp. 413-419.Damoiseaux J. Autoantibodies in the grocery shop: does quantity matter? Immunol. Res., 2013, vol. 56, no. 2-3, pp. 413-419.Egerer K., Roggenbuck D., Hiemann R., Weyer M.G., Buttner T., Radau B., Krause R., Lehmann B., Feist E., Burmester G.R. Automated evaluation of autoantibodies on human epithelial-2 cells as an approach to standardize cell-based immunofluorescence tests. Arthritis Res. Ther., 2010, vol. 12, no. 2, p. R40.Egerer K., Roggenbuck D., Hiemann R., Weyer M.G., Buttner T., Radau B., Krause R., Lehmann B., Feist E., Burmester G.R. Automated evaluation of autoantibodies on human epithelial-2 cells as an approach to standardize cell-based immunofluorescence tests. Arthritis Res. Ther., 2010, vol. 12, no. 2, p. R40.Fritzler M.J. Challenges to the use of autoantibodies as predictors of disease onset, diagnosis and outcomes. Autoimmun. Rev., 2008, vol. 7, no. 8, pp. 616-620.Fritzler M.J. Challenges to the use of autoantibodies as predictors of disease onset, diagnosis and outcomes. Autoimmun. Rev., 2008, vol. 7, no. 8, pp. 616-620.Hiemann R., Buttner T., Krieger T., Roggenbuck D., Sack U., Conrad K.Challenges of automated screening and differentiation of non-organ specific autoantibodies on HEp-2 cells. Autoimmun. Rev., 2009, vol. 9, no. 1, pp. 17-22.Hiemann R., Buttner T., Krieger T., Roggenbuck D., Sack U., Conrad K.Challenges of automated screening and differentiation of non-organ specific autoantibodies on HEp-2 cells. Autoimmun. Rev., 2009, vol. 9, no. 1, pp. 17-22.Hiemann R., Hilger N., Michel J., Nitschke J., Bohm A., Anderer U., Weigert M., Sack U. Automatic analysis of immunofluorescence patterns of HEp-2 cells. Ann. N Y Acad. Sci., 2007, vol. 1109, pp. 358-371.Hiemann R., Hilger N., Michel J., Nitschke J., Bohm A., Anderer U., Weigert M., Sack U. Automatic analysis of immunofluorescence patterns of HEp-2 cells. Ann. N Y Acad. Sci., 2007, vol. 1109, pp. 358-371.Kivity S., Gilburd B., Agmon-Levin N., Carrasco M.G., Tzafrir Y., Sofer Y., Mandel M., Buttner T., Roggenbuck D., Matucci-Cerinic M., Danko K., Hoyos M.L., Shoenfeld Y. A novel automated indirect immunofluorescence autoantibody evaluation. Clin. Rheumatol., 2012, vol. 31, no. 3, pp. 503-509.Kivity S., Gilburd B., Agmon-Levin N., Carrasco M.G., Tzafrir Y., Sofer Y., Mandel M., Buttner T., Roggenbuck D., Matucci-Cerinic M., Danko K., Hoyos M.L., Shoenfeld Y. A novel automated indirect immunofluorescence autoantibody evaluation. Clin. Rheumatol., 2012, vol. 31, no. 3, pp. 503-509.Knutter I., Hiemann R., Brumma T., Buttner T., Grossmann K., Cusini M., Pregnolato F., Borghi M.O., Anderer U., Conrad K., Reinhold D., Roggenbuck D., Csernok E.Automated interpretation of ANCA patterns – a new approach in the serology of ANCA-associated vasculitis. Arthritis Res. Ther., 2012, vol. 14, no. 6, p. R271.Knutter I., Hiemann R., Brumma T., Buttner T., Grossmann K., Cusini M., Pregnolato F., Borghi M.O., Anderer U., Conrad K., Reinhold D., Roggenbuck D., Csernok E.Automated interpretation of ANCA patterns – a new approach in the serology of ANCA-associated vasculitis. Arthritis Res. Ther., 2012, vol. 14, no. 6, p. R271.Meroni P.L., Borghi M.O., Raschi E., Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat. Rev. Rheumatol., 2011, vol. 7, no. 6, pp. 330-339.Meroni P.L., Borghi M.O., Raschi E., Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat. Rev. Rheumatol., 2011, vol. 7, no. 6, pp. 330-339.Meroni P.L., Schur P.H. ANA screening: an old test with new recommendations. Ann. Rheum. Dis., 2010, vol. 69, no. 8, pp. 1420-1422.Meroni P.L., Schur P.H. ANA screening: an old test with new recommendations. Ann. Rheum. Dis., 2010, vol. 69, no. 8, pp. 1420-1422.Pakozdi A., Nihtyanova S., Moinzadeh P., Ong V.H., Black C.M., Denton C.P. Clinical and serological hallmarks of systemic sclerosis overlap syndromes. J. Rheumatol., 2011, vol. 38, no. 11, pp. 2406-2409.Pakozdi A., Nihtyanova S., Moinzadeh P., Ong V.H., Black C.M., Denton C.P. Clinical and serological hallmarks of systemic sclerosis overlap syndromes. J. Rheumatol., 2011, vol. 38, no. 11, pp. 2406-2409.Roggenbuck D., Hiemann R., Bogdanos D., Reinhold D., Conrad K. Standardization of automated interpretation of immunofluorescence tests. Clin. Chim. Acta, 2013, vol. 421, pp. 168-169.Roggenbuck D., Hiemann R., Bogdanos D., Reinhold D., Conrad K. Standardization of automated interpretation of immunofluorescence tests. Clin. Chim. Acta, 2013, vol. 421, pp. 168-169.Roggenbuck D., Reinhold D., Hiemann R., Anderer U., Conrad K.Standardized detection of anti-ds DNA antibodies by indirect immunofluorescence – a new age for confirmatory tests in SLE diagnostics. Clin. Chim. Acta, 2011, vol. 412, no. 21-22, pp. 2011-2012.Roggenbuck D., Reinhold D., Hiemann R., Anderer U., Conrad K.Standardized detection of anti-ds DNA antibodies by indirect immunofluorescence – a new age for confirmatory tests in SLE diagnostics. Clin. Chim. Acta, 2011, vol. 412, no. 21-22, pp. 2011-2012.Savige J., Davies D., Falk R.J., Jennette J.C., Wiik A. Antineutrophil cytoplasmic antibodies and associated diseases: a review of the clinical and laboratory features. Kidney Int., 2000, vol. 57, no. 3, pp. 846-862.Savige J., Davies D., Falk R.J., Jennette J.C., Wiik A. Antineutrophil cytoplasmic antibodies and associated diseases: a review of the clinical and laboratory features. Kidney Int., 2000, vol. 57, no. 3, pp. 846-862.Savige J., Dimech W., Fritzler M., Goeken J., Hagen E.C., Jennette J.C., McEvoy R., Pusey C., Pollock W., Trevisin M., Wiik A., Wong R. Addendum to the International Consensus Statement on testing and reporting of antineutrophil cytoplasmic antibodies. Quality control guidelines, comments, and recommendations for testing in other autoimmune diseases. Am. J. Clin. Pathol., 2003, vol. 120, no. 3, pp. 312-318.Savige J., Dimech W., Fritzler M., Goeken J., Hagen E.C., Jennette J.C., McEvoy R., Pusey C., Pollock W., Trevisin M., Wiik A., Wong R. Addendum to the International Consensus Statement on testing and reporting of antineutrophil cytoplasmic antibodies. Quality control guidelines, comments, and recommendations for testing in other autoimmune diseases. Am. J. Clin. Pathol., 2003, vol. 120, no. 3, pp. 312-318.Tozzoli R., Antico A., Porcelli B., Bassetti D. Automation in indirect immunofluorescense testing: a new step in the evolution of the autoimmunology laboratory. Autoimmun. Highlights, 2012, vol. 3, pp. 59-65.Tozzoli R., Antico A., Porcelli B., Bassetti D. Automation in indirect immunofluorescense testing: a new step in the evolution of the autoimmunology laboratory. Autoimmun. Highlights, 2012, vol. 3, pp. 59-65.van Venrooij W.J., Zendman A.J., Pruijn G.J. Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. Autoimmun. Rev., 2006, vol. 6, no. 1, pp. 37-41.van Venrooij W.J., Zendman A.J., Pruijn G.J. Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. Autoimmun. Rev., 2006, vol. 6, no. 1, pp. 37-41.Wiik A. Autoantibodies in vasculitis. Arthritis Res. Ther., 2003, vol. 5, no. 3, pp. 147-152.Wiik A. Autoantibodies in vasculitis. Arthritis Res. Ther., 2003, vol. 5, no. 3, pp. 147-152.Wiik A., Cervera R., Haass M., Kallenberg C., Khamashta M., Meroni P.L., Piette J.C., Schmitt R., Shoenfeld Y. European attempts to set guidelines for improving diagnostics of autoimmune rheumatic disorders. Lupus, 2006, vol. 15, no. 7, pp. 391-396.Wiik A., Cervera R., Haass M., Kallenberg C., Khamashta M., Meroni P.L., Piette J.C., Schmitt R., Shoenfeld Y. European attempts to set guidelines for improving diagnostics of autoimmune rheumatic disorders. Lupus, 2006, vol. 15, no. 7, pp. 391-396.Wiik A.S., Gordon T.P., Kavanaugh A.F., Lahita R.G., Reeves W., van Venrooij W.J., Wilson M.R., Fritzler M. Cutting edge diagnostics in rheumatology: the role of patients, clinicians, and laboratory scientists in optimizing the use of autoimmune serology. Arthritis Rheum., 2004, vol. 51, no. 2, pp. 291-298.Wiik A.S., Gordon T.P., Kavanaugh A.F., Lahita R.G., Reeves W., van Venrooij W.J., Wilson M.R., Fritzler M. Cutting edge diagnostics in rheumatology: the role of patients, clinicians, and laboratory scientists in optimizing the use of autoimmune serology. Arthritis Rheum., 2004, vol. 51, no. 2, pp. 291-298.Willitzki A., Lorenz S., Hiemann R., Guttek K., Goihl A., Hartig R., Conrad K., Feist E., Sack U., Schierack P., Heiserich L., Eberle C., Peters V., Roggenbuck D., Reinhold D. Fully automated analysis of chemically induced gammaH2AX foci in human peripheral blood mononuclear cells by indirect immunofluorescence. Cytometry A, 2013, vol. 83, no. 11, pp. 1017-1026.Willitzki A., Lorenz S., Hiemann R., Guttek K., Goihl A., Hartig R., Conrad K., Feist E., Sack U., Schierack P., Heiserich L., Eberle C., Peters V., Roggenbuck D., Reinhold D. Fully automated analysis of chemically induced gammaH2AX foci in human peripheral blood mononuclear cells by indirect immunofluorescence. Cytometry A, 2013, vol. 83, no. 11, pp. 1017-1026.

The authors declare that there are no conflicts of interest present.