rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2003-1126rsp-1044Research ArticleСтатьиArticlesНЕЙТРОПЕНИЯ ПРИ РЕВМАТОИДНОМ АРТРИТЕ И ЛЕЙКОЗ ИЗ БОЛЬШИХ ГРАНУЛЯРНЫХ ЛИМФОЦИТОВNeutropenia in rheumatoid arthritis and large granular lymphocyte leucosisDoroninV ADoroninV A-NikitinE ANikitinE A-SidorovaJ. V.SidorovaJ. V.-PivnikA. V.PivnikA. V.-200315022003411№1 (2003)1518Copyright © Doronin V.A., Nikitin E.A., Sidorova J.V., Pivnik A.V., 20032003Doronin V.A., Nikitin E.A., Sidorova J.V., Pivnik A.V.Doronin V.A., Nikitin E.A., Sidorova J.V., Pivnik A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/1044

Клинико-лабораторная картина лейкоза из больших гранулярных лимфоцитов (ЛБГЛ) - нейт ропенин, спленомегалия, ассоциации с ревматоидным артиртом (РА) - часто сходна с таковой при синдроме Фелти. Цель. Сравнение клинико-гематолоптческих, иммунофенотипических и иммуногенетически.', особенностей больных с синдромом Фелти и ЛБГЛ с и без РА. Материалы и методы. Представлена клинико-лабораторная характеристика 10 больных с ЛБГЛ. Иммунофеиотипическое исследование лимфоцитов проводилось с помошью моноклональных антител CD8-PE и CD3-FITC/CDI6-PE (двойная метка) (Caliag. USA) методом проточной цитометрии (Partec, Daco). При исследовании клональной перестройки генов гамма-цепи Т-клеточного рецептора использовался ПЦР анализ конформаиионного полиморфизма одноцепочечных фрагментов ДНК в растворе с низкой ионной силой. Результаты. ЛБГА является отдельной нозологической формой. Заболевание часто ассоциирует с РА (около 20%). Пациенты с ЛБГЛ + РА и пациенты с синдромом Фелти имеют схожие иммуногенетические характеристики , которые не выяатяются у больных с ЛБГЛ без РА. Заключение. Морфологическое, иммунофеиотипическое и молекулярногенетическое исследования являются крайне важными и высокорепрезентативными методами в дифференциальной диагностике нейтропении при РА. Синдром Фелти и ЛБГЛ являются вариантами синдрома, характеризующегося нейтропенией, спленомегалией, наличием РА и пролиферацией больших гранулярных лимфоцитов. Т-БГЛ распознают чужеродный антиген в комплексе с молекулой главного комплекса гистосовместимости (МНС) 1 класса через Т-клеточный рецептор. Гены Т-клеточного рецептора в этих клетках перестроены. В западных странах ЛБГД в подавляющем большинстве случаев возникает именно из Т-БГЛ. Около 80-90% БГЛ являются естественными киллерами (НК-клетки). НК-БГЛ принципиально отличаются от Т-БГЛ (таблица 1). Опухоли из НК-клеток в западных странах встречаются крайне редко, имеют совершенно иную клинику и не сочетаются с РА. В таблице 1 приведена сравнительная характеристика двух популяций БГЛ. Ключевые слова: лейкоз из больших гранулярных лимфоцитов, ревматоидный

Objective. Pts with chronic clonal proliferation of large granular lymphocytes (LGL leukemia) often have neutropenia, splenomegaly, and rheumatoid arthritis (RA), thereby resembling the manifestations observed in pts with Felty’s syndrome. The present study sought to indicate that pts with these disorders represent two distinct subsets. We compare clinical, hematological, immunophenotiping and immunogenetic features in Felty’s syndrome pts with and without the LGL leukemia. Material and methods 10 pts with T-LGL leukemia were studied. Surface phenotype was estimated using monoclonal antibodies CD8-PE and CD3-FITC/CD16-PE (two-color) (Caltag, USA) by the flow cytometric analysis (Partec, Daco). Analysis of TCR gene rearrangement was performed by using PCR-LIS SSCP (low ionic strength single strand conformational polymorphism). Comparison with Felty s syndrome and RA pts based on the review of literature. Results. LGL leukemia is a distinct clinicopathologic entity often associated with RA. LGL leukemia pts with RA showed the same immunogenetis associations seen in RA/Felty’s syndrome, while LGL leukemia pts without arthritis did not. Conclusion. Hematologic, immunophenotyping and molecular genetic analysis are very important and highly representative tools in differential diagnosis of neutropenia in RA, and propose that Felty’s syndrome and LGL leukemia represent different variants of broader syndrome comprising RA, neutropenia, LGL expansions, and splenomegaly.

лейкоз из больших гранулярных лимфоцитовревматоидный артритсиндром ФелтиLarge granular lymphocytes leukemiarheumatoid arthritisFelty's syndromeReferences<div><p>Agnarsson В.А., Loughran Т.Р. Jr, Starkebaum G., Kadin M.E. The pathology of large granular lymphocyte leukemia. Hum Pathol., 1989, 20 (7), 643-51. '</p><p>Breedveld F.C., Lafeber GJ., Doekes G. et al. Felty, syndrome: autoimmune neutropenia or immune-complex- mediated disease? Rheumatol. Int., 1985, 5 (6), 253-8.</p><p>Breedveld F.C., Lafeber G.J., de Vries E. et al. Immune complexes and the pathogenesis of neutropenia in Felty’s syndrome. Ann.Rheum.Dis., 1986, 45(8), 696-702.</p><p>Bowman S.J., CorrigaU V., Panayi G.S., Lanchbury J.S. Hematologic and cytofluorographic analysis of patients with Felty's syndrome. A hypothesis that a discrete event leads to large granular lymphocyte expansions in this condition. Arthr. Rheum., 1995,38(9), 1252-9.</p><p>Bowman S.J., Sivakumaran М., Snowden N. et al. The large granular lymphocyte syndrome with rheumatoid arthritis. Immunogenetic evidence for a broader definition of Felty's syndrome. Arthr. Rheum., 1994,37(9), 1326-30.</p><p>Coakley G., Brooks D., Iqbal M. et al. Major histocompatility complex haplotypic associations in Felty's syndrome and large granular lymphocyte syndrome are secondary to allelic association with HLA-DRB1 *0401. Rheumatol., 2000, 39, 393-398</p><p>Coakley G., Iqbal М., Brooks D. et al. CD8+, CD57+ T cells from healthy elderly subjects suppress neutrophil development in vitro: implications for the neutropenia of Felty's and large granular lymphocyte syndromes. Arthr.Rheum.,2000,43(4),834-43</p><p>Dhodapkar M.V., Li C.Y., Lust J.A. et al. Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood. 1994, 84(5), 1620-7.</p><p>Gabor E.P., Mishalani S., Lee S. Rapid response to cyclosporine therapy and sustained, remission in large granular lymphocyte leukemia. Blood.,1996,87(3),1199-200.</p><p>Hellmich B., Csemok E., Schatz H. et al. Autoantibodies against granulocyte colony-stimulating factor in Felty's syndrome and neutropenic systemic lupus ervthematosus. Arthr. Rheum., 2002,46(9),2384-91.</p><p>Kumakura S., Kobayashi S., Ishikura H. Neutrophil phagocytosis in Feltv's syndrome. Am.J. Med., 2001,111(7),579- 80.</p><p>Lamy Т., LePrise P.Y., Amiot L. et al. Response to granu- locyte-macrophage colony-stimulating factor (GM-CSF) but not to G-CSF in a case of agranulocytosis associated with large granular lymphocyte (LGL) leukemia. Blood,1995,85(10,3352-3.</p><p>Lamy Т.,Loughran TP. Large Granular lymphocyte leukemia. Cancer Control., 1998,5(1),25-33.</p><p>Loughran T.P. Jr.Clonal diseases of large granular lymphocytes. Review. Blood, 1993,82(1), 1-14.</p><p>Loughran T.P.Jr.,Kidd P.G., Starkebaum G. Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood, 1994,84(7),2164-70.</p><p>Maher G.M., Hartman K.R. Detection of antineutrophil autoantibodies by flow cytometry: use of unfixed neutrophils as antigenic targets. J.Clin.Lab.Anal., 1993,7(6),334-40.</p><p>Matutes E. T-cell lymphoproliferative disorders. Classification, clinical and laboratory aspects. Ed: A. Polliack. Harwood Academic Publishers., 1999, 23.</p><p>McKenna R.W., Parkin J., Kersey J.H. et al. Chronic lymphoproliferative disorder with unusual clinical, morphological, ultrastructural and membrane surface marker characteristics. Am. J. Med. 1977,62(4),588-96.</p><p>Petersen J., Wiik A. Lack of evidence for granulocyte specific membrane-directed autoantibodies in neutropenic cases of rheumatoid arthritis and in autoimmune neutropenia. Acta Pathol. Microbiol. Immunol. Scand. [C]., 1983,91(1),15-22.</p><p>Starkebaum G., Loughran T.P. Jr, Gaur L.K. el al. Immunogenetic similarities between patients with Felty's syndrome and those with clonal expansions of large granular lymphocytes in rheumatoid arthritis. Arthr.Rheum.,1997,40(4),624-6.</p><p>Timonen Т., Saksela E., Ranki A., Hayry P. Fractionation, morphological and functional characterization of effector cells responsible for human natural killer activity against cell-line targets. Cell Immunol.,1979,48(1),133-48.</p><p>Yoe J.,Gause B.L.,Curti B.D. et al. Development of rheumatoid arthritis after treatment of large granular lymphocyte leukemia with deoxycoformycin. Am.J. Hematol.,1998,57(3) ,253-257.</p></div><br /><div><p>Agnarsson В.А., Loughran Т.Р. Jr, Starkebaum G., Kadin M.E. The pathology of large granular lymphocyte leukemia. Hum Pathol., 1989, 20 (7), 643-51. '</p><p>Breedveld F.C., Lafeber GJ., Doekes G. et al. Felty, syndrome: autoimmune neutropenia or immune-complex- mediated disease? Rheumatol. Int., 1985, 5 (6), 253-8.</p><p>Breedveld F.C., Lafeber G.J., de Vries E. et al. Immune complexes and the pathogenesis of neutropenia in Felty’s syndrome. Ann.Rheum.Dis., 1986, 45(8), 696-702.</p><p>Bowman S.J., CorrigaU V., Panayi G.S., Lanchbury J.S. Hematologic and cytofluorographic analysis of patients with Felty's syndrome. A hypothesis that a discrete event leads to large granular lymphocyte expansions in this condition. Arthr. Rheum., 1995,38(9), 1252-9.</p><p>Bowman S.J., Sivakumaran М., Snowden N. et al. The large granular lymphocyte syndrome with rheumatoid arthritis. Immunogenetic evidence for a broader definition of Felty's syndrome. Arthr. Rheum., 1994,37(9), 1326-30.</p><p>Coakley G., Brooks D., Iqbal M. et al. Major histocompatility complex haplotypic associations in Felty's syndrome and large granular lymphocyte syndrome are secondary to allelic association with HLA-DRB1 *0401. Rheumatol., 2000, 39, 393-398</p><p>Coakley G., Iqbal М., Brooks D. et al. CD8+, CD57+ T cells from healthy elderly subjects suppress neutrophil development in vitro: implications for the neutropenia of Felty's and large granular lymphocyte syndromes. Arthr.Rheum.,2000,43(4),834-43</p><p>Dhodapkar M.V., Li C.Y., Lust J.A. et al. Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood. 1994, 84(5), 1620-7.</p><p>Gabor E.P., Mishalani S., Lee S. Rapid response to cyclosporine therapy and sustained, remission in large granular lymphocyte leukemia. Blood.,1996,87(3),1199-200.</p><p>Hellmich B., Csemok E., Schatz H. et al. Autoantibodies against granulocyte colony-stimulating factor in Felty's syndrome and neutropenic systemic lupus ervthematosus. Arthr. Rheum., 2002,46(9),2384-91.</p><p>Kumakura S., Kobayashi S., Ishikura H. Neutrophil phagocytosis in Feltv's syndrome. Am.J. Med., 2001,111(7),579- 80.</p><p>Lamy Т., LePrise P.Y., Amiot L. et al. Response to granu- locyte-macrophage colony-stimulating factor (GM-CSF) but not to G-CSF in a case of agranulocytosis associated with large granular lymphocyte (LGL) leukemia. Blood,1995,85(10,3352-3.</p><p>Lamy Т.,Loughran TP. Large Granular lymphocyte leukemia. Cancer Control., 1998,5(1),25-33.</p><p>Loughran T.P. Jr.Clonal diseases of large granular lymphocytes. Review. Blood, 1993,82(1), 1-14.</p><p>Loughran T.P.Jr.,Kidd P.G., Starkebaum G. Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood, 1994,84(7),2164-70.</p><p>Maher G.M., Hartman K.R. Detection of antineutrophil autoantibodies by flow cytometry: use of unfixed neutrophils as antigenic targets. J.Clin.Lab.Anal., 1993,7(6),334-40.</p><p>Matutes E. T-cell lymphoproliferative disorders. Classification, clinical and laboratory aspects. Ed: A. Polliack. Harwood Academic Publishers., 1999, 23.</p><p>McKenna R.W., Parkin J., Kersey J.H. et al. Chronic lymphoproliferative disorder with unusual clinical, morphological, ultrastructural and membrane surface marker characteristics. Am. J. Med. 1977,62(4),588-96.</p><p>Petersen J., Wiik A. Lack of evidence for granulocyte specific membrane-directed autoantibodies in neutropenic cases of rheumatoid arthritis and in autoimmune neutropenia. Acta Pathol. Microbiol. Immunol. Scand. [C]., 1983,91(1),15-22.</p><p>Starkebaum G., Loughran T.P. Jr, Gaur L.K. el al. Immunogenetic similarities between patients with Felty's syndrome and those with clonal expansions of large granular lymphocytes in rheumatoid arthritis. Arthr.Rheum.,1997,40(4),624-6.</p><p>Timonen Т., Saksela E., Ranki A., Hayry P. Fractionation, morphological and functional characterization of effector cells responsible for human natural killer activity against cell-line targets. Cell Immunol.,1979,48(1),133-48.</p><p>Yoe J.,Gause B.L.,Curti B.D. et al. Development of rheumatoid arthritis after treatment of large granular lymphocyte leukemia with deoxycoformycin. Am.J. Hematol.,1998,57(3) ,253-257.</p></div><br />

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