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Analysis of TNF-receptor and ligand superfamily molecules in patients with lymphoproliferative disease of granular lymphocytes

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BLOOD 2000年第2期96卷 647-654页

作者： Zambello, R Trentin, L Facco, M Siviero, M Galvan, S Piazza, F Perin, A Agostini, C Semenzato, G Univ Padua Dipartimento Med Clin & Sperimentale Immunol Clin Sch MedClin Immunol Branch I-35128 Padua Italy Vicenza Hosp Div Hematol Vicenza Italy

In 21 patients with lymphoproliferative disease of granular lymphocytes (LDGL), we investigated the expression and the function of molecules belonging to TNF-receptor and TNF-ligand superfamilies (CD30/CD30L;CD40/CD40L;CD27/CD70;Fas [CD95]/FasL[CD95L]), Fourteen patients were characterized by a proliferation of granular lymphocytes (GLs) expressing the CD3(+)CD16(+) phenotype, whereas 7 cases showed the CD3(-)CD16(+) CD56 +/- phenotype, Our data show that both CD3(+) and CD3-GLs are preferentially equipped with CD30, CD40, CD40L, CD70, and CD95 antigens;this pattern Is usually associated with the lack of CD27 and CD30L antigens expression. CD95L was demonstrated in the cytoplasm in 14 of 21 cases by flow cytometry, but a definite signal was demonstrated in all cases studied using polymerase chain reaction analysis. On functional grounds, a stimulatory activity on rIL-2 mediated redirected-cytotoxicity against Fc gamma+ P815 targets was demonstrated with anti-CD30, CD40, CD40L, CD70, CD95, and CD95L mAbs, although resting cells were unable to exhibit significant redirected-cell lysis. The addition of anti-CD30, CD30L, CD40, CD40L, CD95, and CD95L mAbs did not show any significant effect on cell proliferation at resting conditions or after rIL-2 stimulation, whereas anti-CD70 mAb mediated cell proliferation in 6 of 10 cases tested. This figure was not related to an increase in apoptotic cells, as investigated by Annexin-V expression. Our data indicate that both CD3(+) and CD3(-) GLs are equipped with different costimulatory antigens, supporting the concept that these cells are in vivo activated and suggesting that these molecules might play a role in the cytotoxic mechanisms of GLs, (C) 2000 by The American Society of Hematology.

关键词：抗原 CD3/分析抗原 CD30/分析抗原 CD40/分析抗原 CD95/分析细胞分裂细胞毒性免疫流式细胞术白细胞介素2/药理学杀伤细胞天然/免疫学杀伤细胞天然/病理学配体淋巴细胞/免疫学淋巴细胞/病理学淋巴组织增殖性疾病/免疫学淋巴组织增殖性疾病/病理学受体 IgG/分析受体肿瘤坏死因子/分析逆转录聚合酶链反应 T淋巴细胞/免疫学 T淋巴细胞/病理学肿瘤坏死因子α/分析成年人老年人女(雌)性人类男(雄)性中年人

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IMMUNOLOGICALLY DIAGNOSED MALIGNANCY IN SJOGRENS PSEUDOLYMPHOMA

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AMERICAN JOURNAL OF MEDICINE 1978年第3期65卷 424-429页

作者： FAGUET, GB WEBB, HH AGEE, JF RICKS, WB SHARBAUGH, AH DWIGHT D EISENHOWER ARMY MED CTR DEPT MED FT GORDON GA USA

Studies of lymphocyte markers in a patient with Sjogren''s syndrome who exhibited histologically benign lymphoproliferation in the lung revealed a malignant cell clone. T [thymus-derived] and B [bone marrow-derived] cells were quantitated according to their ability to form spontaneous rosettes with sheep erythrocytes and to fluoresce with fluorescein-conjugated antiserums, respectively. Circulating lymphocytes were 66% T cells (N = 58 .+-. 2%) and 14% B cells (N = 22 .+-. 1%), the latter exhibiting normal polyclonal distribution of membrane immunoglobulins. Lymphocyte suspensions obtained from fresh lymph node and biopsy specimens from a lymphoid lung nodule revealed 95% and 88% B cells, with 1 percent and 2% T cells, respectively. When cryostat-frozen sections from both tissues were reacted with each of the heavy and light chain-specific antiserums, most cells demonstrated the presence of intracytoplasmic .mu. kappa immunoglobulin exclusively. Twenty-two months later, a clinically and histologically classic lymphoma developed. Repeat marker studies performed on cells freshly isolated and frozen sections from the histologically malignant lymph node revealed persistence of the monoclonal marker on most cells.

关键词： B淋巴细胞/免疫学免疫球蛋白κ链/分析肺/病理学肺肿瘤/诊断肺肿瘤/病因学肺肿瘤/病理学淋巴细胞活化淋巴瘤/诊断淋巴瘤/病因学淋巴瘤/病理学淋巴组织增殖性疾病/诊断淋巴组织增殖性疾病/病因学淋巴组织增殖性疾病/病理学受体抗原 B细胞/分析玫瑰花结形成干燥综合征/并发症干燥综合征/病理学 T淋巴细胞/免疫学人类男(雄)性中年人

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TCRαβ⁺/CD4⁺ large granular lymphocytosis -: A new clonal T-cell lymphoproliferative disorder

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AMERICAN JOURNAL OF PATHOLOGY 2003年第2期163卷 763-771页

作者： Lima, M Almeida, J Teixeira, MD Alguero, MD Santos, AH Balanzategui, A Queirós, ML Bárcena, P Izarra, A Fonseca, S Bueno, C Justiça, B Gonzalez, M San Miguel, JF Orfao, A Univ Salamanca CSIC Ctr Canc Res Serv CytometryLab 11 Salamanca 37007 Spain Hosp Geral Santo Antonio Unidade Citometria Serv Hematol Clin Oporto Portugal Ctr Invest Canc Salamanca Spain Hosp Univ Salamanca Hematol Serv Salamanca Spain

Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8(+) or less frequently natural killer cells;in contrast, monoclonal expansions of CD4(+) T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4(+) T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4(+) T cells of a series of 34 consecutive cases. Like CD8(+) T-LGL leukemias, CD4+ T-LGL leukemia patients have an indolent disease;however, in contrast to CD8(+) T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4+ T-LGL showed expression of TCRalphabeta, variable levels of CD8 (CD8(-/+dim)) and a homogeneous typical cytotoxic (granzyme B+, CD56(+), CD57(+), CD11b(+/-)) and activated/memory T cell (CD2(+bright), CD7(-/+dim) CD11a(+bright), CD28(-), CD62L(-) HLA-DR+) immunophenotype. in addition, they exhibited a Th1 pattern of cytokine production [interferon-gamma(++), tumor necrosis factor-alpha(++), interleukin (IL-2)(-/+), IL-4(-), IL-10(-), IL-13(-)]. Phenotypic analysis of the TCR-Vbeta repertoire revealed Large monoclonal TCR-Vbeta expansions;only a restricted number of TCR-Vbeta families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRalphabeta(+)/CD4(+)/NKa(+)/CD8(-/+dim) T-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8(+) T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine die exact significance of this clonal disorder.

关键词：抗体单克隆/免疫学 CD4阳性T淋巴细胞/免疫学 CD4阳性T淋巴细胞/代谢细胞因子类/免疫学细胞因子类/代谢随访研究免疫表型分型白血病 T细胞/免疫学白血病 T细胞/病理学淋巴细胞亚群/免疫学淋巴细胞增多/免疫学淋巴细胞增多/病理学淋巴组织增殖性疾病/免疫学淋巴组织增殖性疾病/病理学受体抗原 T细胞 α-β/免疫学受体抗原 T细胞 α-β/代谢成年人人类

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An animal model for human EBV-associated hemophagocytic syndrome -: Herpesvirus papio frequently induces fatal lymphoproliferative disorders with hemophagocytic syndrome in rabbits

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AMERICAN JOURNAL OF PATHOLOGY 2001年第4期158卷 1533-1542页

作者： Hayashi, K Ohara, N Teramoto, N Onoda, S Chen, HL Oka, T Kondo, E Yoshino, T Takahashi, K Yates, J Akagi, T Okayama Univ Sch Med Dept Pathol 2 Okayama 7008558 Japan Okayama Univ Sch Hlth Sci Okayama 7008558 Japan Roswell Pk Canc Inst Dept Human Genet Buffalo NY 14263 USA

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) Is often associated with fatal infectious mononucleosis. However, the animal model for EBV-AHS has not been developed. We reported the first animal model for EBV-AHS using rabbits infected with EBV-related herpesvirus of baboon (HVP), Eleven of 13 (85%) rabbits inoculated intravenously with HVP-producing cells developed fatal lymphoproliferative disorders (LPD) between 22 and 105 days after Inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in nine of these 11 rabbits, The peroral spray of cell-free HVP induced the virus infection with increased anti-EBV-viral capsid antigen-IgG titers in three of five rabbits, and two of these three infected rabbits died of LPD with HPS, Autopsy revealed hepatosplenomegaly and swollen lymph nodes. Atypical lymphoid T cells expressing EBV-encoded small RNA-I infiltrated diffusely in many organs, frequently involving the lymph nodes, spleen, and liver. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus, HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by polymerase chain reaction or Southern blot analysis. Re-verse transcriptase-polymerase chain reaction revealed both HVP-EBNA1 and HVP-EBNA2 transcripts, suggesting latency type Ri infection. These data indicate that the high rate of rabbit LPD with HPS induction is caused by HVP, This system is useful for studying the pathogenesis, prevention, and treatment of human EBV-AHS.

关键词：抗体病毒/分析细胞系疾病模型动物爱泼斯坦巴尔病毒感染/并发症基因组病毒疱疹病毒科感染/并发症疱疹病毒1型猕猴疱疹病毒4型人/遗传学疱疹病毒4型人/免疫学组织细胞增多症非郎格尔汉斯细胞/病毒学免疫表型分型淋巴组织增殖性疾病/免疫学淋巴组织增殖性疾病/死亡率淋巴组织增殖性疾病/病理学淋巴组织增殖性疾病/病毒学狒狒属动物人类兔

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Simultaneous presence of t(2;8)(p12;q24) and t(14;18) (q32;q21) in a B-cell lymphoproliferative disorder with features suggestive of an aggressive variant of splenic marginal-zone lymphoma

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CANCER GENETICS AND CYTOGENETICS 2000年第2期120卷 136-140页

作者： Batanian, JR Dunphy, CH Richart, JM Petruska, PJ Perkins, SL St Louis Univ Cardinal Glennon Childrens Hosp Dept Pediat Pediat Res Inst St Louis MO 63104 USA St Louis Univ Sch Med Dept Pediat St Louis MO 63104 USA St Louis Univ Sch Med Dept Pathol St Louis MO 63104 USA St Louis Univ Sch Med Dept Internal Med St Louis MO USA Univ Utah Hlth Sci Ctr Div Anat Pathol Salt Lake City UT USA

We report a case of an aggressive variant of splenic marginal-zone lymphona (SMZL) with circulating villous lymphocytes. The karyotype of all examined cells bad multiple structural and numerical abnormalities, including two lymphoma characteristic translocations, t(2;8)(p12;q24) and t(14;18)(q32;q21). Based on a literature review of cytogenetic aberrations of splenic lymphoma with villous lymphocytes (SLVL) and SMZL, this is apparently the first documentation of these two translocations in a case of SMZL, and could reflect the heterogeneity of the disorder. (C) 2000 Elsevier Science Inc. All rights reserved.

关键词：染色体人 14对/遗传学染色体人 18对/遗传学染色体人 2对/遗传学染色体人 8对/遗传学诊断鉴别免疫表型分型核型分析淋巴瘤 B细胞/遗传学淋巴瘤 B细胞/免疫学淋巴瘤 B细胞/病理学淋巴组织增殖性疾病/遗传学淋巴组织增殖性疾病/免疫学淋巴组织增殖性疾病/病理学脾肿瘤/遗传学脾肿瘤/免疫学脾肿瘤/病理学易位遗传老年人女(雌)性人类

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Expression of p16/INK4a in posttransplantation lymphoproliferative disorders

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AMERICAN JOURNAL OF PATHOLOGY 2000年第5期156卷 1573-1579页

作者： Martin, A Baran-Marzak, F El Mansouri, S Legendre, C Leblond, V Charlotte, F Davi, F Canioni, D Raphaël, M Univ Avicenne Ctr Hosp Serv Anat & Cytol Pathol Bobigny France Univ Avicenne Ctr Hosp Unite Propre Enseignement Super Equipe Acceuil 1625 Paris France Univ Paris Unite Format Rech Sante Med Biol Humaine Paris France Univ Pitie Salpetriere Ctr Hosp Serv Hematol Paris France Univ Pitie Salpetriere Ctr Hosp Serv Anat & Cytol Pathol Paris France Univ Pitie Salpetriere Ctr Hosp Serv Hematol Biol Paris France Hop Necker Enfants Malad Serv Anat & Cytol Pathol Paris France

It was recently demonstrated that classification of posttransplantation lymphoproliferative disorders (PT-LPDs) into morphological and molecular categories is clinically relevant. It was also reported that PT-LPD not associated with Epstein-Barr virus (EBV) had a more aggressive course than most lesions associated with EBV, Because the cyclin-dependent kinase inhibitor p16/INK4a has been reported to be frequently inactivated in high-grade lymphomas, we evaluated 17 PT-LPD to determine whether p16/ INK4a expression could be correlated to morphology, EBV detection, and a Ki-67 labeling index. We demonstrated that tumors with no p16/INK4a expression (n = 8) had a predominantly monomorphic appearance, and most were EBV negative (respectively, 7/8 and 5/8), whereas lesions with p16/INK4a expression (n = 9) were mostly polymorphic PT-LPD (6/9) (p = 0.049) and associated with EBV (9/9) (P = 0.015). In particular, strong p16/INK4a expression was observed in atypical immunoblasts and Reed-Sternberg-like cells. Furthermore, the proliferation index was significantly higher in tumors lacking p16/ INK4a expression than in other lesions (P = 0.0008). In conclusion, down-regulation of p16/INK4a was mostly observed in PT-LPD lesions known to follow more aggressive courses: monomorphic tumors and EBV-negative PT-neoplasms. Conversely, overexpression of p16/INK4a was associated with EBV-positive PT-LPD. While p16/INK4a might play a role in the proliferative rate of LP-LPD, further investigations are needed to assess the clinical relevance of p16/INK4a expression in predicting the evolution of tumors and to explain how EBV could favor p16/INK4a protein accumulation in lesions.

关键词：印迹法 DNA 载体蛋白质类/分析载体蛋白质类/遗传学克隆细胞周期素依赖激酶抑制剂p16 DNA/遗传学 DNA/代谢 DNA甲基化 DNA 病毒/遗传学爱泼斯坦巴尔病毒感染/病毒学基因表达调控疱疹病毒4型人/遗传学免疫组织化学 Ki-67抗原/分析淋巴组织增殖性疾病/病因学淋巴组织增殖性疾病/代谢淋巴组织增殖性疾病/病理学成年人老年人女(雌)性人类男(雄)性中年人

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In vivo models for Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disease (BLPD)

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REVIEWS IN MEDICAL VIROLOGY 1999年第4期9卷 263-277页

作者： Johannessen, I Crawford, DH Univ Edinburgh Sch Med Dept Med Microbiol Edinburgh EH8 9AG Midlothian Scotland

EBV infects B lymphocytes in vivo and establishes a life-long persistent infection in the host. The latent infection is controlled by EBV-specific MHC class I-restricted CTL. Immunosuppression reduces CTL activity, and this facilitates outgrowth of EBV+ve B cell lymphoproliferative disease (BLPD). BLPD are aggressive lesions with high mortality. This review presents some key facets in the development of EBV-associated BLPD and in vivo studies on its pathogenesis. The animal models used to date include the common marmoset (Callithrix jacchtas), the cottontop tamarin (Saguinus oedipus oedipus), rhesus monkey, murine herpesvirus 68 (MHV68), and the severe combined immunodeficient (scid) mouse, each of which has been used to address particular aspects of EBV biology and BLPD development. Scid mice inoculated i.p. with PBMC from EBV-seropositive individuals develop EBV+ve BLPD-like tumours. Thus this small animal model (hu-PBMC-scid) is currently used by many laboratories to investigate EBV-associated diseases. We and others have studied BLPD pathogenesis in the hu-PBMC-scid model and shown that EBV + ve B cells on their own do not give rise to rumours in this model without inclusion of autologous T cell subsets in the inoculum. Based on the findings that (1) established rumours do not contain T cells and (2) tumour cells express a variety of B cell growth factors, a stepwise model of lymphomagenesis in the scid mouse model can be defined. Additionally, the hu-PBMC-scid model can be used to assess novel therapeutic regimes against BLPD before introduction into a clinical setting. Copyright (C) 1999 John Wiley & Sons, Ltd.

关键词： B淋巴细胞/病理学狨猴属疾病模型动物爱泼斯坦巴尔病毒感染/并发症疱疹病毒4型人/免疫学淋巴组织增殖性疾病/病理学淋巴组织增殖性疾病/病毒学恒河猴小鼠 SCID 狨猴动物人类小鼠

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Fulminant EBV⁺ T-cell lymphoproliferative disorder following acute/chronic EBV infection:: a distinct clinicopathologic syndrome

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BLOOD 2000年第2期96卷 443-451页

作者： Quintanilla-Martinez, L Kumar, S Fend, F Reyes, E Teruya-Feldstein, J Kingma, DW Sorbara, L Raffeld, M Straus, SE Jaffe, ES NCI Pathol Lab Hematopathol Sect Bethesda MD 20892 USA NIAID Clin Invest Lab NIH Bethesda MD 20892 USA Inst Nacl Nutr Salvador Zubiran Dept Pathol Mexico City DF Mexico GSF Res Ctr Environm & Hlth Inst Pathol Neuherberg Germany

This study describes the clinicopathologic features of 5 patients who developed a fulminant Epstein-Barr virus (EBV)-positive clonal T-cell lymphoproliferative disorder (LPD) after acute EBV infection. One additional patient developed a similar disorder in the setting of long-standing chronic active EBV infection. Detailed immunophenotyping, in situ hybridization for EBV early RNA-1 (EBER1) and polymerase chain reaction (PCR) analyses for immunoglobulin (Ig) heavy chain and T-cell receptor (TCR)-gamma gene rearrangements were performed on paraffin-embedded tissue from all patients. In addition, EBV strain typing and detection of the characteristic 30-bp deletion of the latent membrane protein-1 (LMP-1) gene were performed by PCR, Controls included 8 cases of uncomplicated infectious mononucleosis (IM). patients included 4 males and 2 females with a median age of 18 years (2-37 years). Three patients were Mexican, 2 were white, and 1 was of Asian descent. All presented with fever, hepatosplenomegaly, and pancytopenia;5 were previously healthy, but had a clinical history of a recent viral-like upper respiratory illness (1 week to 2 months), and 1 patient had documented chronic active EBV infection for 7 years. Serologic data for EBV were incomplete but titers were either negative or only modestly elevated in 3 cases. In 1 case serology was consistent with severe chronic active EBV infection. In the remaining 2 cases serologic studies were not performed. All patients died within 7 days to 8 months of presentation with T-cell LPD. On histologic examination, the liver and spleen showed prominent sinusoidal and portal lymphoid infiltrates of CD3(+), beta F1(+), EBER1(+) T cells lacking significant cytologic atypia. Two cases were CD4(+), 2 cases were CD8(+), and 2 cases had admired CD4+ and CD8+ cells without clear subset predominance. All were TIA-1(+), CD56(-), Only rare B cells were noted. Marked erythrophagocytosis was present Molecular analysis revealed identical T-c

关键词：爱泼斯坦巴尔病毒感染致命性结局基因重排 B淋巴细胞重链基因重排 γ链T细胞抗原受体疱疹病毒4型人/分类疱疹病毒4型人/遗传学免疫球蛋白重链/遗传学免疫表型分型原位杂交肝/病理学淋巴组织增殖性疾病/免疫学淋巴组织增殖性疾病/病理学淋巴组织增殖性疾病/病毒学 RNA 病毒/分析 RNA 病毒/遗传学脾/病理学 T淋巴细胞/免疫学 T淋巴细胞/病理学青少年成年人儿童学龄前女(雌)性人类男(雄)性

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Treatment of intractable autoimmune diseases in MRL/lpr mice using a new strategy for allogeneic bone marrow transplantation

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BLOOD 2000年第5期95卷 1862-1868页

作者： Kushida, T Inaba, M Takeuchi, K Sugiura, K Ogawa, R Ikehara, S Kansai Med Univ Dept Pathol 1 Moriguchi Osaka 5708506 Japan Kansai Med Univ Dept Orthoped Surg Moriguchi Osaka 5708506 Japan

A new bone marrow transplantation (BMT) method for treating severe autoimmune diseases in chimeric resistant MRL/lpr mice is presented. The method consists of fractionated irradiation (5.5 Gy x 2), followed by portal venous (PV) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice and intravenous (IV) injection of whole B6 BMCs 5 days after the PV injection (abbreviated as 5.5 Gy x 2 + PY + IV). AII recipients survived more than 1 year after this treatment (more than 64 weeks after birth), Abnormal T cells (Thy1.2(+)/B220(+)/CD3(+)/CD4(-)/CD8(-)) present in MRL/lpr mice before the treatment disappear, and hematolymphoid cells are reconstituted with donor-derived cells, The treated mice are free from autoimmune diseases, Levels of autoantibodies (IgG/IgM anti-ssDNA antibodies and IgG/IgM rheumatoid factors) decrease to normal levels. Successful cooperation is achieved among T cells, B cells, and antigen-presenting cells (APCs) of the treated MRL/lpr mice when evaluated by in vitro anti-SRBC responses. Newly developed T cells are tolerant to both donor (B6)-type and host (MRL/lpr)-type major histocompatibility complex (MHC) determinants. These findings clearly indicate that severe autoimmune diseases in MRL/lpr mice are completely ameliorated by the treatment without recourse to immunosuppressants, and that the treated MRL/ lpr mice show normal immune functions, strongly suggesting that this strategy would be applicable to humans. (C) 2000 by The American Society of Hematology.

关键词：自身抗体/血液自身抗体/免疫学自身免疫疾病/免疫学自身免疫疾病/病理学自身免疫疾病/治疗骨髓移植/方法环磷酰胺/药理学放射剂量分次注射静脉内肾/病理学淋巴组织增殖性疾病/免疫学淋巴组织增殖性疾病/病理学淋巴组织增殖性疾病/治疗小鼠近交BALBC 小鼠近交C3H 小鼠近交C57BL 小鼠近交MRLlpr 门静脉辐射嵌合体移植预处理/方法全身照射/方法动物女(雌)性小鼠

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Recommendations for the reporting of lymphoid neoplasms

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AMERICAN JOURNAL OF CLINICAL PATHOLOGY 2003年第2期119卷 185-189页

作者： Jaffe, ES Banks, PM Nathwani, B Said, J Swerdlow, SH

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