Taxl of human T-ceU leukemia virus type 1 (HTLV-1
Category Clinical investigations Word countsTotal text word count: 3412 words Abstract word count: 240 words 2 ABSTRACTObjective. Although a number of reports have documented a significantly increased incidence of HLA-DR15 in aplastic anemia (AA), the exact role of HLA-DR15 in the immune mechanisms of AA remains unclear. We herein clarify the difference between DRB1*1501 and DRB1*1502, the 2 DRB1 alleles which determine the presentation of HLA-DR15, in the pathophysiology of AA. Materials and Methods.We investigated the relationships of the patients' HLA-DRB1 allele with both the presence of a small population of CD55 -CD59 -(PNH-type) blood cells and the response to antithymocyte globulin (ATG) plus cyclosporine (CsA) therapy in 140 Japanese AA patients. Results. Of the 30 different DRB1 alleles, only DRB1*1501 (33.6% vs. 12.8%, P c <0.01) and DRB1*1502 (43.6% vs. 24.4%, P c <0.01) displayed significantly higher frequencies among the AA patients than among a control. AA patients possessing HLA-DR15 tended to be old, and especially, the frequency of DRB1*1502 in patients ≥40 years old (52.4%) was markedly higher than that in those <40 years old (16.2%, P c <0.01). Only DRB1*1501 was significantly associated with the presence of a small population of PNH-type cells and it also showed a good response to ATG plus CsA therapy in a univariate analysis. A multivariate analysis showed only the presence of a small population of PNH-type cells to be a significant factor associated with a good response to the immunosuppressive therapy (P<0.01). Conclusion.Although both DRB1*1501 and DRB1*1502 contribute to the development of AA, the methods of contribution differ between the two alleles.3
Hematopoietic function of some aplastic anemia (AA) patients is dependent on the administration of cyclosporine (CyA). To investigate whether certain HLA class II genes are associated with susceptibility to such CyA-dependent AA, we determined the HLA class II alleles of 59 AA patients treated with CyA. Among 26 patients successfully treated with CyA, 13 required a small dose of CyA to maintain stable hematopoiesis. Of these 13 AA patients, 10 shared an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602. None of the 13 responders who obtained a sustained remission off CyA therapy possessed this haplotype. In the 10 patients who shared the HLA class II haplotype, single-strand conformation polymorphism analysis of each gene fragment of this haplotype failed to detect a polymorphism in the nucleotide sequence. When the AA patients were assessed for their likelihood to respond to CyA therapy, the response rate in patients with this haplotype (71%) was significantly higher than that of patients with another haplotype associated with HLA-DR2, DRB1*1502-DQA1*0103- DQB1*0601 (36%) and that of patients without HLA-DR2 (35%). These findings indicate that the CyA-dependent response of AA is closely related to an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602 and suggest that, in AA patients with this haplotype, immune mechanisms play an important role in the pathogenesis of bone marrow failure.
IntroductionAcquired aplastic anemia (AA), a bone marrow failure syndrome characterized by pancytopenia and bone marrow hypoplasia, has been the subject of study by hematologists for many years, as more than 70% of AA patients improve under immunosuppressive therapies such as antithymocyte globulin (ATG) and cyclosporine (CsA). [1][2][3] The dramatic effects of such T-cell suppressants on in vivo hematopoiesis suggest that immune system attack against hematopoietic stem cells plays an essential role in the development of AA. [4][5][6] However, despite extensive efforts to clarify the immune mechanisms of AA, the key antigens provoking immune response against hematopoietic stem cells remain unknown. This is largely due to a lack of animal models and the heterogeneity of pathogenesis in AA. Lack of good progenitor cell assays in humans has also hindered the elucidation of immune mechanisms in AA.In organ-specific autoimmune diseases, such as insulindependent diabetes mellitus (IDDM) and multiple sclerosis where autoreactive T cells play a primary role in pathogenesis, autoantibodies against target proteins of the pathogenic T cells are often detected. [7][8][9][10] Although such antibodies do not usually contribute to the pathogenesis of T-cell-mediated diseases, detection of the antibodies may prove useful in both identifying autoantigens and diagnosing immune mechanisms underlying the diseases. 11 We recently demonstrated that HLA-DRB1*1501 and increased paroxysmal nocturnal hemoglobinuria (PNH)-type cells represent prognostic markers for the immune mechanisms of AA. 12,13 Extensive investigation of antibodies in the sera of patients possessing HLA-DRB1*1501 and a minor population of PNH-type cells may be useful in identifying novel autoantigens in AA. Using immunofluorescent analysis, we previously found that antibodies to UT-7, a megakaryoblastic cell line, are frequently detectable in sera of AA patients who display increased PNH-type cells (PNH ϩ patients; unpublished observation, T.C. and S.N., May 2001). These antibodies may recognize antigens that elicit T-cell responses against hematopoietic stem cells, allowing expansion of PNH-type stem cells. 14,15 To examine these hypotheses, we screened proteins derived from UT-7 cDNA library using serum from a PNH ϩ patient with HLA-DRB1*1501. Serologic identification of antigens by recombinant expression cloning (SEREX) analysis identified diazepambinding inhibitor-related protein 1 (DRS-1) as an autoantigen that raises both antibody production and T-cell responses to antigenpresenting cells transfected with DRS-1 gene. AA and MDS were diagnosed in patients at Kanazawa University Hospital and other hospitals taking part in the bone marrow failure study group led by the Ministry of Health, Labor, and Welfare of Japan. MDS was diagnosed on the basis of cytopenia in peripheral blood, hypercellularity or normocellularity in the sternal or iliac bone marrow, and presence of dysplasia in at least 2 lineages of bone marrow cells. Cytogenetic abnormalities such as trisomy...
To clarify the pathologic significance of granulocytes exhibiting the paroxysmal nocturnal haemoglobinuria (PNH) phenotype in patients with aplastic anaemia (AA), we examined peripheral blood from 100 patients with AA for the presence of granulocytes deficient in glycosylphosphatidylinositol (GPI)-anchored proteins using a sensitive flow cytometric assay. A significant increase in the frequency of CD55-CD59-CD11b+ granulocytes (>0.003%) compared to normal individuals was observed in 31 of 35 (88.6%) patients with untreated AA at diagnosis. The proportions of patients showing increased PNH granulocytes in treated AA patients with a short (<5 yr) and long (>5 yr) disease duration were 68.6% (11/16) and 20.4% (10/49), respectively. When 19 patients showing increased frequency of PNH granulocytes before therapy were studied 6-12 months after antithymocyte globulin plus cyclosporin A therapy, the frequency decreased to 0.01-90% of pretreatment values in 15 recovering patients. These findings suggest that a relative increase in the number of PNH granulocytes is a common feature of AA at diagnosis, and that it may represent the presence of immunologic pressure to normal haematopoietic stem cells as a cause of AA.
Although a minor population of paroxysmal nocturnal hemoglobinuria (PNH)-type blood cells is often detected in patients with aplastic anemia (AA) and refractory anemia (RA), the significance of such cells in the pathophysiology of bone marrow (BM) failure remains obscure. We therefore examined clonality in peripheral blood granulocytes from 118 female patients with AA or myelodysplastic syndrome using the X chromosome inactivation pattern. Clonality, defined as a clonal population accounting for 35% or more of total granulocytes, was confirmed in 22 of 68 (32.4%) AA patients, in 13 of 44 (29.5%) RA patients, in all 4 RA with excess blasts (RAEB) patients, and in 4 patients with PNH. When the frequency of patients with granulocyte clonality was compared with respect to the presence of increased PNH-type cells, the frequency was significantly lower in AA patients with (PNH ؉ ; 21.2%) than without (PNH ؊ ; 42.9%) increased numbers of PNH-type cells (P ؍ .049). Clonality was absent in granulocytes from the 15 PNH ؉ RA patients but present in 13 of 29 (44.8%) PNH ؊ RA patients (P ؍ .0013). The absence of clonality in AA and RA patients before treatment was strongly associated with positive response to immunosuppressive therapy (without clonality, 74.4%; with clonality, 33.3%; P ؍ .0031) in all patients as well as in PNH ؉ patients (without clonality, 96.2%; with clonality, 66.6%, P ؍ .026). These results suggest that AA and RA with a minor population of PNHtype cells are benign types of BM failure with immune pathophysiology that have little relationship to clonal disorders such as RAEB or acute myeloid leukemia. IntroductionAplastic anemia (AA) and myelodysplastic syndrome (MDS) are hematopoietic dyscrasias characterized by pancytopenia and inappropriate production of mature blood cells from the bone marrow. They differ in terms of disease definition: AA is basically benign bone marrow (BM) failure due to extrinsic insult to hematopoietic stem cells, while MDS is a clonal disorder derived from a defective stem cell. 1-3 However, to differentiate AA from refractory anemia (RA) of MDS in clinical practice can be difficult, as a diagnosis of RA depends largely on a subjective judgment of morphologic abnormalities in mature blood cells, and a laboratory marker that can discriminate between them remains unknown. 4,5 We recently demonstrated that a minor (Ͻ 1%) population of CD55 Ϫ CD59 Ϫ granulocytes or red blood cells (RBCs) can be detected in numerous AA patients 6 and in about 20% of RA patients. 7 RA patients with a subtle increase in such paroxysmal nocturnal hemoglobinuria (PNH)-type cells (PNH ϩ patients) had distinct clinical features compared with RA patients without increased PNH-type cells (PNH Ϫ patients), such as lower rates of karyotypic abnormality and higher probability of response to cyclosporine (CyA) therapy. The presence of PNH-type cells therefore appeared to represent a marker for benign types of BM failure. However, several studies contradict this hypothesis. Some reports described AA pati...
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