Yumiko Sato

Age-Related EBV-Associated B-Cell Lymphoproliferative Disorders Constitute a Distinct Clinicopathologic Group: A Study of 96 Patients

Purpose: We have recently reported EBV+ B-cell lymphoproliferative disorders (LPD) occurring predominantly in elderly patients, which shared features of EBV+ B-cell neoplasms arising in the immunologically deteriorated patients despite no predisposing immunodeficiency and were named as senile or age-related EBV+ B-cell LPDs. To further characterize this disease, age-related EBV+ B-cell LPDs were compared with EBV-negative diffuse large B-cell lymphomas (DLBCL). Experimental Design: Among 1,792 large B-cell LPD cases, 96 EBV+ cases with available clinical data set were enrolled for the present study. For the control group, 107 patients aged over 40 years with EBV-negative DLBCL were selected. We compared clinicopathologic data between two groups and determined prognostic factors by univariate and multivariate analysis. Results: Patients with age-related EBV+ B-cell LPDs showed a higher age distribution and aggressive clinical features or parameters than EBV-negative DLBCLs: 44% with performance status >1, 58% with serum lactate dehydrogenase level higher than normal, 49% with B symptoms, and higher involvement of skin and lung. Overall survival was thus significantly inferior in age-related EBV+ group than in DLBCLs. Univariate and multivariate analyses further identified two factors, B symptoms and age older than 70 years, independently predictive for survival. A prognostic model using these two variables well defined three risk groups: low risk (no adverse factors), intermediate risk (one factor), and high risk (two factors). Conclusions: These findings suggest that age-related EBV+ B-cell LPDs constitute a distinct group, and innovative therapeutic strategies such as EBV-targeted T-cell therapy should be developed for this uncommon disease.

Plasmacytoid Dendritic Cells Are Crucial for the Initiation of Inflammation and T Cell Immunity In Vivo

Plasmacytoid dendritic cells (pDCs) are characterized as type I interferon-producing cells that engage endosomal toll-like receptors (TLRs) and exclusively express sialic acid binding Ig-like lectin (Siglec)-H. However, their role in vivo remains unclear. Here we report a critical role for pDCs in the regulation of inflammation and T cell immunity in vivo by using gene-targeted mice with a deficiency of Siglec-H and conditional ablation of pDCs. pDCs were required for inflammation triggered by a TLR ligand as well as by bacterial and viral infections. pDCs controlled homeostasis of effector and regulatory CD4(+) T cells. Upon antigenic stimulation and microbial infection, pDCs suppressed the induction of CD4(+) T cell responses and participated in the initiation of CD8(+) T cell responses. Furthermore, Siglec-H appeared to modulate the function of pDCs in vivo. Thus, our findings highlight previously unidentified roles of pDCs and the regulation of their function for the control of innate and adaptive immunity.

Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymph node dendritic cells in the generation of antigen-specific CD4+Foxp3+ regulatory T cells in the establishment of oral tolerance.

Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to fed antigens. However, the molecular mechanism mediating oral tolerance remains unclear. In this study, we examined the role of the B7 family members of costimulatory molecules in the establishment of oral tolerance. Deficiencies of B7-H1 and B7-DC abrogated the oral tolerance, accompanied by enhanced antigen-specific CD4(+) T-cell response and IgG(1) production. Mesenteric lymph node (MLN) dendritic cells (DCs) displayed higher levels of B7-H1 and B7-DC than systemic DCs, whereas they showed similar levels of CD80, CD86, and B7-H2. MLN DCs enhanced the antigen-specific generation of CD4(+)Foxp3(+) inducible regulatory T cells (iT(regs)) from CD4(+)Foxp3(-) T cells rather than CD4(+) effector T cells (T(eff)) relative to systemic DCs, owing to the dominant expression of B7-H1 and B7-DC. Furthermore, the antigen-specific conversion of CD4(+)Foxp3(-) T cells into CD4(+)Foxp3(+) iT(regs) occurred in MLNs greater than in peripheral organs during oral tolerance under steady-state conditions, and such conversion required B7-H1 and B7-DC more than other B7 family members, whereas it was severely impaired under inflammatory conditions. In conclusion, our findings suggest that B7-H1 and B7-DC expressed on MLN DCs are essential for establishing oral tolerance through the de novo generation of antigen-specific CD4(+)Foxp3(+) iT(regs).

Conditional ablation of CD205+ conventional dendritic cells impacts the regulation of T-cell immunity and homeostasis in vivo

Dendritic cells (DCs) are composed of multiple subsets that play a dual role in inducing immunity and tolerance. However, it is unclear how CD205+ conventional DCs (cDCs) control immune responses in vivo. Here we generated knock-in mice with the selective conditional ablation of CD205+ cDCs. CD205+ cDCs contributed to antigen-specific priming of CD4+ T cells under steady-state conditions, whereas they were dispensable for antigen-specific CD4+ T-cell responses under inflammatory conditions. In contrast, CD205+ cDCs were required for antigen-specific priming of CD8+ T cells to generate cytotoxic T lymphocytes (CTLs) mediated through cross-presentation. Although CD205+ cDCs were involved in the thymic generation of CD4+ regulatory T cells (Tregs), they maintained the homeostasis of CD4+ Tregs and CD4+ effector T cells in peripheral and mucosal tissues. On the other hand, CD205+ cDCs were involved in the inflammation triggered by Toll-like receptor ligand as well as bacterial and viral infections. Upon microbial infections, CD205+ cDCs contributed to the cross-priming of CD8+ T cells for generating antimicrobial CTLs to efficiently eliminate pathogens, whereas they suppressed antimicrobial CD4+ T-cell responses. Thus, these findings reveal a critical role for CD205+ cDCs in the regulation of T-cell immunity and homeostasis in vivo.

Naturally occurring regulatory dendritic cells regulate murine cutaneous chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a limiting factor in allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of leukemia and other malignancies. Relative to the process that initiates and promotes cGVHD, the regulation is poorly understood. In this study, we examined the role of naturally occurring regulatory dendritic cells (DC(regs)) in murine major histocompatibility complex (MHC)-compatible and multiple minor histocompatibility antigen (miHAg)-incompatible model of cGVHD in alloHSCT. DC(regs) generated from bone marrow in vitro (BM-DC(regs)) exclusively expressed CD200 receptor 3 (CD200R3), which exerted a suppressive function in the Ag-specific CD4(+) T-cell response. CD49(+)CD200R3(+) cells showed similarities in phenotype and function to BM-DC(regs), which formally distinguishes them from other leukocytes, suggesting that they are the natural counterpart of BM-DC(regs). Treatment of the recipient mice after alloHSCT with the recipient-type CD49(+)CD200R3(+) cells as well as BM-DC(regs) protected against cGVHD, and the protection was associated with the generation of Ag-specific anergic CD4(+) T cells as well as CD4(+)CD25(+)Foxp3(+) regulatory T cells (T(regs)) from donor-derived alloreactive CD4(+)CD25(-)Foxp3(-) T cells. In addition, the depletion of CD49(+)CD200R3(+) cells before alloHSCT enhanced the progression of cGVHD. In conclusion, CD49(+)CD200R3(+) cells act as naturally occurring DC(regs) to regulate the pathogenesis of cGVHD in alloHSCT mediated through the control of the transplanted alloreactive CD4(+) T cells.

Follicular lymphoma frequently originates in the salivary gland.

The aim of the present study was to examine the clinicopathological presentations of follicular lymphomas (FL) of the salivary glands, as compared to mucosa‐associated lymphoid tissue (MALT) lymphomas. A total of 27 primary salivary gland lymphomas were examined: 6 FL (five, grade 1; one, grade 2); 19 MALT lymphomas; and two diffuse large B‐cell lymphomas. The FL patients ranged in age from 24 to 73 years, with a mean of 49 years, which was younger than that of MALT patients (mean: 64 years; P < 0.05). Four of the six FL arose from the submandibular gland, which was the origin of only five out of a total of 19 MALT lymphomas. One FL patient was in clinical stage (CS) IE, two in CS IIE, and two in CS III and IV. As regards the MALT lymphoma patients, 13 (68%) were in CS IE and five (26%) in CS IIE. None of the FL patients had clinical diagnosis of autoimmune disease but eight MALT lymphoma patients had autoimmune disease. The present study found a relatively high incidence of FL in the salivary glands. The observed differences in age of onset, background of autoimmune disease, and lesion site suggests that the pathogenesis of FL may differ from that of MALT lymphoma.

Deviated VH4 immunoglobulin gene usage is found among thyroid mucosa-associated lymphoid tissue lymphomas, similar to the usage at other sites, but is not found in thyroid diffuse large B-cell lymphomas

It remains unclear whether or not diffuse large B-cell lymphomas of extranodal sites arise from mucosa-associated lymphoid tissue (MALT) lymphomas. We studied the clinicopathological features of MALT lymphoma and diffuse large B-cell lymphoma in the thyroid gland, with special reference to VH usage of immunoglobulin gene rearrangement, to clarify the relationships between these two types of lymphomas. In addition, t(11; 18) (q21; q21) translocation was examined by multiplex reverse transcription-polymerase chain reaction. We examined 58 patients with primary thyroid lymphoma: 31 (male seven and female 24) with MALT lymphoma and 27 (male three and female 24) with diffuse large B-cell lymphoma. Interestingly, the sequence of VH genes revealed that the two subtypes differed significantly in their use of the VH4 family (P<0.05). Of the seven MALT lymphomas, three used the VH4 family and the other four used the VH3 family, whereas eight out of nine diffuse large B-cell lymphoma used the VH3 family, one used the VH1 family, and none used the VH4 family. It was also interesting that, in one diffuse large B-cell lymphoma patient with MALT lymphoma, the diffuse large B-cell lymphoma component used the VH3 family and the MALT lymphoma component used the VH4 family. These data imply that, in a subset of cases, these two subtypes do not share a common origin and that at least some diffuse large B-cell lymphomas have a de novo origin. No t(11; 18) (q21; q21) was detected in thyroid lymphomas, which are different from MALT lymphoma of the stomach, lungs, large intestine and ocular adnexa. This strongly indicated that the presence of t(11; 18) (q21; q21) in MALT lymphoma is organ-specific.

Cytotoxic molecule expression is predictive of prognosis in Hodgkin's-like anaplastic large cell lymphoma.

Aims:  The Revised European American Lymphoma classification uses the term Hodgkins‐like anaplastic large cell lymphoma (HD‐like ALCL) for borderline cases with features of both anaplastic large cell lymphoma (ALCL) and classical Hodgkins lymphoma (HL). The aim of this study was to clarify the association between cytotoxic molecule (CM) expression and clinical outcome in HD‐like ALCL.

Systemic Malignant Lymphoma 17 Years after Bilateral Orbital Pseudotumor

PurposeTo report a patient who developed systemic malignant lymphoma 17 years after bilateral orbital pseudotumor.CaseA 24-year-old man developed bilateral orbital pseudotumor. He was stable until 17 years later, when he was afflicted with systemic malignant lymphoma, a diffuse large B-cell lymphoma, and he died of the disease. He showed no new orbital lesion at the presentation of systemic lymphoma. Pathological diagnosis at autopsy was systemic malignant lymphoma with bilateral orbital pseudotumor.MethodsImmunohistochemical reexamination of the paraffin-embedded tissue and polymerase chain reaction of paraffin sections.ResultsHistopathologically, the orbital masses resected on different occasions consisted of small lymphocytes and plasma cells. Immunohistochemical staining revealed an immunoglobulin light chain κ and λ bitype of B-cell lymphocytes and plasma cells. In contrast, the cervical lymph node showed large lymphoma cells that were positive only for λ light chain, indicative of a λ monotype. Amplification by polymerase chain reaction of the immunoglobulin heavy chain gene from paraffin sections demonstrated clonal rearrangement in the cervical lymph node but showed no clonality in the orbital tumor, supporting altogether the diagnosis of orbital pseudotumor.ConclusionOrbital pseudotumor should be carefully followed for possible development of systemic malignant lymphoma.

Magnetooptical Characterization of Clb-Type Heusler Compounds, Pt1-x/2Mn1+xSb1-x/2 (x=-0.1 and 0, 0.1)

Diagonal (exx) and off-diagonal (exy) elements of the dielectric tensor for a polished surface of a bulk sample of stoichiometric PtMnSb were obtained from the measured spectra of reflectance (R), magnetooptical Kerr rotation (θK) and ellipticity (ηK). The enhancement of θK by annealing was found to be due mainly to the decrease in the imaginary part of exx. The magnetooptical absorption spectrum was in good agreement with that estimated from the joint density of states calculated by van der Heide et al. The spectra of exx and exyx were also obtained for nonstoichiometric Pt1-x/2Mn1+xSb1-x/2 (x=-0.1 and 0.1). It was suggested that the band structure was changed by the existence of excess Mn atoms.