Representation of Biomedical Expertise in Ontologies: a Case Study about Knowledge Acquisition on HTLV viruses and their clinical manifestations.

In this paper, we introduce a set of methodological steps for knowledge acquisition applied to the organization of biomedical information through ontologies. Those steps are tested in a real case involving Human T Cell Lymphotropic Virus (HTLV), which causes myriad infectious diseases. We hope to contribute to providing suitable knowledge representation of scientific domains.

Questions on the evolution of primate T-lymphotropic viruses raised by molecular and epidemiological studies of divergent strains.

In human and simian T-lymphotropic viruses (HTLV and STLV), collectively referred to as primate T-lymphotropic viruses (PTLV), four distinct clades can be distinguished: PTLV-I, PTLV-II, and the newly discovered divergent STLVs isolated from hamadryas baboons and from bonobos (pygmy chimpanzees). The hamadryas STLV is clearly distinct from types I and II, in terms both of sequence divergence and of genomic structure, and would qualify as a separate type, provisionally called PTLV-L. The bonobo STLV is closer to, although clearly distinct from, PTLV-II, at present known only in humans. While PTLV-II, PTLV-L, and the bonobo STLV appear presently to be species specific, PTLV-I has spread during its evolution through repeated interspecies transmissions between primates and is now present in many species of Old World monkeys and apes and in humans. The human subtypes of PTLV-I arose from at least three acquisitions from separate simian reservoirs.

Soluble IL-2 receptor in AIDS. Correlation of its serum level with the classification of HIV-induced diseases and its characterization.

By using a fluorescence sandwich ELISA, elevated IL-2R levels were detected in the sera from both HIV-infected hemophiliacs and other HIV-infected patients. The serum IL-2R levels were reflective of the classification of HIV-induced diseases by the Centers for Disease Control. Moreover, the IL-2R levels were negatively correlated most prominently with CD4 cell counts, with lymphocyte counts, and with a decrease in the CD4-CD8 ratio but not with either WBC counts or B cell counts. As striking elevations of serum IL-2R were noted in AIDS patients with group IVD infection, the serum IL-2R was purified sequentially by using size-exclusion HPLC, high-pressure chromatofocusing, and H48 affinity HPLC. The isoelectric point values of IL-2R were separated into 4.2 and 3.8, whereas the Mr was determined to be only 45 kDa by immunoprecipitation with H48 antibody followed by SDS-PAGE. However, production of cellular and supernatant IL-2R was not elevated in PBMC of patients with AIDS or in any of the 19 HIV-I- or HIV-II-infected cell line cells. In contrast, PBMC from patients with adult T cell leukemia and cell line cells that expressed human T cell lymphotropic virus -I or -II produced soluble IL-2R, constitutively. The mechanisms by which serum levels of IL-2R might be elevated in HIV-infected patients are discussed in comparison with that in adult T cell leukemia patients.

Reclassification of leukemia among A-bomb survivors in Nagasaki using French-American-British (FAB) classification for acute leukemia.

The concordance rate for diagnoses of atomic bomb-related cases of leukemia in Nagasaki was determined using the French-American-British (FAB) classification for acute leukemias and myelodysplastic syndromes (MDS). Two Radiation Effects Research Foundation (RERF) hematologists and one of the members (JMB) of the FAB cooperative group reviewed independently the peripheral blood and/or bone marrow smears from 193 people with leukemia or a related disorder. There was 85% agreement in the identification of types and subtypes of acute leukemia. There was almost complete agreement for the diagnoses of non-FAB disorders (chronic myeloid leukemia (CML), adult T-cell leukemia (ATL) and others) resulting in overall concordance of 88.2%. The present study suggests that the previously established leukemia types for about a quarter of the cases of acute leukemia and related disorders except CML should be changed. Considerable numbers of cases of ATL and MDS were involved in this series. The frequency of the former disease was not high in the high-dose irradiated group, but that of the latter was considerably high. All subtypes of AML except M3 and M6 were present in the high-dose group. The striking difference in CML incidence between Nagasaki and Hiroshima may continue to be a problem in relation to biological response to radiation exposure.

Leukemias and lymphomas of thymic differentiation.

Neoplasms of thymic T-cell derivation include two closely related malignancies: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma. The recognition of these tumors as distinct biologic entities dates back to the early 1970s, when patients with these diseases were found to have tumor cells that formed spontaneous rosettes with sheep erythrocytes. In the last decade, however, the growth of new technologies and availability of new reagents has enabled us to characterize this group of diseases with more precision. When studied with a panel of monoclonal antibodies, there is tremendous phenotypic diversity in the types of T-cell leukemias that are encountered. In spite of this diversity, a few general facts have become apparent. To a first approximation, thymic T-cell malignancies can be related to stages of normal T-cell development. Surprisingly, in spite of the overall similarity between T-ALL and T-lymphoblastic lymphoma, the antigenic phenotypes encountered suggest a biologic difference between these two diseases. Although there is not currently any single reagent that permits recognition of T-ALL or lymphoblastic lymphoma in all cases, a combination of technologic approaches using conventional morphology and histochemistry, immunologic studies, and, in some cases, newer genetic studies should permit great precision in the definition of this disease. The clinical picture of T-cell ALL or lymphoblastic lymphoma has traditionally been one of a poor prognosis disease with high WBC count, bulky adenopathy, and mediastinal mass. Although encountering this clinical presentation should suggest the T-cell phenotype, not all patients with T-cell leukemia will fit this stereotype. Clinical studies have also served to provide support for the expanding biologic definition of T-cell neoplasia, particularly insofar as it has been demonstrated that patients with T antigen-positive but E rosette-negative ALL behave like other patients with T-cell disease. In short, patients with thymic T-cell malignancies not only have distinctive biologic characteristics to their blasts, but also have a distinctive pattern of clinical presentation, response to therapy, and sites of relapse. These differences have prompted the search for specific therapies and also directed approaches to understanding the variable clinical outcome of patients with these malignancies.

[Overview of ATL (adult T-cell leukemia) research].

ATL is a unique T-cell malignancy first described by Takatsuki and colleagues in 1970s. We estimate that more than 300 patients a year have been detected in the endemic areas of Kyushu, Japan. The surface phenotype of ATL cells characterized by monoclonal antibodies is T3+, T4+, T8-, T11+ and Tac+. In all cases the serum is positive for anti-HTLV-I antibodies and the ATL cells contain the proviral DNA of HTLV-I. Variations in the clinical features of atypical ATL suggested a division of the spectrum of ATL into five types: acute; chronic; smoldering; crisis; and lymphoma. Typical ATL takes an acute course. The survival time is short, with 50% mortality within approximately 5 months. In general a poor prognosis is indicated by the elevation of serum lactate dehydrogenase, calcium, and bilirubin, as well as by high WBC. Smoldering ATL is characterized by the presence of a few abnormal cells (0.5%-3%) in the peripheral blood over a long period. Crisis in chronic or smoldering ATL means the progression of the disease to acute ATL. The lymphoma type of ATL is considered to be a form of T-cell-type non-Hodgkin's lymphoma in which malignant cells contain proviral DNA of HTLV-I. Screening of the sera from healthy adults for presence of the anti-HTLV-I antibodies revealed that 3.6% of healthy individuals in Kumamoto Prefecture, which is located in the middle of Kyushu, were HTLV-I carriers. Family studies showed that the routes of natural infection of HTLV-I are from mother to child and also from husband to wife. The borderline between the healthy carrier state and smoldering ATL remains unclear. Smoldering ATL is frequently diagnosed in patients with fungus infection of the skin, chronic lymphadenopathy, interstitial pneumonitis, chronic renal failure and strongyloidiasis. Five patients with ATL refractory to conventional chemotherapeutic agents were treated with 2'-deoxy-coformycin (DCF), a potent inhibitor of adenosine deaminase. Two patients showed a good response, and three were resistant to DCF. In addition our experiences with a concurrence of lymphoma-type ATL in three sisters and spontaneous remissions in a patients with chronic ATL will be referred.

Heterogeneity in response to interleukin 2 and interleukin 2-producing ability of adult T cell leukemic cells.

To examine the possibility of heterogeneous mechanisms in the proliferation of adult T cell leukemia (ATL) cells, leukemic cells from 13 patients, nine acute-type and four chronic-type ATL, were examined for the production of interleukin 2 (IL 2) with or without mitogenic stimulation and their response to recombinant IL 2 when exogeneously added. The leukemic cells were classified into four groups, as follows. Group 1 (two patients): Cells of this group produced IL 2 messenger RNA, secreted IL 2, and proliferated when cultured in mitogen-free medium. The spontaneous proliferation of the cells in mitogen-free medium was inhibited by anti-Tac/IL 2 receptor and anti-IL 2 monoclonal antibodies. Moreover, the thymidine incorporation by the cells was enhanced in response to exogeneously added recombinant IL 2 and IL 2 produced by themselves. These results indicate that the ATL cells of this group proliferate with autostimulation by IL 2. Group 2 (seven patients): Cells of this group did not secrete IL 2 when cultured in mitogen-free medium, but the cells showed response to exogeneously added recombinant IL 2 and proliferated in culture. These results indicate that the ATL cells of this group proliferate by a paracrine mechanism. Group 3 (one patient): Cells of this group secreted IL 2 in mitogen-free medium. However, the spontaneous proliferation of these cells in vitro was very low, and the response to recombinant IL 2 was also very low. Group 4 (three patients): Cells of this group did not secrete IL 2 in mitogen-free medium. Spontaneous proliferation and the response to recombinant IL 2 were also very low. The clinical feature of all patients of Groups 1 and 2 was acute-type, and that of Groups 3 and 4 was chronic-type. Thus, we conclude that heterogeneous mechanisms exist in the proliferation of leukemic cells, and that growth rate in mitogen-free medium and response to IL 2 of the cells may have a significant relationship to the clinical feature, acute- or chronic-type.

Relationship of classification to biologic behavior of non-Hodgkin's lymphomas.

The classification of non-Hodgkin's lymphomas (NHLs) is an important factor in treatment. Most clinical protocols divide these tumors into two broad categories--indolent, or low-grade, and aggressive, or high-grade. Patients with low-grade NHLs usually have a relatively long survival, with or without the use of aggressive therapy. Although the tumors can be controlled with conventional chemotherapeutic approaches, they are rarely cured. Patients with high-grade tumors usually die within 1 to 2 years without therapy. However, with aggressive treatment, many patients can be cured if complete remissions can be sustained for at least 2 years. Several types of NHLs represent distinct clinicopathologic entities--lymphoblastic lymphoma, adult T cell leukemia/lymphoma, true histiocytic lymphoma, Burkitt's lymphoma, and hairy cell leukemia. Immunologic concepts are now used to classify NHLs. Identifying the cell of origin of a malignant lymphoma has important therapeutic implications, since malignant cells retain phenotypic and functional properties of their precursors. It is possible, therefore, to predict both the sites of involvement and the patterns of dissemination. Clinical applications are beginning to be developed. These include the use of monoclonal antibodies, monoclonal antibodies coupled to a toxin, alpha interferon, and monoclonal anti-idiotype antibodies. Human leukocyte interferon has been used experimentally to induce spontaneous regressions. Excellent results have been achieved so far only for patients with low-grade lymphomas.

The histopathologic classification of cutaneous lymphomas.

A classification of malignant lymphomas has been formulated to identify distinct clinical groups of patients for future therapeutic trials. The unifying concept of primary cutaneous lymphomas as of either T- or B-cell origin does not conflict with the Working Formulation but encompasses its categories. This classification requires immunologic data in addition to morphologic assessment for accurate evaluation. Cytomorphologic subdivision of the cutaneous T-cell lymphomas does not have the same clinical significance as for the cutaneous B-cell lymphomas. However, the pattern of skin involvement in cutaneous T-cell lymphoma (epidermotropic versus nonepidermotropic) does appear to be important clinically and should be included in future classifications.