In the immunological field, many substances that have biological activities on lymphocytes or hematopoietic cells have been purified and cloned. These substances are called “lymphokines” or “cytokines”, and have important roles on cell activation and differentiation. Cytokines have been proved to affect the wide variety of target cell through their receptors in “autocrine” or “paracrine” manner. They are also produced by the many kind of cells other than lymphocytes or hematopoietic cells, and sometimes have multifunctions in the same molecules.
ADF (ATL-derived factor), which we have purified and cloned as an IL2R/p55 (Tac) inducing factor from the HTLV-I infected T-cell line, has high homologus DNA sequence to E. coli thioredoxin. As is the case with the E. coli thioredoxin, ADF has active disulfide bond and potent reducing activity and radical scavenging activity. ADF is also homologous to PDI (Protein Disulfide Isomerase) and has similar isomerase activity. Whereas ADF doesn't have the signal peptide, ADF is released to culture supernatant and has synergistic or additive effects with cytokines including IL-1 and IL-2 on the mitogenic response of some lymphoid cell lines. ADF is highly expressed in many virus-transformed cell lines such as HTLV-I, EBV, HPV and induced in the PHA-stimulated blast of normal PBL. These finding suggest the multifunctional property of ADF/Thioredoxin and the association with the cell activation or blastic transformation.
Majority of EBV-transformed B cell lines express the low affinity Fc receptor for IgE (FcεRII) which is an animal lectin-like protein and is identical to an activation antigen on B cells (CD23). FcεRII/CD23 is expressed on the wide variety of hematopoietic cell lines including EBV (+) B and some HTLV-I (+) T cell lines. These cell lines released the soluble form of FcεRII to the culture supernatant by proteolysis. Soluble FcεRII has been called as IgE binding factor, which has affinity to IgE and other biological activities including growth promoting activity on lymphocytes. Membrane associated FcεRII/CD23 has been proved to be associated with some tyrosine kinase, indicating that IgE or some other ligand may induce activation signal through the FcεRII/CD23.
The possible role of ADF in the induction of IL-2R/p55 (Tac) as well as FcεRII/CD23 is discussed in relation to the normal and abnormal trasformation of lymphocytes.

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A case of cytophagic histiocytic panniculitis (CHP) occurring in a 15-year-old Japanese male is reported. The patient presented with typical fever, painful subcutaneous nodules, liver dysfunction, proteinuria, leukopenia, and coagulopathy shortly after sustaining a blunt trauma to the face, and died 6 months later due to severe hemor rhagic diathesis. Skin biopsy shortly after the onset revealed nonsuppurative lobular panniculitis with active proliferation of histiocytes in inflamed fat. Autopsy revealed systemic nonsuppurative panniculitis as well as proliferation of hemophagocytic histiocytes in inflamed areas and the reticuloendothelial system. Immunological studies suggest autoimmune etiology of CHP. Activation and proliferation of histiocytes may be caused by various lipid molecules released from inflamed adipose tissue, and coagulopathy of CHP may at least partly be caused by direct action of activated histiocytes on certain coagulation factors.

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We report two sporadic cases of familial hemophagocytic lymphohistiocytosis (FHL). One case is a 2-month-old female and another is a 4-month old female. Both patients admitted due to hepatosplenomegaly, fever, and bleeding tendency. Laboratory data showed pancytopenia, hypoproteinemia, hepatic damage, and hemophagocytosis in the bone marrow. The value of serum triglyceride was elevated initialy and normalized with treatment.
One patient was induced to complete remission (CR) with the treatment of VP16, cyclophosphamide, and prednisolon. Another patient failed to be induced to CR by the same treatment, but responded to CHOP-regimen (CPM, ADR, VCR, Pred) and remained in CR for 3 months. She relapsed systemicaly and then the disease could not be controlled completely. FHL is often indistinguishable from IAH (infection associated histiocytosis) especially if the patient is an infant and has no apparent familial histories. Most of the cases of IAH, the outcomes are good with the administration of steroids and/or therapy for DIC. On the other hand, FHL is a disease of which almost all cases result in rapid death if aggressive treatments are not applied immediately. Thus we think the cytotoxic agents, such as VP16 and CPM, should be administered as initial treatment if the patient is an infant and the condition is indistiguishable from IAH.

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The clinical and autopsy findings of three cases of B cell lymphoma simulating malignant histiocytosis are reported. Case 1 was 60y.o. female, case 2 was 75y.o. male and case 3 was 61y.o. female. The presenting symptoms were pyrexia in three cases, dyspnea in case 1 and jaundice in case 2. There was no peripheral lymphadenopathy in these cases. A hyperplasia of monocytes and hemophagocytic histiocytes was seen in their bone marrow and many abnormal lymphoid cells were seen in the marrow of case 3. The lung biopsy revealed infiltration of abnormal cells in case 1. Case 1 and 2 were diagnosed as malignant histiocytosis and case 3 was diagnosed as malignant lymphoma with reactive histiocytosis. After chemotherapy using adriamycin or THP-adriamycin case 1 and 3 improved, however case 2 did not respond. The overall survivals of three cases were 26 months in case 1, 3.5 months in case 2 and 12 months in case 3.
The postmortem examination showed that abnormal cells infiltrated diffusely into many organs such as lungs, liver, spleen and kidneys. Neither lymphadenopathy nor tumor-formation was seen. Infiltrating abnormal cells were positive for pan B cell antibody (L26) but negative for pan T cell antibody, lysozyme and S-100 protein.
These cases indicate that a part of B cell lymphoma is accompanied by reactive histiocytosis simulating malignant histiocytosis.

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An autopsy case of malignant histiocytosis (MH) in a 16 y.o. male is reported. He was acutely ill at admission, complaining of high fever, diarrhea and generalized skin symptoms. Hepatosplenomegaly and an enlarged lymph node were noticed. Bone marrow aspirate showed increased numbers of histiocytoid cells with various degree of atypism. They had vacuoles and azurophilic granules, but rarely showed erythrophagocytosis. Biopsied lymph node microscopically showed proliferation of atypical cells with the distinct appearance of histiocyte. Immunohistochemically, they had positive marker stain for lysozyme, α₁-antitrypsin and anti-macrophage. A diagnosis of MH was made. Genotypic analysis by Southern method showed germline TCR and JH genes. Ultrastructurally, mature tumor cells were rich in organallae and contained 10nm filaments. The patient died after development of marked pancytopenia. Total duration of illness was 4.5 months. Autopsy revealed systemic involvement of lymph nodes, bone marrow, liver, spleen and lungs by diffuse proliferation of atypical histiocytoid cells. They showed a diversity of cellular atypism, including mature and immature histiocytes, and pleomorphic and multinucleated giant cells. The present case is characterised clinically by prominent skin desquamation and progressive course, and pathologically by proliferation of a diversity of neoplastic histiocytoid and its precursor cells.

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Clinical, morphological, and ultrastructual studies are presented of three cases which had been diagnosed from lymph node biopsy as malignant histiocytosis. Three patients had a diffuse type of malignant histiocytosis and developed a leukemic phase at admission. Three patients survived for 1, 4 and 1 months after diagnosis. The neoplastic cells are characterized morphologically in the lymph nodes and in the peripheral blood by light microscopy and in two cases by electron microscopy also. These appear to be a spectrum of cell types in the leukemic malignant histiocytosis ranging from primitive reticulum cells or histiocytes to more differentiated monocytoid cells. No evidence for differentiation toward granulocytes was seen morphologically or immunohistochemically. The leukemic phase of malignant histiocytosis appears to be closely related to or identical histiocytic or monocytic leukemia (Schilling type) and should be differentiated from hairy cell leukemia. Necropsy findings from three cases are shortly reviewed.

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A 17 years old male who had been receiving growth hormone treatment for pituitary dwarfism for 20 months developed malignant histiocytosis (MH). He had had a history of severe hypersensitivity to mosquito bites since the age of 4. Before and upon admission he had 5 episodes of high fever which occurred cyclically about 4 weeks apart. The febrile phase was associated with hepatosplenomegaly, pancytopenia, marked elevation of serum LDH activity and ferritin level, all of which almost subsided or became normal during the afebrile phase. Accordingly, it was difficult to diagnose him as having MH. During the fifth episode of fever, hepatosplenomegaly increased markedly, atypical, immature monocytoid cells appeared in the bone marrow, and serum ferritin and LDH activity were extraordinarily elevated, strongly suggesting a diagnosis of MH. Combination chemotherapy resulted in a marked decrease in hepatosplenomegaly. However, MH was complicated with cerebral hemorrhage, and he died 3 months after admission. Immunohistochemical results showing positivity for lysozyme and α₁ antichymotrypsin and negativity for pan T antigen confirmed the diagnosis of MH. Of several serum cytokines assayed, M-CSF and IFN γ showed increase during the febrile phase and normalization during the afebrile phase.

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Two cases of adult T cell leukemia/lymphoma (ATLL) with unusual surface markers such as CD4^- and CD8⁺ have been reported.
Case 1: A 77-year-old male was admitted to our hospital with complaints of abdominal pain and swelling of testis and lymph nodes. Case 2: A 65-year-old male noticed a lymph node swelling in his right submandibular region. Lymph nodes taken from both patients were diagnosed as non-Hodgkin's lymphoma under histological examination. Integration of HTLV-I proviral DNA in the lymphoma cells and positive HTLV-I antibody in the serum disclosed that these cases were indeed ATLL although tumor cells expressed an unusual combination of the surface markers i.e. CD4^- and CD8⁺. There have been reports as to heterogeneity of the surface markers in ATLL. We believe that these cases could be a rare variant of ATLL.

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We report a case of Hodgkin's disease showing helper/inducer T cell phenotype on Hodgkin & Reed-Sternberg cells.
A 21 years-old Japanese female was admitted for right cervical lymphadenopathy. Laboratory tests including human T lymphocyte virus-I antibody (HTLV-I antibody) were within normal. A biopsy specimen of the cervical lymph node showed Hodgkin's disease, nodular sclerosis (NS).
Immunohistologically, Hodgkin & Reed-Sternberg cells were positive for CD30 (Ki-1), CD15 (Leu-M1), CD25 (IL-2R), HLA-DR, transferrin receptor, CD2 (Leu-5b), CD3 (Leu-4), CD4 (Leu-3a), and CD5 (Leu-1), but were negative for B cell associated antigens and myeloid-monocyte associated antigens. The immunohistochemical data indicate helper/inducer T cell phenotype on Hodgkin & Reed-Sternberg cells.
Southern blot analysis revealed six rearranged bands using T cell receptor gene probe (TCR Jγ1 probe), when genomic DNA of the biopsied lymph node was digested with EcoRI. Although the TCRγ gene rearrangement bands were not well evaluated, the finding of TCRγ gene rearrangement is unlikely to consider a clonal prolifaration of Hodgkin & Reed-Stenberg cells with T cell phenotype. It would be speculated in this case that rearranged bands for TCRγ may originate from functional T cell clones with transcription of the CD3 molecule and unique TCRγ rearrangements.
The patient is free from the disease 2 years after the biopsy.

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A 24-year-old female who was diagnosed as having idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL) was admitted to our hospital because of general fatigue and fever. Physical examination revealed general lymphadenopathy but no hepatosplenomegaly. Hematological findings were: red cell count, 283×10⁴/μl; hemoglobin 4.9g/dl; hematocrit, 33%; platelet, 72.6×10⁴/μl; and white cell count, 11000/μl. Cervical lymph node rebiopsy revealed folliclar hyperplasia with germinal centers, prominent mature plasma cells proliferation between follicles and sinuses, and the findings were identical to those of IPL. After administration of prednisone, the hemoglobin level increased to 9.0g/dl accompanied by a reduction in lymphadenopathy. However, she did not achieve complete remission.
Before administration of prednisolone, Interleukin-6 activities in serum as well as the supernatants of lymph node cell and peripheral blood leukocyte cultures were 2.07, 21.3 and 6.6U/ml, respectively.

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