Adult T-cell leukemia (ATL) is as aggressive T-cell malignancy, which was caused by human T-cell leukemia virus type I (HTLV-I). Inverse PCR analysis of HTLV-I provirus disclosed that HTLV-I infected cells proliferated clonally in vivo, and such clones survived for at least up to seven years. During such clonal proliferation, accumulating mutations of various genes have been thought to cause leukemia in vivo. We found mutations of Fas antigen, which is the key molecule of apoptosis, in the fresh ATL cells. Mutated Fas gene was also associated with drug resistancy in vivo and in vitro.

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We examined the histopathologic changes of lymph nodes from 10 patients with mild lymphadenopathy, a few atypical lymphocytes in peripheral blood, skin lesions, and proviral DNA of human T-cell leukemia virus type I (HTLV-I) in the nodes. The proviral DNA of HTLV-I was detected by Southern blot analysis, in situ hybridization technique, and/or polymerase chain reaction. The lymph nodes showed preserved nodal architecture with diffuse infiltration of small to intermediate sized lymphocytes in association with scattered transformed lymphocytes and few immunoblast-like cells in the enlarged paracortex. The infiltrating lymphocytes were positive for CD4, but neither rearrangement nor deletion of T-cell receptors and immunoglobulin heavy chain genes was detected. All patients were alive and healthy at more than 5 months after the biopsies. The histology resembled that of a viral infection and could be distinguished from HTLV-I associated lymphomas.

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Recent molecular biological studies have been reporting that HTLV-1 p40Tax protein (Tax) induces pathological conditions in the infected host cells whereas HTLV-1 p27Rex protein (Rex) modulates activation of the integrated HTLV-1 proviral DNA to yield new viruses. Thus, histochemical detection of Tax and Rex is necessary to analyze lesions of HTLV-1-related diseases such as adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and HTLV-1-associated non-neoplastic lymphadenopathy (HANNLA). The mRNAs of HTLV-1 proviral DNA pX region have been reported to be detected by in-situ hybridization (ISH) in ATLL cells and lymphocytes in fresh sections of HTLV-1-related diseases under developing procedures for ISH such as usage of biotinylated double stranded DNA probe that was synthesized by polymerase chain reaction (PCR) and alkaline phosphorylase coloration in the polyvinyl alcohol solvent. HTLV-1 proviral DNA could be detected by means of PCR-ISH labeling nuclei having integrated HTLV-1 proviral DNA, whereas the HTLV-1 proviral DNA in large cells must be detected by a single cell PCR because the thickness of section was smaller than those of nuclei. The Tax retrieved in paraffin section could be labeled dominantly in cytoplasm of ATLL cells by means of Elite avidin-biotin complex method (Elite ABC) of immunohistochemistry (IHC) of anti-Tax monoclonal antibody, Lt-4. In spite of detecting the mRNAs, the retrieved Tax could not be labeled by the Elite ABC in a few ATLL cases. The paraffin-IHC (modified ImmunoMax) that comprises streptavidinbiotin complex method (sABC) and peroxidase reaction catalyzing biotinylated tyramide got 1, 000 times higher sensitivity than Elite-ABC and was introduced in the IHC detecting the Tax in 1997. The modified ImmunoMax could detect Tax and Rex in ATLL cells and lymphocytes in HANNLA, whereas the frozen-IHC showed in a few cases of ATLL poor stain that might be explained by an extremely small amount of Tax and the Tax-antigen masked in combination with other cellular factors. A cross reaction of anti-Tax monoclonal antibody, Lt-4, with intranuclear substance in HTLV-1-not-related T-cell lymphoma was reported. The modified ImmunoMax of anti Tax monoclonal antibody WATM-1 more specific than Lt-4 revealed that there was a smaller amount of Tax in nuclei and a larger amount of Tax in cytoplasm in ATLL cells. Image analysis of the modified ImmunoMax of WATM-1 and anti-Rex monoclonal antibody Rec-6 reported gradual increase of Tax from HANNLA to ATLL and increase of Rex in HANNLA with developing paracortex and in ATLL. According to the recent molecular biological studies of Tax, Tax acts directly or indirectly on enhancer sequences of host cell genes and LTR of the HTLV-1 proviral DNA, and occupies comparatively stabilizing units of cellular factors activating the host cell genes. The small amount of Tax detected in nuclei would play a role in the former way and the Tax detected in cytoplasm might do in the latter way. Getting the high sensitivity, the IHC will be able to examine life-cycle of HTLV-1, activation of HTLV-1 proviral DNA and the amount of Tax in HTLV-1 carriers and will be expected to clarify how HTLV-1 infection is in HTLV-1 carriers and in patients with HTLV-1-related diseases. And the next histochemistry to analyze effects of Tax on the pathogenesis of the HTLV-1-related diseases will aim to find out the host cell genes or cytoplasmic factors that reveal change according to the amount of Tax in each phase of the HTLV-1-related diseases.

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Collagen diseases are autoimmune diseases which are prone to be associated with lymphoreticular disorders. Reports on such association with each collagen disease are outlined in this review. Hemophagocytic syndrome and B cell lymphoma seem to be most frequently associated with systemic lupus erythematosus and Sjögren's syndrome, respectively. Increase of non-Hodgkin's lymphoma has been shown in patients with rheumatoid arthritis, but not with systemic sclerosis or dermatomyositis/polymyositis. It appears most likely that chronic dysregulation of immune system in collagen diseases leads to proliferation of lymphoreticular system. It should be noted that lymphomas have been observed during immunosuppressive therapy for collagen diseases. More specific treatments for each collagen disease are expected to prevent abnormal proliferation of lymphoreticular system.

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