Monoclonal antibody HML-1 reactivity with adult T-cell leukaemia/lymphoma and other lymphomas

Human T-cell leukaemia/lymphoma virus type 1 (HTLV-1), a causative virus of adult T-cell leukaemia/lymphoma (ATLL), is known to be transmitted by breast-feeding. Using a monoclonal antibody HML-1 which labels human intestinal intra-epithelial T lymphocytes, we have immunohistochemically examined ATLL tissues in order to evaluate the possibility that HTLV-1 infected intestinal T cells are the origin of ATLL cells. Previously this antibody was reported to react with intestinal T-cell malignant lymphomas but not with peripheral tumours, or any B-cell lymphomas. We investigated 181 patients with malignant lymphomas and found that 19 out of 113 ATLLs were positive for HML-1. T-cell malignant lymphomas excluding ATLL also reacted with HML-1 (7/24), but all the B-cell lymphomas 0/33) and non-neoplastic lymph node and skin lesions (0/10) were negative for HML-1. In patients with ATLL and other T-cell malignant lymphomas, the positivity level of HML-1 was relatively higher in stomach (3/7) and tonsil (2/6) than that in lymph nodes (15/100) and skin (8/47). We observed one HML-1 positive ATLL patient with tumour formation in the skin and lymphadenopathy and marked infiltration of the large intestine but minimal involvement of other organs. Although HML-1 was frequently expressed in gastric infiltration of ATLL, the level of positivity was too low in lymph nodes to support the hypothesis that HTLV-1 infected intestinal T cells are the origin of ATLL cells. Some of the HML-1 positive ATLL cases co-expressed CD30. Furthermore, three of six cases of Ki-1 lymphoma (large anaplastic cell lymphoma) were positive for HML-1. We conclude that expression of HML-1 in ATLL reflects an activated state of the lymphoma cells, but not the intestinal origin of ATLL cells.     

Morphological characteristics of malignant T-cell lymphomas in baboons

Fifteen cases of generalized peripheral T-cell non-Hodgkin's lymphoma in baboons were phenotyped immunologically and morphologically. Using the updated Kiel classification the cases included low-grade and high-grade lymphomas and low-grade lymphomas that had transformed into high-grade lymphomas. In the low-grade group there were seven cases of lymphocytic type, partly corresponding to chronic lymphocytic leukaemia of T type and to T-zone lymphoma in man. In addition there were four cases of prolymphocytic-lymphocytic type, which show large nodules (proliferation centres) and which have no equivalent in the Kiel classification. In four cases there was a progression to an immunoblastic lymphoma and in one case to a large cell anaplastic lymphoma. In addition, three cases of large cell anaplastic lymphoma without a low-grade component were found. Both the immunoblastic lymphomas and the large cell anaplastic lymphomas corresponded well with the same types in the Kiel classification. The cases of large cell anaplastic lymphoma were also CD30 positive. Most of these lymphomas were CD4 positive, but there were rare cases that were either CD8 positive, showed both CD4 and CD8 positivity or had lost both antigens. Antigens associated with cell activation were often revealed. All but one baboon had antibodies in the blood against the retrovirus STLV-1 (simian T-cell leukaemia virus 1), which is very similar to human T-cell leukaemia virus 1 (HTLV-1) in man. Despite this virological resemblance, the morphology of these T-cell lymphomas does not resemble that of the HTLV-1-positive Japanese T-cell lymphomas but is like that of the HTLV-1-negative European cases.     

Molecular biology and pathogenesis of the human T-cell leukaemia/lymphotropic virus Type-1 (HTLV-1)

Retroviruses are associated with a variety of diseases, including immunological and neurological disorders, and various forms of cancer. In humans, the Human T-cell Leukaemia/Lymphotropic virus type 1 (HTLV-1), which belongs to the Oncovirus family, is the aetiological agent of two diverse diseases: Adult T-cell leukaemia/lymphoma (ATLL) (Poiesz et al. 1980; Hinuma et al. 1981; Yoshida et al. 1982), as well as the neurological disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) (Gessain et al. 1985; Rodgers-Johnson et al. 1985; Osame et al. 1986). HTLV-1 is the only human retrovirus known to be the aetiological agent of cancer. A genetically related virus, HTLV-2, has been identified and isolated (Kalyanaraman et al. 1982). However, there has been no demonstration of a definitive aetiological role for HTLV-2 in human disease to date. Simian T-cell lymphotropic viruses types 1 and 2 (STLV-1 and -2) and bovine leukaemia virus (BLV) have also been classified in same group, Oncoviridae, based upon their similarities in genetic sequence and structure to HTLV-1 and -2 (Burny et al. 1988; Dekaban et al. 1995; Slattery et al. 1999). This article will focus on HTLV-1, reviewing its discovery, molecular biology, and its role in disease pathogenesis.     

T-cell lymphoma in Singapore: pathology, clinical findings and association with HTLV-1 antibodies

Of 128 cases of malignant lymphomas studied in Singapore between 1986 and 1988, 28 were identified as peripheral T-cell lymphomas. Sera from two of the 128 cases were positive for HTLV-1 antibodies and both cases had the clinical and pathological features of adult T-cell leukaemia/lymphoma. The pathological and clinical features of the 28 cases of peripheral T-cell lymphoma are presented in detail. Survival data indicated no significant difference between the low grade and high grade histological types. Three of the patients had previous or concomitant malignancies. The percentage of T-cell lymphomas associated with HTLV-1 infection in Singapore is low compared to those areas in which HTLV-1 is endemic.     

Non-HTLV-1-associated primary gastric T-cell lymphomas show cytotoxic activity: clinicopathological,immunohistochemical characteristics and TIA-1 expression in 31 cases

AIMS: Most primary gastrointestinal lymphomas are of B-cell origin and T-cell origin is very rare. Recent studies have suggested that human T-cell lymphotrophic virus type 1 (HTLV-1) may be involved in the development of primary gastric T-cell lymphoma. We analysed 31 patients with primary gastric T-cell lymphoma in south-west Japan, an area endemic for HTLV-1, and determined their phenotypes, genotypes, and HTLV-1 status. METHODS AND RESULTS: Here we present 31 cases of primary gastric T-cell lymphoma in a HTLV-1-endemic area in Japan and analyse the clinical status, histology, phenotype and virus status. The median age at onset of primary gastric T-cell lymphoma was 57 years with a gender ratio of M:F = 1.58:1. Six of the 31 primary gastric T-cell lymphoma cases had HTLV-1 proviral DNA (five males, one female), nine of the 31 cases were positive for anti-adult T cell leukaemia antibody, without examination of HTLV-1 proviral DNA (five males, four females), eight were non-HTLV-1-associated primary gastric T-cell lymphoma (four males, four females) and the other eight cases were unknown. Primary gastric T-cell lymphoma usually presented as a large ulcerated tumour at the corpus to the antrum and histologically consisted of anaplastic large cell type (n = 2), pleomorphic large cell type (n = 3), pleomorphic medium and large cell type (n = 14), pleomorphic medium cell type (n = 11), and angioimmunoblastic T-cell lymphoma type (n = 1). There were no clear macroscopic and microscopic differences between HTLV-1-associated and non-HTLV-1-associated primary gastric T-cell lymphoma. Most patients died within 2 years of diagnosis, and both types of primary gastric T-cell lymphoma (with and without HTLV-1) were associated with poor prognosis. Cytotoxic marker analysis showed that HTLV-1-associated lymphomas were negative for TIA-1, while non-HTLV-1-associated lymphomas were positive for TIA-1. CONCLUSIONS: Our results suggest that in HTLV-1-endemic areas, patients with HTLV-1-associated primary gastric T-cell lymphoma should be managed carefully and that TIA-1 seems to be useful for identifying the aetiology of this lesion.     

Epidemiology of human T-cell leukaemia/lymphoma virus type 1 (HTLV-1) infections in a subpopulation of Afro-Caribbean origin in England

Epidemiological studies on neurological diseases in residents of Afro-Caribbean origin in the West Midlands region of England have identified eight patients with tropical spastic paraparesis (TSP), all of whom were found to be infected with human T-cell leukaemia/lymphoma virus type 1 (HTLV-1). The husband of one of the patients with TSP was also infected with HTLV-1 and had a T-cell lymphoma. In addition, six asymptomatic HTLV-1-infected first-degree relatives of the TSP patients have been found. By anonymous testing of over 700 sera obtained from individuals of Afro-Caribbean, African, or Asian ethnic origin, seven HTLV-1-infected individuals were detected, who were all immigrants from the Caribbean. Overall, these numbers yielded a seroprevalence of HTLV-1 infections of 3.4% among the immigrant population of Afro-Caribbean origin, which is comparable with the prevalence of HTLV-1 in Jamaica in an equivalent age and sex cohort. Sera were tested for HTLV-1 antibody by means of three different procedures: passive particle agglutination test (Serodia), indirect enzyme-labeled immunosorbent assay (ELISA; Dupont), and indirect immunofluorescence test (in-house, using HTLV-1-infected MT2 cells). The results of all three tests correlated very well with each other. HTLV-1 antibody titres in TSP patients were on the whole significantly higher than those of asymptomatic carriers, but some of the apparently healthy first-degree relatives and one anonymously tested individual had titres as high as most of the TSP patients.     

T-cell lymphoma in Hashimoto's thyroiditis

An elderly Caucasian woman with a 2-year-history of hypothyroidism, treated with thyroxine, presented with a rapidly growing mass in the thyroid. The morphological and immunological features of this thyroid tumour were those of a peripheral T-cell lymphoma with an immunophenotype commonly associated with HTLV-1 positive-adult T-cell leukaemia/lymphoma, although serology for HTLV1 antibody was negative. Monoclonal gene rearrangements were demonstrated with T-cell receptor beta- and gamma-specific primers. There are several interesting features in this case (i): although primary B-cell lymphomas (MALT-associated lymphomas) of thyroid are a well-recognized sequel to thyroiditis, primary T-cell lymphomas are rare, even in areas of the world where adult T-cell lymphomas predominate; (ii) the tumour showed the typical immunophenotype of an HTLV-1 positive T-cell lymphoma but the patient is English, has not visited endemic areas, and is serologically negative for HTLV–1; (iii) the residual thyroid gland showed a florid lymphocytic thyroiditis with Hu¨rthle cell change, typical of Hashimoto's thyroiditis; (iv) unlike other reports of thyroid T-cell lymphoma, which have presented with stage III-IV disease, this tumour presented in the favourable clinical stage of IE.     

Histopathology and immunohistochemistry of peripheral T cell lymphomas: a proposal for their classification.

Based on the results of histological and immunohistochemical observations of a large number of peripheral T cell lymphomas from China, England, Germany and Japan, histological and cytological morphology were correlated with immunophenotype, aetiological association with HTLV-1, and clinical behaviour to produce a working classification of the T cell lymphomas. This classification, based mainly on cytological criteria, divides the peripheral T cell lymphomas into tumours of low grade and high grade malignancy. Adult T cell lymphoma/leukaemia (ATLL) is caused by HTLV-1 and belongs chiefly to the high grade category. Some tumours are characterised by an admixture of other cells (epithelioid cells, follicular dendritic cells, etc) and structures (high endothelial venules, follicles), which may indicate the secretion of lymphokines by the tumour cells. Clear cells seem to be specific for T cell lymphomas and may occur in various types of peripheral T cell lymphoma.     

A case of adult T-cell leukemia/lymphoma, histologically presenting CD30-positive large cell lymphoma.

A 48-year-old Japanese woman with adult T-cell leukemia/lymphoma (ATLL), histologically presenting CD30-positive large cell lymphoma is reported. The patient, who was from an ATLL endemic area in Japan, had cutaneous nodules in the head, trunk, and extremities, and cervical lymph node swelling; these had been found three months before her admission to our hospital. A biopsy specimen of a skin lesion showed diffuse large cell lymphoma; the lymphoma cells were positively stained with CD30 (Ki-1/Ber H-2), CD4 (helper-T), and CD25 (interleukin-2 receptor) antibodies. Anti HTLV-1 antibody (ATLA) was detected in the serum, and molecular cytogenetic studies of lymphoma cells showed both positive T-cell receptor rearrangement and HTLV-1 specific DNA sequences.     

A Case of Adult T-cell Leukemia/Lymphoma, Histologically Presenting CD30-Positive Large Cell Lymphoma

A 48 year old Japanese woman with adult T-cell leuke-mia/lymphoma (ATLL), histologically presenting CD30 positive large cell lymphoma is reported. The patient, who was from an ATLL endemic area in Japan, had cutaneous nodules in the head, trunk, and extremities, and cervical lymph node swelling; these had been found three months before her admission to our hospital. A biopsy specimen of a skin lesion showed diffuse large cell lymphoma; the lymphoma cells were positively stained with CD30 (Ki 1/ Ber H 2), CD4 (helper T), and CD25 (interleukin 2 receptor) antibodies. Anti HTLV-1 antibody (ATLA) was detected in the serum, and molecular cytogenetic studies of lymphoma cells showed both positive T-cell receptor rearrangement and HTLV-1 specific DNA sequences.     

Intravascular malignant lymphomatosis: a case of T-cell lymphoma probably associated with human T-cell lymphotropic virus

Intravascular malignant lymphomatosis (IML) is an unusual condition characterized by proliferation of lymphoma cells exclusively within the blood vessels. Most of the cases reported are of B-cell origin. We report a rare case of T-cell IML probably associated with human T-lymphotropic virus (HTLV-1) infection. The present case suggests that T-cell lymphoma and HTLV-1-associated lymphoma occasionally represent a form of intravascular proliferation.     

Human CD4+ T lymphocytes recognize a highly conserved epitope of human T lymphotropic virus type 1 (HTLV-1) env gp21 restricted by HLA DRB1*0101

HTLV-1 causes two distinct human diseases, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukaemia/lymphoma (ATL). Persistently infected individuals carry a risk of < 1% of developing either disease. These basic epidemiological data imply that virus–host interactions, especially immunogenetic factors, influence the outcome of infection. Several studies showed that the HLA class II DR1 DQ5 haplotype is over-represented in HAM/TSP, but rare in ATL. Therefore, we selected four patients with HAM/TSP and one seronegative control who all carried the HLA DR1 DQ5 haplotype. We analysed the CD4⁺ T lymphocyte response against eight synthetic peptides of HTLV-1 envelope (env) glycoprotein gp21, a crucial target antigen in HAM/TSP. The first of two immunodominant epitopes corresponded to a domain of the HTLV-1 envelope protein which had previously been shown to be essential for HTLV-1 envelope function. The second immunodominant epitope overlapped a highly conserved sequence of the retroviral transmembrane envelope protein. DR1 (DRB1*0101)-restricted T lymphocytes were activated by the conserved peptide sequence in nanomolar concentrations. In contrast, this conserved sequence can also induce non-specific, cAMP-mediated immunosuppressive effects on T cells when added in micromolar concentrations to culture media, as shown by Haraguchi S, Good RA, James-Yarish M, Cianciolo GJ, Day NK, Proc Natl Acad Sci USA 1995; 92 :5568–71. Hence, HTLV-1 env gp21 might exert either stimulating immunological or immunosuppressive effects in HTLV-1-infected individuals, depending on the level of its expression and the presence of HLA DRB1*0101.     

新疆南疆地区嗜人T淋巴细胞病毒I型血清流行病学调查

通过血清流行病学调查，了解人嗜Ｔ淋巴细胞病毒Ｉ型（ＨＴＬＶ－１）在新疆南部（南疆）少数民族地区的流行情况，自南疆喀什，和田，阿图什地区采集正常人群中不同年龄组，不同民族的血清标本２６４２份，其中维吾尔族（维族）１０８２份，汉族１０８９份，柯尔克孜族（柯族）４７１份。用免疫荧光法（ＩＦＡ）检测上述血清中ＨＴＬＶ－１ＩｇＧ抗体，结果维族抗体阳性者为０．７４％（８／１０８２）汉族为０（０／１０８９）柯族     

NF-kappaB in pathogenesis and treatment of adult T-cell leukemia/lymphoma

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) induces aberrant nuclear factor-kappaB (NF-kappaB) activation. Although Tax is thought to play major roles in NF-kappaB activation, cells expressing Tax become a target of cytotoxic T cells. Accordingly, HTLV-1-infected cells lose Tax expression and acquire Tax-independent NF-kappaB activation. Blocking NF-kappaB not only induces apoptosis in adult T-cell leukemia/lymphoma (ATL) cells but also reduces the number of HTLV-1-infected cells in virus carriers. Therefore, because constitutively activated NF-kappaB appears to be the common biological basis shared between HTLV-1-infected untransformed cells and ATL cells, blocking NF-kappaB might be a potential strategy for treating and preventing ATL.     

Target epitopes of HTLV-1 recognized by class I MHC-restricted cytotoxic T lymphocytes in patients with myelopathy and spastic paraparesis and infected patients with autoimmune disorders

Human T-cell lymphotropic virus type I (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The different patterns of clinical diseases are thought to be linked to immunogenetic host factors. A variety of autoimmune diseases, such as Sj?gren's syndrome, have been reported in persons infected with HTLV-1, although the precise relationship between these disorders and HTLV-1 infection remains unknown. There is no report on the repertoire of HTLV-1-specific CD8+ T-cells in HAM/TSP patients or carriers with autoimmune diseases, both characterized by an abnormal immune state. In this study, to characterize HTLV-1-specific CD8+ T-cells in asymptomatic HTLV-1 carriers, HAM/TSP patients and carriers with autoimmune diseases, we examined the frequency and diversity of HTLV-1-specific CD8+ T-cells using HTLV-1 tetramers. HTLV-1 Env-specific CD8+ T-cells were significantly more frequent in HAM/TSP and carriers with autoimmune diseases compared with asymptomatic HTLV-1 carriers, while the frequency of HTLV-1 Tax-specific CD8+ T-cells was not significantly different among them. CD8+ cells binding to HTLV-1 Tax tetramers in carriers with autoimmune diseases were significantly reduced compared with HAM/TSP patients. This study demonstrates the importance of CD8+ T-cells recognizing HTLV-1 Env-tetramers in HAM/TSP patients and carriers with autoimmune diseases, thereby suggesting that the diversity, frequency and repertoire of HTLV-1 Env-specific CD8+ T-cell clones may be related to the hyperimmune response in HAM/TSP and carriers with autoimmune diseases, although different immunological mechanisms may mediate the hyperimmunity in these conditions.     

The human HTLV-3 and HTLV-4 retroviruses: new members of the HTLV family

Human T cell leukemia/lymphoma virus Type 1 and 2 (HTLV-1 and HTLV-2), together with their simian counterparts (STLV-1, STLV-2), belong to the Primate T lymphotropic viruses group (PTLV). HTLV-1 infects 15 to 20million people worldwide, while STLV-1 is endemic in a number of simian or ape species living in Africa or Asia. The high percentage of homologies between HTLV-1 and STLV-1 strains, led to the demonstration that most HTLV-1 subtypes arose from interspecies transmission between monkeys and humans. STLV-3 viruses belong to the third PTLV type and are equally divergent from HTLV-1 than from HTLV-2. They are endemic in several monkey species that live in West, Central, and East Africa. In 2005, we and others reported the discovery of the human homolog (HTLV-3) of STLV-3 in two asymptomatic inhabitants from South Cameroon whose sera exhibited HTLV indeterminate serologies. More recently, we reported a third case of HTLV-3 infection in Cameroon suggesting that this virus is not rare in the human population living in Central Africa. Together with STLV-3, these three human viral strains belong therefore to the PTLV-3 type. A fourth HTLV type (HTLV-4) was also discovered in the same geographical area. Current studies are aimed at determining the prevalence, distribution and modes of transmission of these viruses as well as their possible association with human diseases. Furthermore, molecular characterization of their viral transactivator Tax is ongoing in order to look for possible oncogenic properties.     

Human T-lymphotropic virus type-1 related adult T-cell leukemia/lymphoma presenting as a parotid mass diagnosed by fine-needle aspiration biopsy

A 48-yr-old black woman with a history of blood transfusions for menorrhagia secondary to uterine fibroids but no known Caribbean association presented with a 6-wk history of a rapidly enlarging right parotid mass. At the time of presentation, she could not close her right eye. An aspiration biopsy showed small, medium, and large lymphoma cells with angulated nuclei, red macronucleoli, and basophilic cytoplasm with fine vacuoles. Flow cytometry indicated a (CD25(+)/CD7(-)) T-cell lineage, suggesting an human T-lymphotropic virus (HTLV) 1-related T-cell leukemia/lymphoma, which was confirmed by polymerase chain reaction (PCR)-based amplification on DNA extracted from fresh tissue with specific oligonucleotide primers for HTLV-1 DNA sequence. Histology showed interstitial infiltration and destruction of the parotid parenchyma by lymphoma cells without involvement of adjacent lymph nodes. Total body CT scan and magnetic resonance imaging (MRI) studies were negative for lymphadenopathy but showed liver metastasis. To our knowledge, this is the first reported case of HTLV-1-related primary parotid lymphoma as the initial presentation of adult T-cell leukemia/lymphoma.     

Development of T cell lymphoma in HTLV-1 bZIP factor and Tax double transgenic mice

Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection.     

Adult T-cell leukemia/lymphoma in Jujuy,north-west Argentina

Human T-cell leukemia virus type 1 (HTLV-1) infection is prevalent in native Americans living in the Andes. Some of their malignant lymphomas (ML) show a peculiar histology suggestive of adult T-cell leukemia/lymphoma (ATLL). To determine whether ML resembling ATLL are indeed ATLL, re-analysis of 34 cases occurring in Jujuy, a province of Argentina, was conducted, concentrating on immunological phenotype, integration of HTLV-1 proviral DNA, expression of HTLV-1 p40Tax and p27Rex, and infection of Epstein-Barr virus (EBV). The ML were 22 cases of mature peripheral T-cell and natural killer (NK)-cell neoplasm (mT/NKN), 11 B-cell malignant neoplasms and one Hodgkin's lymphoma. Polymerase chain reaction against the HTLV-1 proviral DNA, using DNA extracted from paraffin sections, indicated integration of the HTLV-1 proviral DNA in three cases of eight mT/NKN. Two other cases of mT/NKN were positive for anti-HTLV-1 antibodies. Expression of p40Tax and p27Rex was detected in all five of these mT/NKN cases associated with HTLV-1. As such, these five mT/NKN were rediagnosed as ATLL. In situ hybridization signals for EBV-encoded small nuclear early region-1 were detected in nine cases of mT/NKN, of which five cases of NK-cell lymphoma were found to have cytoplasmic CD3 expression, a CD56 phenotype and positivity of TIA1. According to the new World Health Organization classification, the mT/NKN class includes five cases of ATLL and five cases of NK-cell lymphomas. The five cases of ATLL were of native American extraction from an HTLV-1-endemic area around Jujuy, north-west Argentina.