Cellular immune surveillance against HTLV-I infected T lymphocytes in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP).

To investigate the cellular immune surveillance against HTLV-I infected T lymphocytes in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), we studied the cytotoxic T lymphocytes (CTL) activity against an HTLV-I infected human T cell line (MT-2) and the natural killer (NK) cell activity in 15 HAM patients, 6 HTLV-I carriers, and 15 controls. The activity of CTL against MT-2 cells was found to be significantly elevated in HAM compared with that in the controls. This cytotoxicity in HAM was higher than in HTLV-I carriers, although the difference was not statistically significant. There was an HLA class I restriction in this CTL activity against MT-2 cells in HAM. On the other hand, NK cell activity was significantly lower in HAM than in controls. Cold target inhibition studies suggested that NK cells could not lyse MT-2 cells effectively. There was a positive correlation between the CTL activity against MT-2 cells and the serum antibody titers to HTLV-I in HAM.     

Pathogenetic significance of HTLV-I infection and immune surveillance in HAM]

HTLV-I proviral DNA load is significantly increased in HTLV-I associated myelopathy (HAM) compared with asymptomatic HTLV-I seropositive carriers (SPC), and this spread of HTLV-I infection seems to be critically important in the pathogenesis of HAM. Thus, in this report, cellular immune surveillance against HTLV-I was reviewed. (1) MHC class I-restricted cytotoxic T lymphocytes (CTL) activities are detected in peripheral blood mononuclear cells (PBMC) of HAM. CTL release various proinflammatory and cytotoxic cytokines, chemokines, and proteases. Since CTL are also found in the spinal lesions of HAM, CTL may contribute to the tissue damage. In spontaneous proliferation of PBMC in HAM, CD 4/CD 8 is decreased due to the proliferation of CD 8 + CTL. CD 4/CD 8 is inversely correlated with the clinical severity of HAM. Collectively, CTL may be involved in the pathogenesis of HAM. (2) Activity and subsets of natural killer (NK) cells are lower in HTLV-I-seropositive individuals. Moreover, NK have only a weak cytotoxicity against HTLV-I infected cells. (3) Antibody-dependent cell-mediated cytotoxicity (ADCC) are impaired in HAM compared with SPC due to the suppressed effector cell activity. Since ADCC effectively lyse HTLV-I infected cells in vitro, the impaired ADCC may in part allow the spread of HTLV-I infection in HAM, and potentiation of ADCC may have an anti-HTLV-I therapeutic effect.     

Flow cytometric differentiation of Asian and Western types of multiple sclerosis, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and hyperIgEaemic myelitis by analyses of memory CD4 positive T cell subsets and NK cell subsets

We examined the alterations of memory CD4(+) T cell subsets bearing surface receptors linked to either Th1 or Th2 cytokine production as well as natural killer (NK) cell subsets by three color flow cytometry in the peripheral blood from 36 patients with clinically definite multiple sclerosis (MS), 27 patients with HAM/TSP, 13 patients with hyperIgEaemic myelitis who had mite antigen-specific IgE and 25 healthy controls (HC). The patients with MS were clinically classified into an optico-spinal form of MS (Asian type, MS-A) and the conventional form of MS (Western type, MS-W). MS-A showed a significant increase of CD4(+)CD45RA(-)CCR5(+) cells (Th1 cells) through the relapse and remission phases in comparison to HC, while MS-W showed a significant increase of CD4(+)CD45RO(+)CD62L(-) cells (Th1 cells) only at the relapse phase. HAM/TSP showed a significant increase of CCR5(+) and CD62L(-) memory CD4(+) T cells as well as CD30(+) memory CD4(+) T cells (Th2 cells) in comparison to HC. On the other hand, a selective increase of CD4(+)CD45RO(+)CD30(+) cells was found in hyperIgEaemic myelitis. The percentage of mature NK cells (CD3(-)CD16(+)CD56(+) cells) as well as double negative T cells (CD3(+)CD4(-)CD8(-) cells) decreased significantly in HAM/TSP in comparison to HC. Our findings therefore suggest a flow cytometric analysis of Th1/Th2-associated markers on memory CD4(+) T cells as well as NK cell subsets to be useful for differentiating various inflammatory neurologic conditions.     

Cell surface phenotype of in vitro proliferating lymphocytes in HTLV-I-associated myelopathy (HAM/TSP)

The in vitro proliferation of peripheral blood lymphocytes (PBLs) without any mitogenic stimulation is one of the hallmarks of human T lymphotropic virus type I (HTLV-I) infection. Recent evidence suggests a difference in the degree of the phenomenon between HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and asymptomatic HTLV-I carriers (AC). In this article, we demonstrated several alterations in the features of the in vitro transformed lymphocytes between patients with HAM/TSP (n = 16) and AC (n = 8). The percentages of total CD8+ and CD8+CD28+ cells were significantly increased in the in vitro proliferating T lymphocytes derived from the patients with HAM/TSP when compared to those from AC. HAM/TSP was segregated from AC by the high degree of the proliferation of CD8+CD28+ cells. The expression of HTLV-I-specific antigens on the cultured PBLs was detected only in the subjects which showed low CD8+CD28+/CD4+ ratio of the in vitro proliferating lymphocytes. These findings suggest that this phenomenon distinguishes HAM/TSP from AC, not only in quantity but also in quality.     

Enhanced adherence of endothelial cells to blood mononuclear cells in HAM/TSP]

We investigated the adhesion of blood mononuclear cells (MNC) isolated from patients with HTLV-1-associated myelopathy (HAM/TSP). MNC from HAM/TSP patients were significantly more adherent to activated endothelial monolayers than MNC from non-HAM/TSP (controls and HTLV-1 carriers) subjects. Blocking studies demonstrated that the adhesion molecules VLA-4 (CD49d), ICAM-1 (CD54), and L-selectin (CD62L) all contributed to increased binding. However, anti-ICAM-1 antibody was the most efficient in inhibiting binding HAM/TSP patients MNC to activated endothelial cells. Expression on MNC of molecules involved in adhesion was also studied by flow cytometry in HAM/TSP patients, HTLV-1 carriers, and healthy control subjects after two days culture without any mitogen. In HAM/TSP patients, L-selectin expression on CD4+ and CD8+ subsets was lower than in controls; interestingly, HAM/TSP patients had lower percentage of CD4+ subset expressing L-selectin than HTLV-1 carriers. The percentage of CD4+ and CD8+ cells expressing VLA-4 was found to be similar to controls in both HAM/TSP patients and HTLV-1 carriers. Following two days in culture without mitogen, the percentage of T cells expressing ICAM-1 increased in HAM/TSP and carriers, but not in controls. This study provides information regarding trans-endothelial migration of MNC across the blood brain barrier in HAM/TSP and suggests ICAM-1 and its counterpart molecule LAF-1 are involved in massive infiltration of lymphocytes observed in the spinal cord.     

Antibody titers to HTLV-I-p40tax protein and gag-env hybrid protein in HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with increased HTLV-I proviral DNA load.

We studied the relationship between antibody titers to recombinant HTLV-I p40tax protein and gag-env hybrid protein in serum (by an enzyme-linked immunosorbent assay) and HTLV-I proviral DNA load in peripheral blood mononuclear cells (by a quantitative polymerase chain reaction method) in 18 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), 17 HTLV-I carriers without HAM/TSP and 16 HTLV-I uninfected controls. The IgG and IgA antibody titers to either of the proteins correlated significantly with the HTLV-I pX (coding p40tax protein) and pol DNA amounts in HTLV-I infected subjects. HAM/TSP patients had significantly higher titers of IgG and IgA antibodies to the HTLV-I proteins than did the HTLV-I carriers without HAM/TSP. While the IgM antibodies to the HTLV-I proteins were found in only 6% of HTLV-I carriers without HAM/TSP, they were found in 40% of HAM/TSP patients, especially those having both a high HTLV-I proviral DNA load and high titers of the IgG and IgA antibodies. HAM/TSP patients with the IgM antibodies had a tendency to deteriorate more frequently on the Kurtzke's disability status scale and magnetic resonance imaging of the brain (leukoencephalopathy) than did those without in the two-year follow-up. Thus, the presence of IgM antibody and high titers of IgG and IgA antibodies to the HTLV-I proteins, together with the increased HTLV-I proviral DNA load, appears to distinguish HAM/TSP patients from HTLV-I carriers without HAM/TSP.     

Reduced Foxp3 expression with increased cytomegalovirus-specific CTL in HTLV-I-associated myelopathy

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients show high immune responses to HTLV-I. However, it is unclear whether the cytotoxic T lymphocyte (CTL) responses to other chronic viruses also increase. We investigated the responses in the peripheral blood by using HLA-A*0201/peptide pentamers. The frequency of cytomegalovirus (CMV)-specific CTL tended to be higher in HAM/TSP patients than in healthy controls (HCs). The frequency of CMV-specific CTL positively correlated with that of HTLV-I Tax-specific CTL. The frequency of Foxp3+ cells in CD4+ lymphocytes tended to be higher in HAM/TSP patients than in ACs and HCs. The expression level of Foxp3 was lower in HAM/TSP patients than in HCs and was inversely correlated with the CMV-specific CTL frequency. A percentage of Foxp3+ cells showed a positive correlation with the HTLV-I proviral load. These results suggest that a decrease in the Foxp3 expression may contribute to the high immune response to CMV and that the Foxp3+ regulatory T cells may play a role in the immune surveillance of HTLV-I.     

HTLV-I specific IFN-gamma+ CD8+ lymphocytes correlate with the proviral load in peripheral blood of infected individuals

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurological disease caused by HTLV-I infection. It has been shown that HAM/TSP patients have high proviral loads and an extraordinarily high frequency of circulating CD8 + cytotoxic T lymphocytes specific for HTLV-I in their peripheral blood when compared to asymptomatic HTLV-I carriers (AC). We have previously described an intracellular cytokine detection assay, in which interferon-gamma (IFN-gamma) + CD8 + lymphocytes are specific for HTLV-I in infected individuals. Here, we have established a competitive polymerase chain reaction assay to measure the proviral load of patients and investigate a potential relationship between proviral load and virus-specific CD8 + lymphocytes. Genomic DNA was extracted from peripheral blood lymphocytes (PBL) from eight HAM/TSP patients and seven AC for the measurement of HTLV-I measuring proviral loads. The same PBL were analyzed for intracellular IFN-gamma expression by flow cytometry. In the HAM/TSP patients and AC, the average proviral loads were 34,482 and 9784 copy/microg DNA (P = 0.021), and the average of IFN-gamma + CD8 + lymphocytes in total PBL were 1.47 and 0.08% (P = 0.001), respectively. It was confirmed that HAM/TSP patients have both high proviral loads and increased HTLV-I-specific CD8 + lymphocytes. Furthermore, we found a positive correlation between both factors in the patients with HAM/TSP (P = 0.044) but not in the AC (P = 0.508). These findings suggest that the high number of HTLV-I-specific lymphocytes may result from the increased proviral load in HAM/TSP patients.     

Increased frequency of CD4+T cells expressing fractalkine receptor CX3CR1 in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), but its AIDS susceptible polymorphisms are not associated with the disease

To investigate whether fractalkine receptor CX3CR1 polymorphisms that have been associated with rapid progression to AIDS among HIV-1 positive individuals also affects the risk of human T cell lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP), we compared the allele frequencies of V249I and T280M between 233 HAM/TSP patients and 213 HTLV-1 seropositive asymptomatic carriers (HCs). Although the frequency and absolute number of peripheral blood CX3CR1+CD4+T cells were significantly increased in HAM/TSP patients compared to HCs and uninfected controls independent of HTLV-1 trans-activator protein Tax, we could not observe any association between the two polymorphisms and the risk of HAM/TSP in our cohort.     

Characterization of humoral and cellular immunity in the central nervous system of HAM/TSP

In HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP) immunopathological processes in the central nervous system (CNS) have not been clarified. We compared the humoral and cellular immunity within the CNS and in the systemic circulation of 24 patients with HAM/TSP (8 men and 16 women) to 6 asymptomatic HTLV-I carriers, 7 patients with active multiple sclerosis, 6 patients with acute viral encephalitis, and 39 patients with other non-inflammatory neurological diseases. Significant differences were observed between the HAM/TSP patients and one or more of the control groups: HAM/TSP cerebrospinal fluids (CSF) exhibited higher levels of IgG, IgG index, de novo IgG synthesis rate, and β₂-microglobulin, and also a predominance of CD8⁺ cells that expressed CD11a and CD45RO but lacked CD28 antigens. Results in the 6 patients with acute viral encephalitis suggested that the CD8⁺ population in the CSF which is positive for CD28 and CD45RO is important for the elimination of virus from infected CNS tissues. Therefore, potentially cytotoxic T cells of a unique CD8⁺ CD11a⁺CD45RO⁺CD28⁻ phenotype may play a key role in the CNS pathogenesis of HAM/TSP.     

Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high proviral load strongly predisposes to HAM/TSP

In order to examine the effect of HTLV-I proviral load on the pathogenesis of HAM/TSP, we measured the HTLV-I proviral load in peripheral blood mononuclear cells (PBMC) from a large number of HAM/TSP patients and asymptomatic HTLV-I carriers. To measure the proviral load, we used an accurate and reproducible quantitative PCR method using a dual-labeled fluorogenic probe (ABI PRISM 7700 Sequence Detection System). The mean +/- standard error of mean (s.e.m.) HTLV-I proviral copy number per 1 x 10(4) PBMC was 798 +/- 51 (median 544) in 202 HAM/TSP patients; 120 +/- 17 (median 34) in 200 non HAM-related (general) asymptomatic HTLV-I carriers (RC); and 496 +/- 82 (median 321) in 43 asymptomatic HTLV-I carriers genetically related to HAM/TSP patients (FA). The prevalence of HAM/TSP rises exponentially with log (proviral load) once the proviral load exceeds 1% PBMC. The HTLV-I proviral load of female patients with HAM/TSP was significantly higher than that of male patients, however there was no significant difference in proviral load between sexes in RC. There was a significant correlation between the proviral load and the concentration of neopterin in CSF of HAM/TSP patients. These results indicate that the HTLV-I proviral load in PBMC may be related to the inflammatory process in the spinal cord lesion. The increased proviral load in FA suggests the existence of genetic factors contributing to the replication of HTLV-I in vivo.     

Serum concentration and genetic polymorphism in the 5'-untraslated region of VEGF is not associated with susceptibility to HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-I infected individuals

HTLV-I- associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of human T-cell lymphotropic virus type I (HTLV-I) infection. It remains unknown why the majority of infected people remain healthy whereas only approximately 2-3% of infected individuals develop the disease. Recently, it has been reported that increased plasma concentrations of VEGF were significantly related to high ATL cell infiltration, and the viral transactivator Tax activates the VEGF promoter, linking the induction of angiogenesis to viral gene expression. To investigate whether VEGF promoter -634C/G single nucleotide polymorphism (SNP) and serum concentration of VEGF are associated with the development of HAM/TSP, we studied a group of 202 HAM/TSP patients, 202 asymptomatic HTLV-I seropositive carriers (HCs) and 108 seronegative healthy controls (NCs) in Kagoshima, Japan by using PCR-RFLP analysis. The serum concentration of VEGF was also compared among patients with HAM/TSP, ATL, HCs as well as with NCs. Our results indicate that both VEGF gene polymorphism and serum VEGF levels are not specifically associated with the risk of HAM/TSP in our cohort.     

Tc1/Tc2 and Th1/Th2 balance in Asian and Western types of multiple sclerosis, HTLV-I-associated myelopathy/tropical spastic paraparesis and hyperIgEaemic myelitis

CD8+ T cells, like CD4+ T cells, can differentiate into at least two subsets with distinct cytokine patterns: Tc1 cells produce Th1-like cytokines and Tc2 cells produce Th2-like cytokines. To clarify the immunopathological roles of Tc1 and Tc2 cells in central nervous system (CNS) inflammation, we examined intracellular cytokines in CD8+ and CD4+ T cells by flow cytometry and analyzed the Tc1/Tc2 balance as well as the Th1/Th2 balance in 80 patients with various CNS inflammatory diseases, including 20 with optico-spinal multiple sclerosis (OS-MS), 21 with conventional MS (C-MS), 22 with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 17 with hyperIgEaemic myelitis. Twenty-two healthy subjects were also examined as controls. Patients with OS-MS showed a significantly higher percentage of INF-gamma+IL-4- CD8+ T cells as well as CD4+ T cells and a significantly higher intracellular interferon-gamma (IFN-gamma)/interleukin-4 (IL-4) ratio both in CD8+ and CD4+ T cells throughout the relapse and remission phases than the healthy controls. Furthermore, the patients with OS-MS showed a significantly lower percentage of INF-gamma-IL-4+ CD4+ T cells as well as CD8+ T cells during the relapse phase than the healthy controls. On the other hand, the patients with C-MS showed a significantly higher percentage of IFN-gamma-IL-4+ CD8+ T cells in addition to more IFN-gamma+IL-4- CD4+ T cells during the relapse phase than the healthy controls. The HAM/TSP patients showed a significantly higher percentage of INF-gamma+IL-4- CD8+ T cells and a significantly higher intracellular IFN-gamma/IL-4 ratio in CD8+ T cells than the healthy controls. In contrast, in hyperIgEaemic myelitis, in addition to a significantly lower intracellular IFN-gamma/IL-4 ratio in CD4+ T cells, a tendency toward a lower intracellular IFN-gamma/IL-4 ratio in CD8+ T cells in comparison to the healthy controls was observed. These results clarified for the first time the distinct Tc1/Tc2 balance in each disease condition as follows: Tc1 cell response is predominant in OS-MS and HAM/TSP, while Tc2 cell response is predominant in hyperIgEaemic myelitis and at relapse phase of C-MS. Furthermore, our results suggest that CD8+ T cells play an adjunctive role in disease induction and the clinical course of MS.     

Neuropsychological assessment in HTLV-1 infection: a comparative study among TSP/HAM,asymptomatic carriers,and healthy controls

BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-I) can cause tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) and adult T cell leukaemia/lymphoma. More recently other diseases such as isolated peripheral polyneuropathy, myopathy, artropathy, and uveitis have been associated with this retrovirus. Only a few uncontrolled studies, without necessary exclusion criteria, have described mild cognitive deficits among TSP/HAM patients. To further clarify this the authors evaluated, through neuropsychological testing patients with TSP/HAM and asymptomatic infected carriers, comparing both groups with healthy controls. OBJECTIVES: To verify the presence of cognitive deficits among TSP/HAM patients and asymptomatic HTLV-1 infected carriers. In addition, the authors aimed to investigate if these deficits correlated with the degree of motor impairment in TSP/HAM patients. METHODS: From a cohort of 501 HTLV-1 infected people the authors selected, according to predefined inclusion and exclusion criteria, 40 asymptomatic HTLV-1 carriers and 37 TSP/HAM patients. Neuropsychological testing was blindly performed in both groups and their scores were compared with those obtained from controls. RESULTS: Both the HTLV-1 carrier group and the group of patients with TSP/HAM exhibited a lower performance in neuropsychological tests when compared with controls. Asymptomatic infected carriers and TSP/HAM patients did not differ in their cognitive results. Also, there was no relation between the degree of motor disability and cognitive deficits in the TSP/HAM group. Psychomotor slowing and deficits in the some domains characterised the neuropsychological impairment in HTLV-1 infection: verbal and visual memory, attention and visuomotor abilities. CONCLUSIONS: TSP/HAM as well as asymptomatic infection can be associated with mild cognitive deficits. This finding, if confirmed by further studies, will permit the inclusion of cognitive impairment among the neurological manifestations of HTLV-1.     

HTLV-I alters the multidrug resistance associated protein 1 (ABCC1/MRP1) expression and activity in human T cells

The human T cell lymphotropic/leukaemia virus type I (HTLV-I) causes HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The multidrug resistance associated protein 1 (ABCC1) plays multiple functions in physiopathologic responses. The expression and activity of ABCC1 was studied in T lymphocytes from uninfected and HTLV-I-infected individuals (both asymptomatic and symptomatic/HAM/TSP). ABCC1 expression and activity was reduced to nearly half in T lymphocytes from infected patients compared to control lymphocytes. Only 51.6% of CD4(+) cells from HAM/TSP patients expressed ABCC1 whereas this was seen in 60.3% from asymptomatic individuals, compared to an expression of around 86% in controls. Our results suggest that ABCC1 is negatively regulated in HTVL-I infection, supplying a novel target to investigate the pathogenesis of HTLV-I.     

Leukoencephalopathy in HTLV-I-associated myelopathy/tropical spastic paraparesis: MRI analysis and a two year follow-up study after corticosteroid therapy.

Magnetic resonance imaging (MRI) of the brain was studied in 35 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), 19 HTLV-I seropositive carriers without HAM/TSP (non-HAM/TSP carriers), 18 patients with HTLV-I seronegative spastic spinal paraparesis (SSP), and 82 HTLV-I seronegative controls with other neurological disorders. The incidence of white matter lesions was significantly higher in HAM/TSP (66%) than in the controls (23%) and SSP (11%). HAM/TSP exceeded non-HAM/TSP carriers significantly in the incidence of multiple white matter lesions (37% vs 10%). HAM/TSP affected the deep and subcortical cerebral white matter multifocally, sparing the periventricular regions. None of the lesions were enhanced by gadolinium-DTPA. HAM/TSP patients with the white matter lesions had both a longer duration of disease and a greater disability than did those without lesions. The white matter lesions gradually increased in number, as the disability status became worse, in spite of the high dose corticosteroid treatment. All these observations suggest that the MRI abnormalities of the HAM/TSP brain may reflect the chronic perivascular inflammation with progressive gliosis (chronic disseminated encephalomyelitis). We propose that brain MRI can be successfully utilized as a reliable and non-invasive measure for following the disease progression in HAM/TSP.     

Mediators of central nervous system damage during the progression of human T-cell leukemia type I-associated myelopathy/tropical spastic paraparesis

Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) represents one of the most devastating diseases associated with HTLV-I infection. Despite the delineation of clinical features associated with this neurologic disease, more progress needs to be made with respect to understanding the molecular mechanisms relating to the genesis of HAM/TSP. Several factors have been hypothesized to contribute to whether an HTLV-I-infected individual remains asymptomatic, develops adult T-cell leukemia (ATL), or progresses to HAM/TSP. Among the most intriguing of these factors is the immune response mounted by the host against HTLV-I. Several cell populations are crucial with respect to generating an efficient immune response against the virus. This includes CD4(+) T cells, CD8(+) T cells, dendritic cells (DCs), monocytes/macrophages, and HTLV-I-infected cells that interact with immune cells to stimulate their effector functions. Although all of these cell types likely play important roles in the etiology of HAM/TSP, this review focuses specifically on the potential function of the CD8(+) T-cell population during the progression of HTLV-I-induced neurologic disease. The immune response in HAM/TSP patients may transition from a beneficial response aimed at controlling the viral infection, to a detrimental response that ultimately participates in mediating the pathology observed in HAM/TSP. In this respect, the generation of a hyperactive CD8(+) cytotoxic T lymphocyte (CTL) response primarily targeting the HTLV-I Tax protein likely plays a key role in the genesis of pathologic abnormalities associated with HAM/TSP. The efficiency and activity of Tax-specific CD8(+) CTLs may be regulated at a number of levels, and deregulation of Tax-specific CTL activation may contribute to HAM/TSP. This review focuses on potential mechanisms of central nervous system (CNS) damage associated with the genesis of HAM/TSP following HTLV-I infection, focusing on the role of the Tax-specific CTL compartment.     

NK细胞参与多发性硬化免疫致病的机制

目的　研究多发性硬化 ( MS)患者外周血 ( PB)中自然杀伤 ( NK)细胞的表达。方法　采用流式细胞仪技术 ,检测 1 5例 MS患者以白细胞介素 -1 2 ( IL-1 2 )刺激 NK细胞增殖前后 PB NK细胞的百分率。结果　MS患者PB中 NK细胞百分率明显低于对照组 ( P <0 .0 5 ) ;以不同浓度的 IL-1 2刺激 NK细胞增殖后 NK细胞百分率呈剂量依赖性增加 ,于 5 d时达到峰值 ,但较刺激前明显减少 ( P <0 .0 5 )。结论　 MS患者 PB中 NK细胞的表达明显减少 ,以 CD1 6+ 和 CD5 6+ 细胞减少为主 ;IL-1 2在 1 0 2 U/m L数量级时可对 NK细胞增殖活性产生最佳激活作用。