HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy.
(1/708)
The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02(+) healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02(-) HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections. (+info)
Primary gastric T-cell lymphomas: report of two cases and a review of the literature.
(2/708)
To understand more fully the clinicopathological features of primary gastric T-cell lymphomas (PGTL), we report two cases of PGTL and review the literature. The present cases were not associated with human T-cell leukemia virus type 1 (HTLV-1) and were at clinical stage IIE. In both cases, T-cell origin of the lymphoma cells was diagnosed immunohistochemically. The clinical courses of these two cases were different: one followed a very aggressive clinical course and the patient died 6 months after the diagnosis, whereas the other patient survived more than 2 years without adjuvant chemotherapy. Clinicopathological features of 23 patients with PGTL are summarized with regard to their differences from primary small intestinal T-cell lymphomas (PSITL) and by association with HTLV-1. The median age at onset of PGTL was 58 years. The gender ratio was male-dominant (M:F = 2.3:1). About two-thirds (10 of 17) of PGTL cases had evidence of HTLV-1 infection. The most common presenting symptom for PGTL was upper abdominal discomfort and/or pain (76%), whereas that in PSITL was weight loss (61%) and diarrhea (42%). Typical lesions for PGTL were large ulcerations at the corpus to antrum. Neoplastic cells had no typical morphological characteristics for PGTL including HTLV-1-associated cases. CD3+4+8- was the most frequently observed surface phenotype of PGTL cells. Laboratory findings at diagnosis were not informative. Most patients were treated by gastrectomy with or without chemotherapy. PGTL, excluding that with HTLV-1, showed better prognosis than PSITL, although PGTL with HTLV-1 had a poorer prognosis. (+info)
HTLV-I associated Sjogren's syndrome is aetiologically distinct from anti-centromere antibodies positive Sjogren's syndrome.
(3/708)
OBJECTIVE: To investigate whether Sjogren's syndrome (SS) with anti-HTLV-I antibodies is aetiopathologically distinguishable from SS without these antibodies, the study compared prevalence of autoantibodies in serum samples of SS patients with or without anti-HTLV-I antibodies. METHODS: The test group included 135 patients with primary SS and 97 patients with secondary SS. Serum samples of the patients were examined for the presence of anti-nuclear antibodies (ANA), anti-SS-A/Ro antibodies, anti-SS-B/La antibodies, anti-centromere antibodies (ACA), and anti-HTLV-I antibodies. RESULTS: Anti-HTLV-I antibodies were detected in 25.0% of primary SS patients and in 29.2% of secondary SS patients. There were no significant differences in the mean age, sex, values of asparate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum complements and IgG between HTLV-I seropositive and seronegative SS patients. The rheumatoid factor, ANA, anti-SS-A/Ro, and anti-SS-B/La antibodies in serum samples of SS patients were detected in 60.0%, 84.0%, 51.9%, and 12.0%, respectively. There was no significant difference in the prevalence of these antibodies between HTLV-I seropositive and seronegative SS patients. Using the indirect immunofluorescence test, 14.2% showed a discrete speckled staining pattern. All serum samples contained significant amounts of ACA determined by enzyme linked immunosorbent assay. These antibodies were detected in only 4% of HTLV-I seropositive SS patients but were present in 19.9% of HTLV-I seronegative SS patients. Furthermore, the prevalences of anti-SS-A/Ro and anti-SS-B/La antibodies in serum samples of ACA positive patients were significantly lower than those in ACA negative SS patients. CONCLUSION: These results suggest that SS patients with anti-SS-A/Ro or anti-SS-B/La antibodies, or both, might be aetiopathologically distinct from SS patients with ACA. HTLV-I might be involved in the pathogenesis of SS in a subset of patients with anti-SS-A/Ro or anti-SS-B/La antibodies, or both, but not SS patients with ACA. (+info)
Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells.
(4/708)
Human T-cells immortalized (interleukin-2 [IL-2] dependent) by the human T-cell lymphotropic/leukemia virus type I (HTLV-I), in time, become transformed (IL-2 independent). To understand the biochemical basis of this transition, we have used the sibling HTLV-I-infected T-cell lines, N1186 (IL-2 dependent) and N1186-94 (IL-2 independent), as models to assess the responses to antiproliferative signals. In N1186 cells arrested in G1 after serum/interleukin-2 (IL-2) deprivation, downregulation of the cyclin E-CDK2 kinase activity correlated with decreased phosphorylation of CDK2 and accumulation of p27Kip1 bound to the cyclin E-CDK2 complex, as seen in normal activated PBMCs (peripheral blood mononuclear cells). In contrast, N1186-94 cells failed to arrest in G1 upon serum starvation, displayed constitutive cyclin E-associated kinase activity, and, although CDK2 was partially dephosphorylated, the amount of p27Kip1 bound to the complex did not increase. This observation, extended to two other IL-2-dependent as well as to three IL-2-independent HTLV-I-infected T-cell lines, suggests that the lack of cyclin E-CDK2 kinase downregulation found in the late phase of HTLV-I transformation may correlate with insufficient amounts of p27Kip1 associated with the cyclin E-CDK2 complex. Reconstitution experiments demonstrated that the addition of p27Kip1 to lysates from N1186-94 starved cells resulted in the downregulation of cyclin E-associated kinase activity supporting the notion that the unresponsiveness of the cyclin E-CDK2 complex to growth inhibitory signals may be due to inadequate amounts of p27Kip1 assembled with the complex in HTLV-I-transformed T-cells. In fact, the amount of p27Kip1 protein was lower in most HTLV-I-transformed (IL-2-independent) than in the immortalized (IL-2-dependent) HTLV-I-infected T-cells. Furthermore, specific inhibitors of the phosphatidylinositol 3-kinase (P13K) induced an increase of p27Kip1 protein levels, which correlated with G1 arrest, in both IL-2-dependent and IL-2-independent HTLV-I-infected T-cells. Altogether, these results suggest that maintaining a low level of expression of p27Kip1 is a key event in HTLV-I transformation. (+info)
Expression of mitogen activated protein kinases in labial salivary glands of patients with Sjogren's syndrome.
(5/708)
OBJECTIVE: The expression of CD40 and CD40 ligand (CD40L) in mononuclear cells (MNCs) infiltrating the salivary glands of patients with Sjogren's syndrome (SS) has recently been reported. This study determined the expression of mitogen activated protein kinase (MAP kinase) superfamilies, which act as downstream effector molecules of CD40, in MNCs infiltrating labial salivary tissues in SS patients. METHODS: Six HTLV-I seronegative SS patients and 10 HTLV-I seropositive patients including five HTLV-I associated myelopathy (HAM) patients were examined. The expression of MAP kinase superfamilies in labial salivary glands was examined by immunohistochemistry containing the mirror section technique. RESULTS: Both active forms of c-Jun N-terminal kinase (JNK) and p38 were found in salivary infiltrating MNCs of SS patients. Only minimal expression of the active form of extracellular signal regulated kinase (ERK) was observed in these tissues, however, co-expression of active JNK and active p38 was confirmed by the mirror section technique. Furthermore, these protein kinases were co-expressed in CD40(+) MNCs. No difference in expression levels of active JNK and p38 was found in patients who were positive or negative for anti-HTLV-I antibody. CONCLUSION: These results indicate that JNK and p38, but not ERK, function as downstream effector molecules of CD40 in salivary infiltrating MNCs in SS patients, and suggest that these molecules may be involved in the pathological process of chronic sialadenitis in SS. (+info)
Prevalence of antibody to human T cell lymphotropic virus types 1/2 among aboriginal groups inhabiting northern Argentina and the Amazon region of Peru.
(6/708)
We carried out a seroepidemiologic survey to define the prevalence of human T cell lymphotropic virus types 1/2 (HTLV-1/2) infections among aboriginal populations from isolated regions of northern Argentina and the Amazon region of Peru. Antibodies against HTLV were measured with agglutination tests and confirmed with by an immunofluorescence assay (IFA) and Western blotting. Five (6.94%) of 72 samples from the Tobas Indians in Argentina were positive by the IFA; two samples were typed as HTLV-1 (2.78%), two as HTLV-2 (2.78%), and one (1.39%) could not be typed because it had similar antibody titers against both viruses. No positive samples were found among 84 Andinos Punenos and 47 Matacos Wichis Indians. Seroprevalences of 2.50% (1 of 40) and 1.43% (1 of 70) for HTLV-1 were observed among Wayku and San Francisco communities in the Amazon region of Peru, and seroprevalences of 4.54% (1 of 22) and 2.38% (1 of 42) for HTLV-2 were observed among Boca Colorada and Galilea communities. No serologic evidence of human immunodeficiency virus (HIV) infection was found among the Indians tested. These results indicated the presence of HTLV-1 and HTLV-2 in the indigenous populations of Argentina and Peru. Moreover, the lack of HIV infection indicates that the virus has probably not yet been introduced into these populations. (+info)
Mechanisms of T-cell activation by human T-cell lymphotropic virus type I.
(7/708)
The interactions between human T-cell lymphotropic virus type I (HTLV-I) and the cellular immune system can be divided into viral interference with functions of the infected host T cell and the subsequent interactions between the infected T cell and the cellular immune system. HTLV-I-mediated activation of the infected host T cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction pathways, cell cycle control, and apoptosis. These properties of Tax may well explain the ability of HTLV-I to immortalize T cells. It is not clear, though, how HTLV-I induces T-cell transformation (interleukin-2 [IL-2] independence). Recent evidence suggests that Tax may promote the G1- to S-phase transition, although this may involve additional proteins. A role for other viral proteins that may constitutively activate the IL-2 receptor pathway has also been suggested. By virtue of their activated state, HTLV-I-infected T cells can nonspecifically activate resting, uninfected T cells via virus-mediated upregulation of adhesion molecules. This may favor viral dissemination. Moreover, the induction of a remarkably high frequency of antiviral CD8(+) T cells does not appear to eliminate the infection. Indeed, individuals with a high frequency of virus-specific CD8(+) T cells have a high viral load, indicating a state of chronic immune system stimulation. Thus, while an activated immune system is needed to eradicate the infection, the spread of the HTLV-I is also accelerated under these conditions. A detailed knowledge of the molecular interactions between virus-specific CD8(+) T cells and immunodominant viral epitopes holds promise for the development of specific antiviral therapy. (+info)
Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells.
(8/708)
Thioredoxin (Trx) is a ubiquitous intracellular protein disulfide oxidoreductase with a CXXC active site that can be released by various cell types upon activation. We show here that Trx is chemotactic for monocytes, polymorphonuclear leukocytes, and T lymphocytes, both in vitro in the standard micro Boyden chamber migration assay and in vivo in the mouse air pouch model. The potency of the chemotactic action of Trx for all leukocyte populations is in the nanomolar range, comparable with that of known chemokines. However, Trx does not increase intracellular Ca2+ and its activity is not inhibited by pertussis toxin. Thus, the chemotactic action of Trx differs from that of known chemokines in that it is G protein independent. Mutation of the active site cysteines resulted in loss of chemotactic activity, suggesting that the latter is mediated by the enzyme activity of Trx. Trx also accounted for part of the chemotactic activity released by human T lymphotropic virus (HTLV)-1-infected cells, which was inhibited by incubation with anti-Trx antibody. Since Trx production is induced by oxidants, it represents a link between oxidative stress and inflammation that is of particular interest because circulating Trx levels are elevated in inflammatory diseases and HIV infection. (+info)