Aurélia F. Porto

HTLV-1 decreases Th2 type of immune response in patients with strongyloidiasis.

Eosinophils, immunoglobilin (Ig)E and cytokines have important roles in defence mechanisms against helminths. In this study, the influence of HTLV‐1 infection, characterized by a Th1 type of immune response, was evaluated on the cytokine pattern and parasitic specific IgE response in patients with strongyloidiasis. Patients were divided into four groups: strongyloidiasis without HTLV‐1 infection, strongyloidiasis with HTLV‐1, HTLV‐1 without strongyloidiasis and controls without either helminth infection or HTLV‐1. The cytokine profile was determined in supernatants of mononuclear cells stimulated with Strongyloides stercoralis crude antigen and the parasite specific IgE was measured by ELISA. Patients coinfected with HTLV‐1 had higher levels of interfron (IFN)‐γ and interleukin (IL)‐10 (P < 0·05) and lower levels of IL‐5 and IgE (P < 0·05) than patients with strongyloidiasis without HTLV‐1. There was an inverse relationship between IFN‐γ and IL‐5 (P = 0·01; rs = − 0·37) and between IFN‐γ and parasite specific IgE (P = 0·01; rs = − 0·39), and a direct relationship between IFN‐γ and IL‐10 (P = 0·04; rs = 0·35). These data show that coinfection with HTLV‐1 decreases IL‐5 and IgE responses in patients with strongyloidiasis consistent with a relative switch from Th2 to Th1 response. Immunological responses such as these are important in the control of this helminthic infection.

Cytokine Profile and Immunomodulation in Asymptomatic Human T-Lymphotropic Virus Type 1-Infected Blood Donors

Summary: The modulation of the immune response has been used as therapy for clinical disorders associated with human T‐lymphotropic virus type 1 (HTLV‐1) infection. In this study, the cytokine profile was evaluated in 26 asymptomatic HTLV‐1 blood donors. Additionally, both the cell responsible for producing interferon‐&ggr; (IFN‐&ggr;) and the role of exogenous interleukin (IL)‐10 in downregulating IFN‐&ggr; production were studied. Cytokine levels were determined in supernatants of unstimulated lymphocyte cultures by enzyme‐linked immunosorbent assay. The levels of IFN‐&ggr;, tumor necrosis factor‐&agr;, IL‐5, and IL‐10 were higher in supernatants of the lymphocyte cultures taken from HTLV‐1‐infected donors than in those taken from healthy subjects. Although depletion of CD8+ T cells and natural killer cells did not affect IFN‐&ggr; production, depletion of CD4+ T cells significantly decreased IFN‐&ggr; production. Furthermore, at a concentration of 2 ng/ml, IL‐10 had only a minimum effect on IFN‐&ggr; production, although at high concentrations (100 ng/ml), IL‐10 decreased IFN‐&ggr; production by 50% in HTLV‐1‐infected individuals. These data indicate that both T helper 1 and T helper 2 cytokines are elevated in HTLV‐1 infection and that IL‐10 in high concentrations modulates IFN‐&ggr; production in these patients.

Exacerbated inflammatory cellular immune response characteristics of HAM/TSP is observed in a large proportion of HTLV-I asymptomatic carriers

BackgroundA small fraction of Human T cell Leukemia Virus type-1 (HTLV-I) infected subjects develop a severe form of myelopathy. It has been established that patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) show an exaggerated immune response when compared with the immunological response observed in HTLV-I asymptomatic carriers. In this study the immunological responses in HAM/TSP patients and in HTLV-I asymptomatic carriers were compared using several immunological assays to identify immunological markers associated with progression from infection to disease.MethodsImmunoproliferation assays, cytokine levels of unstimulated cultures, and flow cytometry analysis were used to evaluate the studied groups. Nonparametric tests (Mann-Whitney U test and Wilcoxon matched-pairs signed ranks) were used to compare the difference between the groups.ResultsAlthough both groups showed great variability, HAM/TSP patients had higher spontaneous lymphoproliferation as well as higher IFN-γ levels in unstimulated supernatants when compared with asymptomatic carriers. Flow cytometry studies demonstrated a high frequency of inflammatory cytokine (IFN-γ and TNF-α) producing lymphocytes in HAM/TSP as compared to the asymptomatic group. This difference was accounted for mainly by an increase in CD8 cell production of these cytokines. Moreover, the HAM/TSP patients also expressed an increased frequency of CD28-/CD8+ T cells. Since forty percent of the asymptomatic carriers had spontaneous lymphoproliferation and IFN-γ production similar to HAM/TSP patients, IFN-γ levels were measured eight months after the first evaluation in some of these patients to observe if this was a transient or a persistent situation. No significant difference was observed between the means of IFN-γ levels in the first and second evaluation.ConclusionsThe finding that a large proportion of HTLV-I carriers present similar immunological responses to those observed in HAM/TSP, strongly argues for further studies to evaluate these parameters as markers of HAM/TSP progression.

Levels of serum chemokines discriminate clinical myelopathy associated with human T lymphotropic virus type 1 (HTLV-1)/tropical spastic paraparesis (HAM/TSP) disease from HTLV-1 carrier state

Approximately 5% of people infected with human T lymphotropic virus type 1 (HTLV‐1) develop clinical myelopathy or tropical spastic paraparesis (HAM/TSP) that is associated with high‐levels of Th1 cytokines, interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α. Chemokines are known to induce cytokine secretion and direct the trafficking of immune cells to sites of disease. The present study measured serum chemokines correlated with autonomously released IFN‐γ in cell cultures. HTLV‐1 infection was defined by enzyme‐linked immunosorbent assay (ELISA) and confirmed by Western blot. Subjects included HTLV‐1 carriers (n = 56), patients with HAM/TSP (n = 31) and healthy HTLV‐1 seronegative volunteer controls (n = 20). Serum chemokines and IFN‐γ autonomously released by mononuclear cells in culture were quantified by ELISA. Compared to HTLV‐1 carriers, serum chemokines in HAM/TSP patients showed significantly increased levels of CXCL9 and CXCL10, significantly diminished levels of CCL2 and similar amounts of CCL11 and CCL24. In contrast, CCL11 and CCL24 were significantly lower in serum of HAM/TSP patients than either control. IFN‐γ was positively correlated with CXCL9 and CXCL10 when HAM/TSP and HTLV‐1 carriers were used as a combined group. However, despite a large proportion of HTLV‐1 carriers having high IFN‐γ levels, these chemokines were not increased in carriers. This study showed that high levels of CXCL9 and CXCL10 in the systemic circulation and low serum CCL2 levels are features of HAM/TSP. HTLV‐1 infection and Tax and/or additional viral encoded factor‐mediated pathological processes triggering T cell activation with autogenous IFN‐γ release are probably involved in regulating chemokine release.

Clinical Manifestations in Individuals with Recent Diagnosis of HTLV Type I Infection

BACKGROUND Human T-lymphotropic virus type 1 (HTLV-1) is known to cause HTLV-associated myelopathy (HAM)/tropical spastic paraparesis and adult T cell leukemia. A growing body of evidence links HTLV-1 infection with an increasing spectrum of disease, including uveitis, periodontal disease, arthropathy, sicca syndrome, and neurologic deficits. OBJECTIVES Despite recent findings, the natural history of HTLV-1 infection remains poorly defined. This study was designed to better characterize initial clinical and neurological findings in individuals diagnosed with HTLV-1 infection. STUDY DESIGN We conducted a cross-sectional study of 71 individuals recently diagnosed with HTLV-1 and 71 uninfected age- and sex-matched blood donors in Salvador, Brazil. Subjects were administered a standardized questionnaire and underwent physical exam. RESULTS HTLV-1 infected subjects were significantly more likely than controls to report complaints of hand and foot numbness (OR=5.3; 95% CI: 1.8-15.3; p=0.002 and OR=4.0; 95% CI: 1.3-12; p=0.013 respectively), difficulty running (OR=4.0; 95% CI: 1.1-14.2; p=0.032), nocturia (OR=5.0; 95% CI: 1.1-22.8; p=0.038), arthralgia (OR=3.3; 95% CI: 1.4-7.7; p=0.006), and photophobia (OR=3.3; 95% CI: 1.4-7.7; p=0.006). CONCLUSIONS Neurologic, ocular and rheumatologic complaints may be the first manifestations of HTLV-1 infection. Therefore, all patients presenting with initial diagnosis should be rigorously screened for these symptoms.

Helminthic infection down-regulates type 1 immune responses in human T cell lymphotropic virus type 1 (HTLV-1) carriers and is more prevalent in HTLV-1 carriers than in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T cell lymphotropic virus type 1 (HTLV-1) infection is associated with an exacerbated type 1 immune response and secretion of high levels of proinflammatory cytokines. In contrast, helminthic infection induces a type 2 immune response. In the present study, the cytokine profile in HTLV-1 carriers coinfected with helminths (Strongyloides stercoralis and/or Schistosoma mansoni) was compared with that in HTLV-1 carriers not coinfected with helminths. Levels of interferon (IFN)- gamma were higher in HTLV-1 carriers not coinfected with helminths than in HTLV-1 carriers coinfected with helminths (P<.05). The overall frequency of IFN- gamma -expressing CD8+ and CD4+ cells was decreased in HTLV-1 carriers coinfected with helminths (P<.05). The percentage of interleukin (IL)-5- and IL-10-expressing T cells in HTLV-1 carriers coinfected with helminths was higher than that in HTLV-1 carriers not coinfected with helminths (P<.05). Moreover, we found that the prevalence of helminthic infection was 7-fold higher in HTLV-1 carriers than in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (P<.05). These data show that helminthic infection decreases activation of type 1 cells, which may influence the clinical outcome of HTLV-1 infection.

HTLV-1 modifies the clinical and immunological response to schistosomiasis

The immunological response in HTLV‐1 infected individuals is characterized by a prominent Type‐1 cytokine response with high production of IFN‐γ and TNF‐α. In contrast, helminthic infections and in particular chronic schistosomiasis are associated with a predominant production of IL‐4, IL‐5, IL‐10 and IL‐13. Liver fibrosis is the main pathological finding in schistosomiasis that occurs after many years of infection. This pathology is T cell dependent but the immune response mechanisms are not completely understood. The North‐east region of Brazil is endemic for both HTLV‐1 and schistosomiasis. In the present study the immune response, clinical severity, and therapeutic response to praziquantel of patients with schistosomiasis coinfected with HTLV‐1 were compared with patients infected only with S. mansoni. Patients with HTLV‐1 and S. mansoni had lower levels of IL‐5 (P < 0·05) and higher levels of IFN‐γ (P < 0·05) in cultures stimulated with S. mansoni antigen and decreased S. mansoni antigen specific IgE levels when compared with patients with schistosomiasis without HTLV‐1 coinfection. Liver fibrosis was mild in all HTLV‐1 coinfected patients and efficacy of praziquantel was lower in patients dually infected than in patients infected only with S. mansoni.

Modulation of T cell responses in HTLV-1 carriers and in patients with myelopathy associated with HTLV-1.

Objective: Human T lymphotropic virus-type 1 (HTLV-1) activates the immune system leading to a persistent and exacerbated T-cell response with increased production of IFN-γ and TNF-α. Overproduction of pro-inflammatory cytokines is correlated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although some HTLV-1 carriers also show high levels of these cytokines. In this study, the ability of regulatory cytokines and cytokine antagonists to inhibit spontaneous IFN-γ production was investigated. Method: IFN-γ levels were measured by ELISA before and after addition of cytokines or anti-cytokines. Results: Addition of IL-10 significantly reduced spontaneous IFN-γ synthesis in cell cultures from HTLV-1 carriers, while no differences were observed in HAM/TSP patients. There was also a tendency to decreased IFN-γ levels in cell cultures from HTLV-1 carriers with exogenous addition of TGF-β. In paired analysis, neutralization of IL-2 significantly decreased IFN-γ production in HTLV-1 carriers but not in HAM/TSP patients. Neutralization of IL-15 was less effective than neutralization of IL-2 in modulating IFN-γ production. In HTLV-1 carriers, anti-IL-2 and simultaneous addition of anti-IL-2 and anti-IL-15 decreased IFN-γ synthesis by 46 and 64%, respectively, whereas in patients with HAM/TSP simultaneous neutralization of both anti-cytokines only decrease IFN-γ levels by 27%. Conclusions: Although a large proportion of HTLV-1 carriers produced high levels of pro-inflammatory cytokines similar to those observed in HAM/TSP patients, immune response can be downregulated by cytokines or cytokine antagonists in most HTLV-1 carriers. This modulation can be an important step in the prevention of tissue damage and progression from the HTLV-1 carrier state to HAM/TSP.

Association of cytokines, neurological disability, and disease duration in HAM/TSP patients

OBJECTIVE To identify clinical and immunological markers associated with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHOD 237 HTLV-I infected individuals were clinically assessed. They were classified according to the Expanded Disability Status Scale (EDSS) and Osames Motor Disability Score (OMDS). Cytokine levels were determined in HTLV-I seropositive individuals. RESULTS 37 patients had HAM/TSP. There was a correlation between the degrees of disability assessed by both scales. There was also a correlation between the duration of HAM/TSP and the severity of disability assessed by either EDSS or OMDS. Higher levels of IFN-gamma were detected in unstimulated peripheral blood mononuclear cells (PBMC) from HAM/TSP patients as compared with HTLV-I carriers. CONCLUSION This study shows the validity of the neurological scales to classify the degree of neurological disability in HTLV-I carriers and suggests a progressive behavior of HAM/TSP. This study also shows that IFN-gamma in PBMC supernatants are markers of HAM/TSP.

Clinical and immunological consequences of human T cell leukemia virus type-I and Schistosoma mansoni co-infection

Human T cell leukemia virus type-I (HTLV-I) infection is associated with spontaneous T cell activation and uncontrolled lymphocyte proliferation. An exacerbated type-1 immune response with production of pro-inflammatory cytokines (interferon-gamma and tumor necrosis factor-alpha) is significantly higher in patients with myelopathy associated to HTLV-I than in HTLV-I asymptomatic carriers. In contrast with HTLV-I, a chronic Schistosoma mansoni infection is associated with a type-2 immune response with high levels of interleukin (IL-4, IL-5, and IL-10) and low levels of IFN-gamma. In this study, clinical and immunological consequences of the HTLV-I and S. mansoni infection were evaluated. The immune response in patients with schistosomiasis co-infected with HTLV-I showed low levels of IL-5 (p < 0.05) in peripheral blood mononuclear cells cultures stimulated with S. mansoni antigen (SWAP) and decreased SWAP-specific IgE levels when compared with patients with only schistosomiasis (p < 0.05). Liver fibrosis was mild in all HTLV-I co-infected patients. Immunological response was also compared in individuals who had only HTLV-I infection with those who were co-infected with HTLV-I and helminths (S. mansoni and Strongyloides stercoralis). In patients HTLV-I positive co-infected with helminths the IFN-gamma levels were lower than in individuals who had only HTLV-I. Moreover, there were fewer cells expressing IFN-gamma and more cells expressing IL-10 in individuals co-infected with HTLV-I and helminths. These dates indicate that HTLV-I infection decrease type 2-response and IgE synthesis and are inversely associated with the development of liver fibrosis. Moreover, helminths may protect HTLV-I infected patients to produce large quantities of pro-inflammatory cytokines such as IFN-gamma.