Silvane Santos

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.

Infective dermatitis has similar immunological features to human T lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis.

Human T lymphotropic virus‐type 1 (HTLV‐1) is the causal agent of the HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP), adult T cell leukaemia/lymphoma and infective dermatitis associated with HTLV‐1 (IDH). Over‐production of proinflammatory cytokines and an increase in HTLV‐1 proviral load are features of HAM/TSP, but the immunological basis of IDH has not been established. In addition to severe cutaneous manifestations, the importance of IDH relies on the observation that up to 30% of children with IDH develop HAM/TSP in childhood and adolescence. In this study we determined the immune response in patients with IDH measuring interleukin (IL)‐4, IL‐5, IL‐10, interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α levels as well as the HTLV‐1 proviral load. Additionally, regulatory cytokines and anti‐cytokines were added to cultures to evaluate the ability of these molecules to down‐modulate TNF‐α and IFN‐γ synthesis. HTLV‐1 carriers and patients with HAM/TSP served as controls. TNF‐α and IFN‐γ levels were higher in IDH than in HTLV‐1 carriers. There was no difference in IFN‐γ and TNF‐α concentrations in IDH and HAM/TSP patients. There was a tendency for higher IL‐4 mRNA expression and immunoglobulin E (IgE) levels in IDH than in HTLV‐1 carriers, but the difference did not reach statistical significance. The HTLV‐1 proviral load was significantly higher in IDH patients than in HTLV‐1 carriers. IDH is characterized by an exaggerated Th1 immune response and high HTLV‐1 proviral load. The similarities between the immunological response in patients with IDH and HAM/TSP and the high proviral load observed in IDH provide support that IDH is a risk factor for development of HAM/TSP.

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 Human T Lymphotropic Virus 1 Amplification of Periodontitis Severity with Altered Cytokine Expression in Response to a Standard Periodontopathogen Infection

BACKGROUND Periodontal diseases (PDs) are infectious diseases in which periodontopathogens trigger chronic inflammatory and immune responses that lead to tissue destruction. Recently, viruses have been implicated in the pathogenesis of PDs. Individuals infected with human T lymphotropic virus 1 (HTLV-1) present with abnormal oral health and a marked increased prevalence of periodontal disease. METHODS In this study, we investigated the patterns of periodontopathogen infection and local inflammatory immune markers in HTLV-1-seropositive individuals with chronic periodontitis (CP/HTLV-1 group) compared with HTLV-1-seronegative individuals with chronic periodontitis (CP group) and periodontally healthy, HTLV-1-seronegative individuals (control group). RESULTS Patients in the CP/HTLV-1 group had significantly higher values of bleeding on probing, mean probing depth, and attachment loss than patients in the CP group. The expression of tumor necrosis factor alpha and interleukin (IL) 4 was found to be similar in the CP and CP/HTLV-1 groups, whereas IL-12 and IL-17 levels trended toward a higher expression in the CP/HTLV-1 group. A significant increase was seen in the levels of IL-1beta and interferon gamma in the CP/HTLV-1 group compared with the CP group, whereas expression of the regulatory T cell marker FOXp3 and IL-10 was significantly decreased in the lesions from the CP/HTLV-1 group. Interestingly, similar frequency and/or load of periodontopathogens (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Aggregatibacter actinomycetemcomitans) and frequency of viruses (herpes simplex virus 1, human cytomegalovirus, and Epstein-Barr virus) characteristically associated with PDs were found in the CP/HTLV and CP groups. CONCLUSIONS HTLV-1 may play a critical role in the pathogenesis of periodontal disease through the deregulation of the local cytokine network, resulting in an exacerbated response against a standard periodontopathogen infection.

Influence of HTLV-1 on the clinical, microbiologic and immunologic presentation of tuberculosis

BackgroundHTLV-1 is associated with increased susceptibility to Mycobacterium tuberculosis infection and severity of tuberculosis. Although previous studies have shown that HTLV-1 infected individuals have a low frequency of positive tuberculin skin test (TST) and decreasing in lymphoproliferative responses compared to HTLV-1 uninfected persons, these studies were not performed in individuals with history of tuberculosis or evidence of M. tuberculosis infection. Therefore the reasons why HTLV-1 infection increases susceptibility to infection and severity of tuberculosis are not understood.The aim of this study was to evaluate how HTLV-1 may influence the clinical, bacteriologic and immunologic presentation of tuberculosis.MethodsThe study prospectively enrolled and followed 13 new cases of tuberculosis associated with HTLV-1 (cases) and 25 patients with tuberculosis without HTLV-1 infection (controls). Clinical findings, bacterial load in the sputum, x-rays, immunological response and death were compared in the two groups.ResultsThere were no differences in the demographic, clinical and TST response between the two study groups. IFN-γ and TNF-α production was higher in unstimulated cultures of mononuclear cells of case than in control patients (p < 0.01). While there was no difference in IFN-γ production in PPD stimulated cultures, TNF-α levels were lower in cases than in controls (p = 0.01). There was no difference in the bacterial load among the groups but sputum smear microscopy results became negative faster in cases than in controls. Death only occurred in two co-infected patients.ConclusionWhile the increased susceptibility for tuberculosis infection in HTLV-1 infected subjects may be related to impairment in TNF-α production, the severity of tuberculosis in co-infected patients may be due to the enhancement of the Th1 inflammatory response, rather than in their decreased ability to control bacterial growth.

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.

Immunopathogenesis and neurological manifestations associated to HTLV-1 infection

The human T lymphotropic virus type-1 (HTLV-1) was the first human retrovirus identified. The virus is transmitted through sexual intercourse, blood transfusion, sharing of contaminated needles or syringes and from mother to child, mainly through breastfeeding. In addition to the well-known association between HTLV-1 and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), several diseases and neurologic manifestations have been associated with the virus. This review was conducted through a PubMed search of the terms HTLV-1, immune response and neurological diseases. Emphasis was given to the most recent data regarding pathogenesis and clinical manifestations of HTLV-1 infection. The aim of the review is to analyze the immune response and the variety of neurological manifestations associated to HTLV-1 infection. A total of 102 articles were reviewed. The literature shows that a large percentage of HTLV-1 infected individuals have others neurological symptoms than HAM/TSP. Increased understanding of these numerous others clinical manifestations associated to the virus than adult T cell leukemia/lymphoma (ATLL) and HAM/TSP has challenged the view that HTLV-1 is a low morbidity infection.