Host genetic factors in American cutaneous leishmaniasis: a critical appraisal of studies conducted in an endemic area of Brazil.

American cutaneous leishmaniasis (ACL) is a vector-transmitted infectious disease with an estimated 1.5 million new cases per year. In Brazil, ACL represents a significant public health problem, with approximately 30,000 new reported cases annually, representing an incidence of 18.5 cases per 100,000 inhabitants. Corte de Pedra is in a region endemic for ACL in the state of Bahia (BA), northeastern Brazil, with 500-1,300 patients treated annually. Over the last decade, population and family-based candidate gene studies were conducted in Corte de Pedra, founded on previous knowledge from studies on mice and humans. Notwithstanding limitations related to sample size and power, these studies contribute important genetic biomarkers that identify novel pathways of disease pathogenesis and possible new therapeutic targets. The present paper is a narrative review about ACL immunogenetics in BA, highlighting in particular the interacting roles of the wound healing gene FLI1 with interleukin-6 and genes SMAD2 and SMAD3 of the transforming growth factor beta signalling pathway. This research highlights the need for well-powered genetic and functional studies on Leishmania braziliensis infection as essential to define and validate the role of host genes in determining resistance/susceptibility regarding this disease.

The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis.

Disseminated leishmaniasis (DL) caused by L. braziliensis is characterized by the presence of 10 to more than 1000 lesions spread on the body. While protection against Leishmania is mediated by macrophages upon activation by IFN-γ produced by CD4+T cells, the pathology of disseminated leishmaniasis (DL) could be mediated by macrophages, NK, and CD8+T cells. Herein, we evaluate the participation of senescent CD8+T cells in the pathogenesis of DL. Methods: Peripheral blood mononuclear cells (PBMCs), biopsies, co-cultures of CD8+T cells with uninfected and infected macrophages (MØ), and PBMC cultures stimulated with soluble L. braziliensis antigen (SLA) for 72 h from patients with cutaneous leishmaniasis (CL) and DL were used to characterize senescent CD8+T cells. Statistical analysis was performed using the Mann-Whitney and Kruskal-Wallis tests, followed by Dunn's. Results: Patients with DL have an increase in the frequency of circulating CD8+T cells that present a memory/senescent phenotype, while lesions from DL patients have an increase in the frequency of infiltrating CD8+T cells with a senescent/degranulation phenotype. In addition, after specific stimuli, DL patients' circulating CD8+T with memory/senescent profile, showing degranulation characteristics, increased upon SLA stimuli, and those specific CD8+T cells from DL patients had an increased degranulation phenotype, causing more apoptosis of infected target cells. Conclusions: DL patients show a higher frequency of cytotoxic senescent CD8+T cells compared to CL patients, and that could promote the lysis of infected cells, although without parasite killing, releasing Leishmania to the extracellular compartment, contributing to the spread of parasites.

Inflammation in disseminated lesions: an analysis of CD4+, CD20+, CD68+, CD31+ and vW+ cells in non-ulcerated lesions of disseminated leishmaniasis.

Disseminated leishmaniasis (DL) differs from other clinical forms of the disease due to the presence of many non-ulcerated lesions (papules and nodules) in non-contiguous areas of the body. We describe the histopathology of DL non-ulcerated lesions and the presence of CD4-, CD20-, CD68-, CD31- and von Willebrand factor (vW)-positive cells in the inflamed area. We analysed eighteen biopsies from non-ulcerated lesions and quantified the inflamed areas and the expression of CD4, CD20, CD68, CD31 and vW using Image-Pro software (Media Cybernetics). Diffuse lymphoplasmacytic perivascular infiltrates were found in dermal skin. Inflammation was observed in 3-73% of the total biopsy area and showed a significant linear correlation with the number of vW+ vessels. The most common cells were CD68+ macrophages, CD20+ B-cells and CD4+ T-cells. A significant linear correlation between CD4+ and CD20+ cells and the size of the inflamed area was also found. Our findings show chronic inflammation in all DL non-ulcerated lesions predominantly formed by macrophages, plasmacytes and T and B-cells. As the inflamed area expanded, the number of granulomas and extent of the vascular framework increased. Thus, we demonstrate that vessels may have an important role in the clinical evolution of DL lesions.

Radiographic aspects in individuals infected by human T-lymphotropic virus type 1 (HTLV-1) with joint pain.

BACKGROUND: Joint pain in the absence or with little synovitis is observed in a large percentage of HTLV-1 infected subjects. As the virus infect CD4 + and CD8 + positive, macrophages and B cells an exaggerated production of pro-inflammatory cytokines is detected in these patients. However, the possible association of HTLV-1 infection with autoimmune diseases has not been documented definitively and the clinical characteristics of HTLV-1 associated arthropathy has not been defined. The objective this study is to describe clinic and radiographic features in HTLV-1-infected individuals with complaints of joint pain. METHODS: Cross-sectional study enrolling HTLV-1-infected individuals with chronic joint pain, aged up to 75 years, both genders and seronegative controls with osteoarthritis. All participants underwent conventional radiography of the hips, knees and ankles. RESULTS: Eighty-one HTLV-1 infected patients and 30 subjects with osteoarthritis participated in the study. Polyarticular and symmetrical arthritis prevailed in the HTLV-1 positive group (54%), while oligoarticular and asymmetrical (44%) were more common in controls (p < 0.05). The frequency of enthesophytes (90%) in HTLV-1-infected patients was greater than in the control group (73%) (p < 0.05). Radiographic features were similar in HTLV-1 carriers and in patients with probable or definite HTLV-1 associated myelopathy. The presence of enthesophytes in the absence of joint space reduction or osteophytes was only observed in HTLV-1-infected individuals (p < 0.001). Magnetic resonance imaging of the ankles of five HTLV-1-infected patients and five controls demonstrated a higher frequency of enthesitis, bursitis and osteitis in the HTLV-1 infected group. CONCLUSION: HTLV-1-associated arthropathy is clinically characterized by symmetrical polyarthralgia and the main radiological finding is the presence of enthesophytes in the absence of osteophytes and joint space narrowing.

Schistosoma mansoni antigens alter the cytokine response in vitro during cutaneous leishmaniasis.

Schistosoma mansoni infection or associated products are able to down-modulate the type 1 CD4+ T cell inflammatory response characteristic of autoimmune diseases. In this study, we evaluated how S. mansoni antigens altered the immune response that was induced by the soluble Leishmania antigen (SLA) from cutaneous leishmaniasis (CL) patients. Cytokines were measured from the supernatants of peripheral blood mononuclear cell cultures stimulated with SLA. This was performed using the sandwich enzyme linked immunosorbent assay technique in the presence or absence of S. mansoni recombinant antigens Sm29, SmTSP-2 and PIII. The addition of S. mansoni antigens to the cultures resulted in the reduction of interferon gamma (IFN-γ) levels in 37-50% of patients. Although to a lesser extent, the antigens were also able to decrease the production of tumour necrosis factor-alpha (TNF-α). We compared patients that either had or did not have reduction in IFN-γ and TNF-α production in cultures stimulated with SLA in the presence of S. mansoni antigens. We found that there was no significant difference in the levels of interleukin (IL)-10 and IL-5 in response to S. mansoni antigens between the groups. The antigens used in this study down-modulated the in vitro proinflammatory response induced by SLA in a group of CL patients through a currently undefined mechanism.

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.

Complete genome sequence of human T-cell lymphotropic type 1 from patients with different clinical profiles, including infective dermatitis.

The HTLV-1 is the first human retrovirus and is associated with several clinical syndromes, however, the pathogenesis of these clinical manifestations is still not fully understood. Furthermore, there are few complete genomes publicly available, about 0.12 complete genomes per 10,000 infected individuals and the databases have a major deficiency of sequences information. This study generated and characterized 31 HTLV-1 complete genomes sequences derived from individuals with Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy (TSP/HAM), Adult T-cell leukemia/lymphoma (ATL), infective dermatitis associated to HTLV-1 (IDH) and asymptomatic patients. These sequences are associated to clinical and epidemiological information about the patients. The sequencing data generated on Ion Torrent PGM platform were assembled and mapped against the reference HTLV-1 genome. These sequences were genotyped as Cosmopolitan subtype, Transcontinental subgroup. We identified the variants in the coding regions of the genome of the different clinical profiles, however, no statistical relation was detected. This study contributed to increase of HTLV-1 complete genomes in the world. Furthermore, to better investigate the contribution of HTLV-1 mutations for the disease outcome it is necessary to evaluate the interaction of the viral genome and characteristics of the human host.

Polymorphism in the interleukin-10 gene is associated with overactive bladder phenotype associated with HTLV-1 infection.

INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1)-associated inflammatory diseases are not well understood; however, their clinical manifestations may be influenced by the host genetic background. METHODS: We genotyped 298 individuals with HTLV-1 and 380 controls for interleukin-10 (IL10) gene variants-rs3024496, rs1800871, rs1800896-and used logistic regression analysis to determine their association with clinical phenotypes. RESULTS: No association with HTLV-1 infection was observed. However, allele A of rs1800896 (1082bp upstream) was associated with protection against neurological impairment, specifically overactive bladder (OR=0.447, 95% CI 0.28-0.70, p=0.001). CONCLUSIONS: Our data suggests that IL10 regulation ameliorates neurological damage in HTLV-1 infections.

Prevalence of Bowel Symptoms in Patients Infected with Human T-Lymphotropic type 1 Virus.

INTRODUCTION: Bowel dysfunction is frequent in patients with spinal cord diseases, but little is known about the prevalence of bowel symptoms in human T-lymphotropic virus-(HTLV-1) infected individuals. The purpose of this study is to determine the frequency of bowel symptoms in HTLV-1 infected individuals and their correlation with the degree of neurologic disease. METHODS: This is a cross-sectional study comparing the frequency of bowel symptoms in HTLV-1-infected individuals* and seronegative donors (controls). Patients answered a questionnaire, the Rome III Criteria was applied, and stool consistency was evaluated by the Bristol Stool Form Scale. The individuals were classified as HTLV-1 carriers, probable HTLV-1 myelopathy and definitive HTLV-1 associated myelopathy or tropical spastic paraparesis (definitive HAM / TSP)**. RESULTS: We studied 72 HTLV-1 infected individuals and 72 controls with equal age and gender distribution. Constipation was the most frequent complaint, occurring in 38 % of HTLV-1 individuals and in 15 % of the controls. In comparison to the seronegative controls, the probability of constipation occurrence was approximately 18 times higher in definitive HAM / TSP patients. Straining, lumpy or hard stools, sensation of anorectal obstruction/blockage, fewer than 3 defecations per week, flatulence, soiling, evacuation pain, and bleeding were also more frequent in the HTLV-1 patients than in the controls. Moreover, bowel symptoms were more frequent in patients with definitive or probable HAM / TSP than in carriers. CONCLUSIONS: Bowel symptoms were more frequent in HTLV-1-infected patients than in seronegative controls and the frequency of bowel symptoms correlated with the severity of neurologic disease.

The relationship between atopy and neurological manifestations in HTLV-1 infection.

INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1)induces exaggerated Th1 responses, whereas atopy is associated with exacerbated Th2 responses. METHODS: Here, a cross-sectional study compared the prevalence of atopy in HTLV-1 carriers and HAM/TSP patients. It also compared the spontaneous cytokine production in HTLV-1-infected individuals. A retrospective cohort study evaluated the development of neurological manifestations in atopic and non-atopic carriers. RESULTS: Atopic HAM/TSP patients with high IFN-γ production exhibited higher IL-5 levels than non-atopic patients. Allergic rhinitis accelerated the development of Babinski signals and overactive bladders. CONCLUSIONS: Abnormal Th1 and Th2 responses coexist in HTLV-1-infected individuals and allergic diseases may worsen the clinical course of HTLV-1 infections.

Oral Pentoxifylline Associated with Pentavalent Antimony: A Randomized Trial for Cutaneous Leishmaniasis.

AbstractCutaneous leishmaniasis (CL) by Leishmania braziliensis is associated with decreasing cure rates in Brazil. Standard treatment with pentavalent antimony (Sbv) cures only 50-60% of the cases. The immunopathogenesis of CL ulcer is associated with high interferon-γ and tumor necrosis factor (TNF) production. Pentoxifylline, a TNF inhibitor, has been successfully used in association with Sbv in mucosal and cutaneous leishmaniasis. This randomized, double-blind, and placebo-controlled trial aimed to evaluate the efficacy and safety of oral pentoxifylline plus Sbv versus placebo plus Sbv in patients with CL in Bahia, Brazil. A total of 164 patients were randomized in two groups to receive the combination or the monotherapy. Cure rate 6 months after treatment was 45% in the pentoxifylline group and 43% in the control group. There was also no difference between the groups regarding the healing time (99.7 ± 66.2 days and 98.1 ± 72.7 days, respectively). Adverse events were more common in the pentoxifylline group (37.8%), versus 23% in the placebo group. This trial shows that Sbv combined therapy with pentoxifylline is not more effective than Sbv monotherapy in the treatment of CL caused by L. braziliensis.

Radiographic aspects in individuals infected by human T-lymphotropic virus type 1 (HTLV-1) with joint pain

Abstract Background: Joint pain in the absence or with little synovitis is observed in a large percentage of HTLV-1 infected subjects. As the virus infect CD4 +and CD8 +positive, macrophages and B cells an exaggerated production of pro-inflammatory cytokines is detected in these patients. However, the possible association of HTLV-1 infection with autoimmune diseases has not been documented definitively and the clinical characteristics of HTLV-1 associated arthropathy has not been defined. The objective this study is to describe clinic and radiographic features in HTLV-1-infected individuals with complaints of joint pain. Methods: Cross-sectional study enrolling HTLV-1-infected individuals with chronic joint pain, aged up to 75 years, both genders and seronegative controls with osteoarthritis. All participants underwent conventional radiography of the hips, knees and ankles. Results: Eighty-one HTLV-1 infected patients and 30 subjects with osteoarthritis participated in the study. Polyarticular and symmetrical arthritis prevailed in the HTLV-1 positive group (54%), while oligoarticular and asymmetrical (44%) were more common in controls ( p < 0.05). The frequency of enthesophytes (90%) in HTLV-1-infected patients was greater than in the control group (73%) ( p < 0.05). Radiographic features were similar in HTLV-1 carriers and in patients with probable or definite HTLV-1 associated myelopathy. The presence of enthesophytes in the absence of joint space reduction or osteophytes was only observed in HTLV-1-infected individuals ( p < 0.001). Magnetic resonance imaging of the ankles of five HTLV-1-infected patients and five controls demonstrated a higher frequency of enthesitis, bursitis and osteitis in the HTLV-1 infected group. Conclusion: HTLV-1-associated arthropathy is clinically characterized by symmetrical polyarthralgia and the main radiological finding is the presence of enthesophytes in the absence of osteophytes and joint space narrowing.

In Vitro Immunomodulatory Activity of a Transition-State Analog Inhibitor of Human Purine Nucleoside Phosphorylase in Cutaneous Leishmaniasis.

Cutaneous leishmaniasis (CL) is the most common clinical form of American tegumentary leishmaniasis caused by Leishmania (Viannia) braziliensis. CL is associated with a strong Th1 immune response. This exacerbated inflammatory response is correlated with severity of disease and delays the healing time of the ulcer. The fourth-generation immucillin derivative (DI4G), a potent inhibitor of purine nucleoside phosphorylase, has been proposed as a promising agent in the treatment of diseases associated with T cell activation. Herein, we evaluated the in vitro immunomodulatory activity of DI4G in cells of patients presenting with CL. Peripheral blood mononuclear cells (PBMC) from CL patients were stimulated with soluble leishmania antigen (SLA), in the presence or absence of DI4G, and IFN-γ, TNF, CXCL9, and CXCL10 levels were determined by ELISA. Lymphocyte proliferation in the presence or absence of DI4G was also evaluated, using flow cytometry. DI4G was able to decrease (p < 0.05) IFN-γ production but did not change the TNF, CXCL9, and CXCL10 levels. DI4G decreased (p < 0.05) the lymphoproliferative response mediated by CD8+ T cells, but not that by CD4+ T cells. DI4G is able to attenuate the exaggerated immune response in CL, exhibiting immunomodulatory activity in IFN-γ production and in CD8+ T cell proliferation.

Diagnosis and underdiagnosis of comorbidities in psoriasis patients - need for a multidisciplinary approach.

BACKGROUND:: Psoriasis is an immune-mediated disease that manifests predominantly in the skin, although systemic involvement may also occur. Although associated comorbidities have long been recognized and despite several studies indicating psoriasis as an independent risk factor for cardiovascular events, little has been done in general medical practice regardind screening. In the United States, less than 50% of clinicians are aware of these recommendations. OBJECTIVE:: To identify the prevalence of these comorbidities in 296 patients followed up at a university dermatology clinic. METHODS:: Systematically investigated comorbidity frequencies were compared with general practitioners' registry frequencies. Clinical features correlated with comorbidities were also investigated. RESULTS:: High prevalences of systematically investigated comorbidities such as hypertension (30%) and dyslipidemia (26.5%) were documented. Conversely, data from general practitioners' records showed that 33% of dyslipidemia cases were undiagnosed and indicated possible underdiagnosis of some comorbidities. Furthermore, an association was found between: the number of comorbidities and psoriasis duration, age and high body mass index an association was found between the number of comorbidities and psoriasis duration, age, high body mass index, waist circumference or waist-to-hip ratio. (p<0.05). CONCLUSION:: Disease duration, age and high body mass index, waist circumference or waist-to-hip ratio are possible criteria for choosing which patients should be screened for comorbidities. Underdiagnosis of comorbidities by general practitioners highlights the need for a multidisciplinary approach in psoriasis management.

Inflammatory and immunological profiles in patients with COPD: relationship with FEV 1 reversibility.

OBJECTIVE:: To determine whether COPD severity correlates with sputum cell counts, atopy, and asthma. METHODS:: This was a cross-sectional study involving 37 patients with COPD and 22 healthy subjects with normal lung function (controls). Sputum cell counts were determined by microscopy after centrifugation of samples. Skin prick tests were performed, and serum cytokines were determined by ELISA. RESULTS:: Patients were stratified by bronchodilator response: a non-reversible airflow limitation (nonRAL) group comprised 24 patients showing no significant post-bronchodilator change in FEV1; and a partially reversible airflow limitation (partialRAL) group comprised 13 patients showing FEV1 reversibility (post-bronchodilator FEV1 increase ≥ 12%). The proportion of eosinophils in sputum was higher in the partialRAL group than in the nonRAL group (p < 0.01), and there was an inverse correlation between the proportion of eosinophils and FEV1 (p < 0.05). However, none of the patients had a history of asthma and skin prick test results did not differ between the two groups. In the patient sputum samples, neutrophils predominated. Serum levels of TNF, IL-6, IL-8, and RANTES (CCL5) were higher in patients than in controls (p < 0.001) but did not differ between the two patient groups. CONCLUSIONS:: COPD patients with partial FEV1 reversibility appear to have higher sputum eosinophil counts and greater airway hyperresponsiveness than do those with no FEV1 reversibility. However, we found that COPD severity did not correlate with atopy or with the cytokine profile. OBJETIVO:: Determinar se a gravidade da DPOC se correlaciona com a contagem de células no escarro, atopia e asma. MÉTODOS:: Estudo transversal com 37 pacientes com DPOC e 22 indivíduos saudáveis com função pulmonar normal (controles). As contagens de células no escarro foram determinadas por microscopia após a centrifugação das amostras. Foram realizados testes cutâneos de puntura, e as citocinas séricas foram determinadas por ELISA. RESULTADOS:: Os pacientes foram estratificados pela resposta ao broncodilatador: o grupo de limitação ao fluxo aéreo não reversível (LFAnr) envolveu 24 pacientes sem alteração significativa do VEF1 pós-broncodilatador, e o grupo de limitação ao fluxo aéreo parcialmente reversível (LFApr) envolveu 13 pacientes com reversibilidade do VEF1 (aumento do VEF1 pós-broncodilatador ≥ 12%). A proporção de eosinófilos no escarro foi maior no grupo LFApr do que no LFAnr (p < 0,01), e houve uma correlação inversa entre a proporção de eosinófilos e VEF1 (p < 0,05). Entretanto, nenhum dos pacientes apresentou histórico de asma e os resultados dos testes cutâneos não diferiram entre os dois grupos. Nas amostras de escarro dos pacientes, os neutrófilos predominaram. Os níveis séricos de TNF, IL-6, IL-8 e RANTES (CCL5) foram maiores nos pacientes que nos controles (p < 0,001), mas não diferiram entre os dois grupos de pacientes. CONCLUSÕES:: Pacientes com DPOC e reversibilidade parcial do VEF1 parecem apresentar maiores contagens de eosinófilos no escarro e maior hiper-responsividade das vias aéreas que aqueles sem reversibilidade do VEF1. Entretanto, a gravidade da DPOC não se correlacionou com atopia ou perfil das citocinas.

Insulin-like growth factor-I serum levels and their biological effects on Leishmania isolates from different clinical forms of American tegumentary leishmaniasis.

BACKGROUND: American tegumentary leishmaniasis (ATL) in Brazil is mostly caused by Leishmania (Viannia) braziliensis, with known forms of the disease being cutaneous (CL), mucosal (ML) and disseminated (DL) leishmaniasis. The development of the lesion in ATL is related both to the persistence of the Leishmania in the skin and to the parasite-triggered immune and inflammatory responses that ensue lesions. In this context one factor with expected role in the pathogenesis is insulin-like growth factor (IGF)-I with known effects on parasite growth and healing and inflammatory processes. In the present study, we addressed the effect of IGF-I on intracellular amastigote isolates from CL, ML and DL patients within human macrophage and we evaluated the IGF-I and IGF-binding protein-3 (IGFBP3) serum levels in patients presenting different clinical forms and controls from the endemic area. METHODS: We evaluated biological variability in the responses of intracellular amastigotes of Leishmania isolates derived from CL, ML, and DL patients from an area for ATL in response to IGF-I. Intracellular amastigote growth was evaluated using the human macrophage cell line THP-1. Arginase activity in infected cells was evaluated quantifying the generated urea concentration. Serum samples from patients and controls were assayed using chemiluminescent immunometric assay to determine IGF-I and IGFBP3 levels. RESULTS: We observed an increase in intracellular parasitism upon IGF-I stimulus in 62.5 % of isolates from CL, in 85.7 % from ML and only 42.8 % from DL cases. In DL, the basal arginase activity was lower than that of CL. We then evaluated the IGF-I and IGFBP3 serum levels in patients, and we observed significantly lower levels in ML and DL than in CL and control samples. CONCLUSIONS: The data suggest that IGF-I is modulated distinctly in different clinical forms of tegumentary leishmaniasis. IGF-I seemingly exerts effect on parasite growth likely contributing to its persistence in the skin in earlier phase. In addition the decreased IGF-I serum levels may affect the modulation of inflammation and lesion healing in chronic phase. In view of potential role of IGF-I in the pathogenesis of ATL we can speculate on therapeutic procedures taking into account the local IGF-I level.

[Clinical and immunological consequences of the association between HTLV-1 and strongyloidiasis]. / Implicações clínicas e imunológicas da associação entre o HTLV-1 e a estrongiloidíase.

Strongyloidiasis is one of most important forms of helminthiasis in tropical countries and epidemiologic studies have shown the association of this parasitic disease with HTLV. It has been observed in regions where both these agents are endemic and coinfection may result in an increase in the disseminated forms of strongyloidiasis as well as recurrent strongyloidiasis. While HTLV-1 is related to a high production of IFN-gamma; and deviation of the immune response towards a Th1 response, the protection against helminths is associated with Th2 like immune response. Individuals infected with HTLV and S. stercoralis have a reduction in the production of IL-4, IL-5, IL-13 and parasitic IgE response, all of which are factors participating in the defense mechanism against S. stercoralis. These abnormalities are the basis for the occurrence of an increase in the severe forms of strongyloidiasis among patients infected with HTLV-1.

The use of botulinum toxin type A in the treatment of HTLV-1-associated overactive bladder refractory to conventional therapy.

Urinary symptoms occur in 19% of human T-cell lymphotropic virus type 1 (HTLV-1)-infected patients who do not fulfill criteria for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and in almost 100% of HAM/TSP patients. Few studies have evaluated therapies for overactive bladder (OAB) caused by HTLV-1 infection. This case report describes the effect of onabotulinum toxin A on the urinary manifestations of three patients with HAM/TSP and OAB symptoms. The patients were intravesically administered 200 units of Botox®. Their incontinence episodes improved, and their OAB symptoms scores (OABSS) reduced significantly. These data indicate that Botox® should be a treatment option for OAB associated with HTLV-1 infection.

Polymorphism in the interleukin-10 gene is associated with overactive bladder phenotype associated with HTLV-1 infection

Abstract INTRODUCTION Human T-cell lymphotropic virus type 1 (HTLV-1)-associated inflammatory diseases are not well understood; however, their clinical manifestations may be influenced by the host genetic background. METHODS We genotyped 298 individuals with HTLV-1 and 380 controls for interleukin-10 (IL10) gene variants-rs3024496, rs1800871, rs1800896-and used logistic regression analysis to determine their association with clinical phenotypes. RESULTS No association with HTLV-1 infection was observed. However, allele A of rs1800896 (1082bp upstream) was associated with protection against neurological impairment, specifically overactive bladder (OR=0.447, 95% CI 0.28-0.70, p=0.001). CONCLUSIONS Our data suggests that IL10 regulation ameliorates neurological damage in HTLV-1 infections.

Prevalence of bowel symptoms in patients infected with human T-lymphotropic type 1 virus

Abstract INTRODUCTION: Bowel dysfunction is frequent in patients with spinal cord diseases, but little is known about the prevalence of bowel symptoms in human T-lymphotropic virus-(HTLV-1) infected individuals. The purpose of this study is to determine the frequency of bowel symptoms in HTLV-1 infected individuals and their correlation with the degree of neurologic disease. METHODS: This is a cross-sectional study comparing the frequency of bowel symptoms in HTLV-1-infected individuals* and seronegative donors (controls). Patients answered a questionnaire, the Rome III Criteria was applied, and stool consistency was evaluated by the Bristol Stool Form Scale. The individuals were classified as HTLV-1 carriers, probable HTLV-1 myelopathy and definitive HTLV-1 associated myelopathy or tropical spastic paraparesis (definitive HAM / TSP)**. RESULTS: We studied 72 HTLV-1 infected individuals and 72 controls with equal age and gender distribution. Constipation was the most frequent complaint, occurring in 38 % of HTLV-1 individuals and in 15 % of the controls. In comparison to the seronegative controls, the probability of constipation occurrence was approximately 18 times higher in definitive HAM / TSP patients. Straining, lumpy or hard stools, sensation of anorectal obstruction/blockage, fewer than 3 defecations per week, flatulence, soiling, evacuation pain, and bleeding were also more frequent in the HTLV-1 patients than in the controls. Moreover, bowel symptoms were more frequent in patients with definitive or probable HAM / TSP than in carriers. CONCLUSIONS: Bowel symptoms were more frequent in HTLV-1-infected patients than in seronegative controls and the frequency of bowel symptoms correlated with the severity of neurologic disease.