Host Th1/Th2 immune response to Taenia solium cyst antigens in relation to cyst burden of neurocysticercosis

Neurocysticercosis (NCC), Taenia solium larval infection of the brain, is an important cause of acquired seizures in endemic countries, which relate to number, location and degenerating cysts in the brain. Multicyst infections are common in endemic countries although single‐cyst infection prevails in India. Single‐cyst infections in an endemic country suggest a role for host immunity limiting the infection. This study examined ex vivo CD4⁺ T cells and in vitro Th1 and Th2 cytokine responses to T. solium cyst antigens of peripheral blood mononuclear cells of healthy subjects from endemic and nonendemic regions and of single‐ and multicyst‐infected patients for association with cyst burden of NCC. T. solium cyst antigens elicited a Th1 cytokine response in healthy subjects of T. solium‐endemic and T. solium‐non‐endemic regions and those with single‐cyst infections and a Th2 cytokine response from subjects with multicyst neurocysticercosis. Multicyst neurocysticercosis subjects also exhibited low levels of effector memory CD4⁺ T cells. Th1 cytokine response of T. solium exposure and low infectious loads may aid in limiting cyst number. Th2 cytokines and low effector T cells may enable multiple‐cyst infections to establish and persist.     

Endothelial Dysfunction in Patients with Asthma: The Role of Polymorphisms of ACE and Endothelial NOS Genes

Both atopy and asthma are claimed to be associated with a Th-2 cytokine pattern. We sought to determine the contribution of atopy and asthma to the observed Th-2/Th-1 imbalance in these conditions. Of 60 children aged 6–16 years that were included in the study, 13 were nonatopic nonasthmatic, 15 atopic nonasthmatic, 14 nonatopic asthmatic, and 18 atopic asthmatic. Atopic children had positive skin prick tests to grass pollens only. All children were studied after an asymptomatic and drug-free period of at least three months. Total IgE was measured in serum. Peripheral blood mononuclear cells were cultured and stimulated in vitro with phytohemagglutinin and interferongamma (IFN-γ) and interleukin-4 (IL-4) measured in the supernatants. Total IgE was significantly higher in atopic asthmatics compared to nonatopic asthmatics (p = 0.004), and nonatopic nonasthmatics (p = 0.001), but was not different from atopic nonasthmatics (p > 0.05). On the other hand, IL-4 was significantly elevated in atopic asthmatics and in nonatopic asthmatics compared to nonatopic nonasthmatics (p = 0.037 and p = 0.009, respectively). Although atopic asthmatics had lower IFN-γ values than nonatopic asthmatics, the difference did not reach statistical significance. No correlation was detected between any two parameters. Our results suggest that both atopy and asthma contribute to the increased levels of IL-4 and that, whereas nonatopic asthma is associated with increases in both IL-4 and IFN-γ release by mononuclear cells, only atopic asthma is characterized by a Th-2 type cytokine dominance.     

Correlations between worm burden and markers of Th1 and Th2 cell subset induction in an inbred strain of mouse infected with Trichuris muris

Helper T cell subset induction was examined within a single inbred strain of mouse ( B10.D2/n) where individuals varied in their ability to expel the nematode parasite Trichuris muris. In this mouse strain approximately half of infected individuals resist infection whilst half are unable to expel the parasite and harbour chronic mature adult worm infections. We here assess various T cell and serological parameters in individual B10.D2/n mice infected with T. muris in relation to the number of parasites harboured. Worm burdens showed very significant negative correlations with five different parameters indicative of the selective expansion within the host of helper T cells of the Th2 subset. Thus, in vitro IL-5 and 1L-9 production by restimulated mesenteric lymph node cells, totallgE levels, the early parasite-specific IgG1 response (all P < 0·01) and intestinal eosinophilia (P < 0·05), were all significantly negatively correlated with worm burden. In addition, levels of IL-3 were significantly greater in mice resistant to infection (P < 0·01). In contrast there was a significant positive correlation between worm burden and parasite-specific IgG2a levels (P < 0·05), IgG2a production being under the tight control of the Th1-specific cytokine IFN-y and thus a reliable marker for in vivo Th1 cell activation. The data demonstrates that an individual infected with T. muris is capable of mounting either a protective Th2-type response or an inappropriate Th1-type response. Thus, under conditions where host genetic factors and route of antigen introduction into the host are identical, polarized helper T cell responses can arise and hence may be due to a parasite-derived influence rather than an intrinsic difference between hosts per se.     

Atopic phenotype is an important determinant of immunoglobulin E-mediated inflammation and expression of T helper cell type 2 cytokines to ascaris antigens in children exposed to ascariasis

Studies have shown a strong inverse relationship between atopy and geohelminth infection, indicating that atopy may protect against geohelminth infection. Resistance to ascariasis in atopic individuals may occur through greater immunoglobulin E-mediated responses and expression of T helper cell type 2 (Th2) cytokines to parasite antigens. To investigate the effect that atopy has on the immune response to Ascaris antigens, school-age children were recruited from rural schools in Ecuador. Immunologic variables were compared between children stratified by atopic and/or A. lumbricoides-infection status; the variables included cytokine expression by peripheral-blood mononuclear cells (PBMCs) and histamine release in response to Ascaris antigens. Atopic children had both greater frequencies of PBMCs expressing interleukin (IL)-4 and IL-5 and enhanced histamine release, compared with those in nonatopic children. Stratification by atopic and A. lumbricoides-infection status revealed the greatest histamine and Th2 cytokine responses in the stratum of atopic, noninfected children. Multivariate regression analyses showed significant effects for atopic status but not for infection status on Th2 cytokine expression and histamine release.     

Schistosoma mansoni‐specific immune responses and allergy in Uganda

Low allergy‐related disease (ARD) prevalence in low‐income countries may be partly attributed to helminth infections. In the Schistosoma mansoni (Sm)‐endemic Lake Victoria islands (Uganda), we recently observed positive helminth‐allergy associations, despite low ARD prevalence. To understand how Sm‐induced cytokine and antibody profiles might influence allergic response profiles in this population, we assessed Schistosoma worm (SWA)‐ and egg antigen (SEA)‐specific Th1 (IFN‐γ), Th2 (IL‐5, IL‐13) and regulatory (IL‐10) cytokine profiles (n = 407), and total (n = 471), SWA‐, SEA‐ and allergen (house dust mite [HDM] and cockroach)‐specific (as)IgE and IgG4 profiles (n = 2117) by ELISA. Wheeze was inversely associated with SWA‐specific IFN‐γ (P < .001) and IL‐10 (P = .058), and SEA‐specific IL‐5 (P = .004). Conversely, having a detectable asIgE response was positively associated with SWA‐specific IL‐5 (P = .006) and IL‐10 (P < .001). Total, SWA‐, SEA‐ and allergen‐specific IgE and IgG4 responses were higher among Sm Kato‐Katz positive (SmKK+) and skin prick test (SPT)+ individuals compared to SmKK‐ and SPT‐ individuals. However, total and asIgG4/IgE ratios were lower among SPT+ and wheezing individuals. We conclude that, in this population, helminth‐induced antibody and cytokine responses may underlie individual positive helminth‐atopy associations, while the overall IgG4‐IgE balance may contribute to the low overall prevalence of clinical allergies in such settings.     

IL-33 Promotes the Induction and Maintenance of Th2 Immune Responses by Enhancing the Function of OX40 Ligand

Background: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses.Methods: Purified human naïve or memory CD4 + T cells were stimulated with recombinant OX40L or TSLP- treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis.Results: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2 + CD4 + Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase.Conclusions: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.     

Interleukin-18 promoter polymorphisms in Japanese patients with rheumatoid arthritis: protective effect of the T allele and T/T genotype at rs360722

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a strong genetic contribution to its pathogenesis. Among numerous candidate genes, cytokine gene polymorphisms have been implicated. Interleukin-18 (IL-18) induces production of tumor necrosis factor-α and promotes T helper (Th)1-type immune responses. This study investigates the association between IL-18 promoter polymorphisms and RA susceptibility. A total of 2471 Japanese case–control samples (1493 RA patients and 978 healthy controls) were examined. Three haplotype tag single-nucleotide polymorphisms, rs1946518A/C, rs360718T/G, and rs360722T/C, spanning from the 5′UTR to intron 1 were genotyped using allelic discrimination with the use of specific TaqMan probes, and three haplotypes (A–T–T, C–T–C, and A–G–C) were determined. Among these polymorphisms, the frequency of the T allele at rs360722, which tags the A–T–T haplotype, was significantly lower in the RA patient group compared with the normal subjects [0.46 versus 0.49, P = 0.0061, Fisher’s exact probability test, odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75–0.95]. Having the T/T genotype further increased the significance (0.20 versus 0.27, P = 0.0006, OR = 0.72, 95% CI = 0.58–0.86). Therefore, presence of the T allele and T/T genotype at rs360722 reduces the susceptibility of Japanese people to RA.     

Role of cytokines in the clinical manifestation of exophthalmia in newborn calves with tropical theileriosis

The present study aimed to evaluate the pathology of the exophthalmia and the host-immune response in naturally Theileria annulata-infected calves. The newborn calves detected positive for theileriosis were grouped into calves with theileriosis and absence of exophthalmia (n = 30), and calves with theileriosis and the presence of exophthalmia (n = 13). Sixteen healthy calves, free from any haemoprotozoal infection, were kept as healthy controls. A significantly (P ≤ .001) higher circulating levels of tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were estimated in diseased calves with and without exophthalmia as compared to healthy controls. Contrarily, significantly (P ≤ .01) lower interferon-γ (IFN-γ) level was estimated in diseased calves. The diseased calves with exophthalmia revealed significantly higher levels of TNF-α (P ≤ .001) and IL-10 (P ≤ .006) as compared to the diseased calves without exophthalmia. The diseased calves were not found to have an elevated intraocular pressure; rather they had significantly (P ≤ .001) lower intraocular pressure compared to the healthy controls. An elevated systemic TNF-α level might be attributed to the exophthalmia in calves with tropical theileriosis. The elevated circulatory IL-10 and reduced IFN-γ levels could be one of the strategies of Theileria annulata to escape the host immunity.     

特发性血小板减少性紫癜患者治疗前后Th1／Th2水平变化及其临床意义

目的：研究特发性血小板减少性紫癜（ITP）患者药物治疗前后辅助性T淋巴细胞（Th）1/Th2细胞因子水平的变化情况及其临床意义。方法：应用流式细胞仪检测60例ITP患者药物治疗前后干扰素γ（IFN-y）、白细胞介素（IL）-2、IL-4、IL-10水平,分析Th1/Th2细胞因子水平的变化情况,并结合疗效作相关性分析。以60名健康体检者为对照。结果：药物治疗有效的ITP患者治疗后Th1细胞因子IL-2、IFN-1水平较治疗前及对照组均显著升高（P〈0．01）。而Th2细胞因子IL-4及IL-10水平在3组间均无显著性差异（P＞0．051．Th1/Th2比例升高。ITP患者Th1细胞因子IL-2、IFN．叮水平在治疗显效组表达均明显高于良效及进步组和无效组（P〈0．05）,良效及进步组与治疗无效组比较亦有显著性差异（P〈0．05）;经相关性分析,患者的疗效与IFN-γ、IL-2均呈正相关。结论：ITP患者药物治疗后Th1细胞因子IL-2、IFN-γ表达升高,且Th1与ITP患者疗效密切相关。     

Neutrophils rapidly produce Th2 cytokines in response to larval but not adult helminth antigen

Host protective immunity to Haemonchus contortus (Hc) infection in parasite-resistant St. Croix (STC) sheep is initiated early and characterized by an influx of innate cells and robust interleukin-4 (IL-4) production, resulting in T-helper type 2 immune (Th2) responses. The purpose of these studies was to elucidate the source of early IL-4 production. Neutrophils were isolated from whole blood, and populations >98% purity were cultured with larval or adult antigen to access cytokine production. Interleukin-4 and IL-13 were measured in sample supernatant using an ovine-specific enzyme-linked immunosorbent assay (ELISA). Neutrophils exposed to HcLA peaked in IL-4 production at 30 minutes (STC, 3153.65 pg/mL and SUF, 4665.22 pg/mL). A similar trend was observed in IL-13 production by 6 hours (STC, 391.02 pg/mL and SUF, 419.6 pg/mL). Adult antigen stimulation resulted in low cytokine production when compared to HcLA stimulation (STC IL-4, 6.04 pg/mL and SUF, 8.05 pg/mL, respectively; STC IL-13, 10 pg/mL and 12.5 pg/mL; P < .001), and no breed differences were observed. Mixed immune cell assays revealed an ability of neutrophils to induce IL-4 production in peripheral blood mononuclear cell (PBMC). Taken together, these data implicate neutrophils as a potential effector cell responsible for Th2 initiation.     

Increased plasma levels of IL-21 and IL-23 in spondyloarthritis are not associated with clinical and MRI findings

We have investigated the role of the Th17-related cytokines interleukin-17A (IL-17A), IL-21, and IL-23 in spondyloarthritis (SpA) by examining their association with disease activity and magnetic resonance imaging (MRI) findings in patients with SpA (n = 80). Furthermore, to investigate the cellular origins of the cytokines, paired mononuclear cells from blood and synovial fluid were examined for the expression of IL-17A, IL-21, and IL-23R using multicolor flow cytometry. Both IL-21 and IL-23 levels were increased in plasma from SpA patients compared with healthy volunteers (P < 0.05), whereas IL-17A was not. A significant correlation was observed between individual levels of IL-21 and IL-23 (r = 0.7, P < 0.001). No association between individual levels of IL-17A, IL-21, and IL-23 with C-reactive protein (CRP), MRI changes, and clinical scoring (BASMI, BASFI, and BASDAI) were observed. The frequency of CD4+CD45RO+ T cells expressing IL-21 and IL-23R was increased in the inflamed SpA joint compared to peripheral blood (P < 0.05). This study demonstrate that the plasma levels of the Th17-related cytokines IL-21 and IL-23, but not IL-17A, are increased in SpA patients, but we did not find evidence that the level of these cytokines reflect disease activity in SpA.     

Th2 immune response by the iron-regulated protein HupB of Mycobacterium tuberculosis

BackgroundHupB is an iron-regulated protein essential for the growth of Mycobacterium tuberculosis inside macrophages. To investigate if HupB induced a dominant Th2 type immune response, we studied the effect of rHupB on PBMCs from TB patients and by infecting mouse macrophages with wild type and hupB KO mutants.MethodsPBMCs from pulmonary TB (n = 60), extra pulmonary TB (n = 23) and healthy controls (n = 30) were stimulated with purified HupB and the cytokines secreted were assayed. The sera were screened for anti-HupB antibodies by ELISA. Mouse macrophages cell line (RAW 264.7) was infected with wild type, hupB KO and hupB-complemented strains of M. tuberculosis grown in high and low iron medium and the expression of cytokines was assayed by qRT-PCR.ResultsMurine macrophages infected with the hupB KO strain produced low levels of the pro-inflammatory cytokines IFN-γ, TNF-α, IL-1, and IL-18 and high levels of IL-10. HupB induced IL-6 and IL-10 production in PBMCs of TB patients and down-regulated IFN-γ and TNF-α production. The influence of HupB was remarkable in the EPTB group.ConclusionHupB shifted the immune response to the Th2 type. Low IFN-γ and elevated IL-10 in EPTB patients is noteworthy.     

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

This study was designed to investigate the functional heterogeneity of human Th17 and how their plasticity shapes the nature of immune cell responses to inflammation and autoimmune diseases, such as systemic lupus erythematosus (SLE). We evaluated functional Th17 cell subsets based on the profile of cytokine production in peripheral blood (PB), bone marrow aspirates (BM) and lymph node biopsies (LN) from healthy individuals (n = 35) and PB from SLE patients (n = 34). Data were analysed by an automated method for merging and calculation of flow cytometric data, allowing us to identify eight Th17 subpopulations. Normal BM presented lower frequencies of Th17 (p = 0.006 and p = 0.05) and lower amount of IL-17 per cell (p = 0.03 and p = 0.02), compared to normal PB and LN biopsies. In the latter tissues were found increased proportions of Th17 producing TNF-α or TNF-α/IL-2 or IFN-γ/TNF-α/IL-2, while in BM, Th17 producing other cytokines than IL-17 was clearly decreased. In SLE patients, the frequency of Th17 was higher than in control, but the levels of IL-17 per cell were significantly reduced (p < 0.05). Among the eight generated subpopulations, despite the great functional heterogeneity of Th17 in SLE, a significant low proportion of Th17 producing TNF-α was found in inactive SLE, while active SLE showed a high proportion producing only IL-17. Our findings support the idea that the functional heterogeneity of Th17 cells could depend on the cytokine microenvironment, which is distinct in normal BM as well as in active SLE, probably due to a Th1/Th2 imbalance previously reported by our group.     

Polymorphism in the methylenetetrahydrofolate reductase (C677T) gene and homocysteine levels: a comparison in Brazilian patients with coronary arterial disease, ischemic stroke and peripheral arterial obstructive disease

This study aimed to compare plasma levels of total homocysteine (tHcy) in different arterial events as well as to investigate an association between homocysteine levels and C677T polymorphism in Brazilian patients. A total of 145 subjects were enrolled in this study including 43 patients with coronary arterial disease (CAD), 21 with ischemic stroke (IS), 44 with peripheral arterial obstructive disease (PAOD) and 37 control subjects. A preliminary analysis showed significant difference for tHcy plasma levels between patients with CAD (P = 0.003) or PAOD (P = 0.03) compared to controls. However, after adjustment for sex, age, total cholesterol, LDL, diabetes, tabagism or C677T polymorphism, no significant differences were detected in tHcy levels among patients groups and controls. No significant correlation was demonstrated for C677T polymorphism and homocysteine levels. These results indicate that increased Hcy levels may not be considered an independent risk factor for atherothrombotic diseases in Brazilian patients.     

Single nucleotide polymorphisms of IL-2, but not IL-12 and IFN-γ, are associated with increased susceptibility to chronic spontaneous urticaria

BackgroundA clear picture of interaction of Th1/Th2 cytokines in pathogenesis of chronic spontaneous urticaria (CSU), remains elusive. Impaired IFN-γ production and decreased levels of IL-2 have been reported. The aim of this study was to evaluate the association of Th1 cytokines; IL-2, IL-12 and IFN-γ polymorphisms with CSU.Methods90 patients with CSU and 140 age-sex matched subjects were included in this study. DNA samples were evaluated through PCR-SSP assay in order to detect single nucleotide polymorphisms of IL-12 (A/C −1188) or (rs3212227), IFN-γ (A/T UTR5644) or (rs2069717) and IL-2 (G/T −330 and G/T +166) or (rs2069762 and rs2069763).ResultsG allele at −330 at promoter region of IL-2 gene was overrepresented in CSU. Heterozygotes (GT) at this locus and heterozygotes at +166 of IL-2 gene (GT) were more prevalent in CSU group. Additionally, the haplotype GT for loci −330 and +166 of IL-2 gene was powerfully associated with CSU (OR (95%CI) = 57.29 (8.43–112.7)).ConclusionsSNP at position −330 and +166 of IL-2 gene are differently expressed in CSU. The haplotype GT of IL-2 at −330 and +166 might confer vulnerability to a number of immunological disorders in Iranian region.     

Distribution and functional plasticity of peripheral blood Th(c)17 and Th(c)1 in rheumatoid arthritis

With the discovery of Th17 cells, it became unclear whether rheumatoid arthritis (RA) is a Th1-mediated and/or a Th17-mediated disease. Objective: The aim of this study was to identify and characterize the pro-inflammatory function of IL-17-producing T cell subsets (Th(c)17) in RA. Flow cytometry analysis was performed on peripheral blood from RA patients with inactive or low disease activity (LDA, n = 19) and moderate to high disease activity (HDA, n = 13) to analyze the number and functional activity of Th(c)17 and Th(c)1 cell subsets according to the frequency of IL-2-, TNF-α- and IFN-γ-producers cells, as well as, their cytokine amount. Additionally, 13 age-matched healthy volunteers were added to the study. Our data point to a slight increase in Tc17 frequency in RA patients, more evident in HDA, and a higher ability of Th17 to produce IL-17, whereas a lower production of TNF-α was noted either in Th17 or Tc17 cells, particularly from HDA. A similar decrease was observed in Th(c)1 for almost all studied pro-inflammatory cytokines, with the exception of IL-2, which was increased in Tc1 from LDA patients. Analysing the proportion of pro-inflammatory cytokines-producing cells, a polarization to a Tc1 phenotype seemed to occur in CD8 T cells, while CD4 T cells appear to be decreased in their frequency of IFN-γ-producing cells. Taken together, the functional plasticity features of Th17 and Tc17 cells suggest a particular contribution to the local cytokine production, pointing an underestimated role, namely of Tc1 and Tc17 cells, in the RA pathophysiology.     

Local Induction of a Specific Th1 Immune Response by Allergen Linked Immunostimulatory DNA in the Nasal Explants of Ragweed- Allergic Subjects

BackgroundAllergen immunotherapy is effective in allergic individuals however efforts are being made to improve its safety, convenience, and efficacy. It has recently been demonstrated that allergen-linked immunostimulatory DNA (ISS) is effective in stimulating an allergen-specific Th1 response with decreased allergenicity. The objective of this study is to investigate whether ISS linked to purified ragweed allergen Amb-a-1 (AIC) can inhibit local allergen-specific Th2 and induce allergen-specific Th1 responses in explanted nasal mucosa of ragweed-sensitive subjects. In addition, we set out to determine whether AIC is more effective compared to stimulation with unlinked Amb a 1 and ISS.MethodsTissue from ragweed-sensitive patients (n = 12) was cultured with whole ragweed allergen (RW), Amb-a-1, AIC, Amb-a-1 and ISS (unlinked), or tetanus toxoid (TT) for 24 hours. IL-4, ? 5, ? 13, TNF-α and IFN-γ mRNA-positive cells were visualized by in situ hybridization and T cells, B cells and neutrophils were enumerated using immunocytochemistry.ResultsRW or Amb-a-1 increased the number of IL-4, IL-5, and IL-13 mRNA + cells in the tissue compared to medium alone. AIC had similar cytokine mRNA reactivity as control tissue. AIC and TT increased IFNγ-mRNA expression. Unlinked Amb-a-1 and ISS showed similar effects to AIC, however this response was weaker. The number of TNF mRNA + cells, T cells, B cells and neutrophils remained unchanged.ConclusionsAIC is effective in stimulating a local allergen-specific Th1- and abolishing Th2-cytokine mRNA reactivity in the nose and may be considered as a strong candidate for an improved approach to immunotherapy in ragweed-sensitive individuals.     

Expression of IL-17A in human atherosclerotic lesions is associated with increased inflammation and plaque vulnerability

A chronic (auto)immune response is the critical mechanism in atherosclerosis. Interleukin-17A is a pivotal effector cytokine, which modulates immune cell trafficking and initiates inflammation in (auto)immune and infectious diseases. However, expression of IL-17A in the context of human atherosclerosis has hardly been explored. Carotid artery plaques were collected from 79 patients undergoing endarterectomy. Patients were grouped according to their symptomatic status (TIA, stroke), plaque morphology and medication. Quantitative RT-PCR was used to analyze tissue inflammation and immunohistochemistry to assess cellular source of IL-17A expression and lesion morphology. Carotid plaques from patients with ischemic symptoms were characterized by a highly activated inflammatory milieu including accumulation of T cells (p = 0.04) and expression of IL-6 and VCAM1 (p = 0.02, 0.01). Expression of IL-17A and its positive regulators IL-21 and IL-23 was present in atherosclerotic lesions, significantly upregulated in atheromas of symptomatic patients (p = 0.005, 0.004, 0.03), and expression of IL-17A and IL-21 showed a strong correlation (p = 0.002, r = 0.52). The cellular sources of lesional IL-17A expression are T cells, macrophages, B cells and plasma cells. Vulnerable/ruptured (complicated) plaques were significantly associated with IL-17A expression levels (p = 0.003). In addition, IL-17A showed a marked negative correlation with the potent anti-inflammatory/atheroprotective cytokine IL-10 (p = 0.0006, r = −0.46). Furthermore, treatment with a HMG-CoA reductase inhibitor or acetylsalicylic acid showed reduced levels of IL-21, IL-23 and VCAM1 (all p < 0.05), but did not influence IL-17A. The association of IL-17A with ischemic symptoms and vulnerable plaque characteristics suggests that the pro-inflammatory cytokine IL-17A may contribute to atherosclerosis und plaque instability.     

Proviral load and the balance of serum cytocines in HTLV-1-asymptomatic infection and in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

This study compared the proviral load and the plasma cytokine profiles (interleukin-IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) in 87 HTLV-1-infected individuals, including 28 with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), 32 with possible pHAM/TSP and 27 asymptomatic carriers (AC). The control group was composed by 21 HTLV-1-seronegative individuals. Our finding demonstrated that HAM/TSP group presented higher proviral load as compared to all other HTLV-1 groups (p < 0.0001). The HAM/TSP group showed higher serum concentration of IL-6 (p = 0.0009) as compared to all other groups. Moreover, higher serum concentration of IFN-γ (p = 0.0118) and IL-4 (p = 0.0166) were observed in HAM/TSP group as compared to the healthy controls. Additionally, the HAM/TSP group also showed higher serum concentration of TNF-α (p = 0.0239) and IFN-γ (p = 0.0118) as compared to AC. No differences in the serum concentration of IL-2 and IL-10 were observed among the groups. The analysis of cytokine balance demonstrated that HAM/TSP presented higher pro-inflammatory profile with enhanced IFN-γ/IL-10 and IFN-γ/IL-4 ratio as compared to AC and pHAM/TSP. Further analysis pointed out to a positive correlation between the IFN-γ response and the proviral load in AC. Conversely, a negative association between TNF-α and IL-2 with the proviral load was the hallmark of HAM/TSP group. These findings suggested that the proviral load and the pro-inflammatory cytokine profile may be independent events in the peripheral blood of HAM/TSP individuals. The knowledge about the existence of individual virological/immunological behavior upon HTLV-1 infection, may guide to the establishment of more effective therapeutic interventions.