IL-33 and its decoy sST2 in patients with Alzheimer's disease and mild cognitive impairment

BACKGROUND: Interleukin-33 is a cytokine endowed with pro- and anti-inflammatory properties that plays a still poorly defined role in the pathogenesis of a number of central nervous system (CNS) conditions including Alzheimer's disease (AD). We analyzed this cytokine and its decoy receptor sST2 in Alzheimer's disease (AD) and mild cognitive impairment (MCI). METHOD: IL-33 and sST2 were analyzed in serum and CSF of AD and MCI patients, comparing the results to those obtained in age-matched healthy controls (HC). Because of the ambiguous role of IL-33 in inflammation, the concentration of both inflammatory (IL-1\u3b2 and IL-6) and anti-inflammatory (IL-10) cytokines was analyzed as well in serum and cerebrospinal fluid (CSF) of the same individuals. Finally, the effect of IL-33 on in vitro A\u3b242-stimulated monocytes of AD, MCI, and HC individuals was examined. RESULTS: As compared to HC, (1) IL-33 was significantly decreased in serum and CSF of AD and MCI, (2) sST2 was increased in serum of AD and MCI but was undetectable in CSF, (3) serum and CSF IL-1\u3b2 concentration was significantly increased and that of IL-10 was reduced in AD and MCI, whereas no differences were observed in IL-6. In vitro addition of IL-33 to LPS+A\u3b2 42-stimulated monocytes downregulated IL-1\u3b2 generation in MCI and HC, but not in AD, and stimulated IL-10 production in HC alone. IL-33 addition also resulted in a significant reduction of NF-kB nuclear translocation in LPS+A\u3b242-stimulated monocytes of HC alone. CONCLUSIONS: These data support the hypothesis that IL-33 plays a complex anti-inflammatory role that is lost in AD- and MCI-associated neuroinflammation; results herein also suggest a possible use of IL-33 as a novel therapeutic approach in AD and MCI

FoxP3 mRNA Expression in Regulatory T Cells from Patients with Tuberculosis

Comment on : V. Guyot-Revol, J.A. Innes, S. Hackforth, T. Hinks, A. Lalvani, Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. [Am J Respir Crit Care Med. 2006 Apr 1 173(7):803-810

Influence of a high‐impact multidimensional rehabilitation program on the gut microbiota of patients with multiple sclerosis

Multiple sclerosis (MS) is a neurodegenerative inflammatory condition mediated by autoreactive immune processes. Due to its potential to influence host immunity and gut‐brain communication, the gut microbiota has been suggested to be involved in the onset and progression of MS. To date, there is no definitive cure for MS, and rehabilitation programs are of the utmost importance, especially in the later stages. However, only a few people generally participate due to poor support, knowledge, and motivation, and no information is available on gut microbiota changes. Herein we evaluated the potential of a brief high‐impact multidimensional rehabilitation program (B‐HIPE) in a leisure environment to affect the gut microbiota, mitigate MS symptoms and improve quality of life. B‐HIPE resulted in modulation of the MS‐typical dysbiosis, with reduced levels of pathobionts and the replenishment of beneficial short‐chain fatty acid producers. This partial recovery of a eubiotic profile could help counteract the inflammatory tone typically observed in MS, as supported by reduced circulating lipopolysaccharide levels and decreased populations of pro‐inflammatory lymphocytes. Improved physical performance and fatigue relief were also found. Our findings pave the way for integrating clinical practice with holistic approaches to mitigate MS symptoms and improve patients’ quality of life

Immune and Imaging Correlates of Mild Cognitive Impairment Conversion to Alzheimer's Disease

Amnestic mild cognitive impairment (aMCI) conversion to Alzheimer's disease (AD) is seen in a sizable portion of aMCI patients; correlates predicting such conversion are poorly defined but neuroinflammation and the reactivation of chronic viral infections are suspected to play a role in this phenomenon. We analyzed these aspects in two homogeneous groups of aMCI who did or did not convert to AD over a 24-months period. Results showed that at baseline in those aMCI individuals who did not convert to AD: 1) A\uce\ub21-42stimulated production of the pro-inflammatory cytokines IL6 and IL1\uce\ub2 by CD14+cells was significantly reduced (p = 0.01), 2) CD14+/IL-33+cells were increased (p = 0.0004); 3) MFI of TLR8 and TLR9 was significantly increased, and 4) better preserved hippocampus volumes were observed and correlated with IL33+/CD14+cells. Notably, A\uce\ub21-42stimulated production of the antiviral cytokine IFN-\uce\ubb was increased as well in non-AD converters, although with a borderline statistical significance (p = 0.05). Data herein indicating that proinflammatory cytokines are reduced, whereas IFN-\uce\ubb production and TLR8 and 9 MFI are augmented in those aMCI in whom AD conversion is not observed suggest that the ability to mount stronger antiviral response within an antiiflammatory milieu associates with lack of AD conversion

The NLRP3 and NLRP1 Inflammasomes are Activated in Alzheimer’s Disease

Background Interleukin-1 beta (IL-1\u3b2) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer\u2019s disease (AD); no conclusive data are nevertheless available in AD patients. Results mRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1\u3b2, IL-18) was up-regulated in severe and MILD AD. Monocytes co-expressing NLRP3 with caspase 1 or caspase 8 were significantly increased in severe AD alone, whereas those co-expressing NLRP1 and NLRP3 with PYCARD were augmented in both severe and MILD AD. Activation of the NLRP1 and NLRP3 inflammasomes in AD was confirmed by confocal microscopy proteins co-localization and by the significantly higher amounts of the pro-inflammatory cytokines IL-1\u3b2 and IL-18 being produced by monocytes. In MCI, the expression of NLRP3, but not the one of PYCARD or caspase 1 was increased, indicating that functional inflammasomes are not assembled in these individuals: this was confirmed by lack of co-localization and of proinflammatory cytokines production. Conclusions The activation of at least two different inflammasome complexes explains AD-associated neuroinflammation. Strategies targeting inflammasome activation could be useful in the therapy of AD

TH17-driven inflammation is present in all clinical forms of multiple sclerosis; disease quiescence is associated with gata3-expressing cells

Multiple Sclerosis (MS) presents in a variety of clinical forms associated with a diverse grade of neurological impairment, different prognosis and, possibly, multiple pathogenic mechanisms. Thus, whereas relapsing-remitting (RR) MS appears to be largely driven by inflammatory processes, neurodegeneration, partially independent from inflammation, drives primary progressive (PP) and secondary progressive (SP) MS. An extensive analysis of neuroinflammation in the different forms of MS was performed by evaluating immunophenotypic and functional parameters in MBP-stimulated T lymphocytes of 103 MS patients (26 benign (BE) MS, 30 RRMS, 33 SPMS and 14 PPMS) and 40 healthy controls (HC). Results showed that: i) IL-17-producing and RORC/\u3b3t-expressing CD4+ T cells (TH17 lymphocytes), as well as IL-6 expressing CD14+ cell were augmented in all patients; ii) IL-22-expressing cells were increased in all forms of MS with the exception of PPMS; iii) TGF-\u3b2-expressing B cells were increased only in RRMS; and iv) GATA3-, NFATc-1, IL-13-, and IL-25-expressing cells (TH2 lymphocytes) were augmented in RRMS and BEMS patients alone. Data herein indicate a pivotal pathogenic role of TH17-driven inflammation in all clinical forms of MS and suggest that control over disease (RRMS and BEMS) is associated not with lack of inflammation per se, but rather with the activation of immune-mediated anti-inflammatory mechanisms. These results could help the design of novel diagnostic and therapeutic approaches

B Lymphocytes in Multiple Sclerosis : Bregs and BTLA/CD272 Expressing-CD19+ Lymphocytes Modulate Disease Severity

B lymphocytes contribute to the pathogenesis of Multiple Sclerosis (MS) by secreting antibodies and producing cytokines. This latter function was analyzed in myelin olygodendrocyte protein (MOG)-stimulated CD19+B lymphocytes of 71 MS patients with different disease phenotypes and 40 age- and sex-matched healthy controls (HC). Results showed that: 1) CD19+/TNF alpha+, CD19+/IL-12+ and CD19+/IFN gamma+ lymphocytes are significantly increased in primary progressive (PP) compared to secondary progressive (SP), relapsing-remitting (RR), benign (BE) MS and HC; 2) CD19+/IL-6+ lymphocytes are significantly increased in PP, SP and RR compared to BEMS and HC; and 3) CD19+/IL-13+, CD19+/IL-10+, and CD19+/IL-10+/TGF beta+ (Bregs) B lymphocytes are reduced overall in MS patients compared to HC. B cells expressing BTLA, a receptor whose binding to HVEM inhibits TcR-initiated cytokine production, as well as CD19+/ BTLA+/IL-10+ cells were also significantly overall reduced in MS patients compared to HC. Analyses performed in RRMS showed that fingolimod-induced disease remission is associated with a significant increase in Bregs, CD19+/BTLA+, and CD19+/BTLA+/IL-10+ B lymphocytes. B lymphocytes participate to the pathogenesis of MS via the secretion of functionally-diverse cytokines that might play a role in determining disease phenotypes. The impairment of Bregs and CD19+/BTLA+ cells, in particular, could play an important pathogenic role in MS

Determinants of disability in multiple sclerosis: an immunological and MRI study

Multiple sclerosis (MS) is characterized by a wide interpatient clinical variability and available biomarkers of disease severity still have suboptimal reliability. We aimed to assess immunological and MRI-derived measures of brain tissue damage in patients with different motor impairment degrees, for in vivo investigating the pathogenesis of MS-related disability. Twenty-two benign (B), 26 secondary progressive (SP), and 11 early, nondisabled relapsing-remitting (RR) MS patients and 37 healthy controls (HC) underwent conventional and diffusion tensor brain MRI and, as regards MS patients, immunophenotypic and functional analysis of stimulated peripheral blood mononuclear cells (PBMC). Corticospinal tract (CST) fractional anisotropy and grey matter volume were lower and CST diffusivity was higher in SPMS compared to RRMS and BMS patients. CD14+IL6+ and CD4+IL25+ cell percentages were higher in BMS than in SPMS patients. A multivariable model having EDSS as the dependent variable retained the following independent predictors: grey matter volume, CD14+IL6+ and CD4+IL25+ cell percentages. In patients without motor impairment after long-lasting MS, the grey matter and CST damage degree seem to remain as low as in the earlier disease stages and an immunological pattern suggestive of balanced pro- and anti-inflammatory activity is observed. MRI-derived and immunological measures might be used as complementary biomarkers of MS severity

CD4+ T Cell Depletion, Immune Activation and Increased Production of Regulatory T Cells in the Thymus of HIV-Infected Individuals

Mechanisms by which HIV affects the thymus are multiple and only partially known, and the role of thymic dysfunction in HIV/AIDS immunopathogenesis remains poorly understood. To evaluate the effects of HIV infection on intra-thymic precursors of T cells in HIV-infected adults, we conducted a detailed immunophenotypic study of thymic tissue isolated from 7 HIV-infected and 10 HIV-negative adults who were to undergo heart surgery. We found that thymuses of HIV-infected individuals were characterized by a relative depletion of CD4+ single positive T cells and a corresponding enrichment of CD8+ single positive T cells. In addition, thymocytes derived from HIV-infected subjects showed increased levels of activated and proliferating cells. Our analysis also revealed a decreased expression of interleukin-7 receptor in early thymocytes from HIV-infected individuals, along with an increase in this same expression in mature double- and single-positive cells. Frequency of regulatory T cells (CD25+FoxP3+) was significantly increased in HIV-infected thymuses, particularly in priorly-committed CD4 single positive cells. Our data suggest that HIV infection is associated with a complex set of changes in the immunophenotype of thymocytes, including a reduction of intrathymic CD4+ T cell precursors, increased expression of activation markers, changes in the expression pattern of IL-7R and enrichment of T regulatory cells generation

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified