Ruolo dell\u2019immunit\ue0 innata nella malattia celiaca

La malattia celiaca (CD) \ue8 una condizione permanente di sensibilit\ue0 al glutine che porta ad un danno all\u2019intestino tenue con conseguente malassorbimento di nutrienti ed infiammazione della mucosa intestinale. Il mancato assorbimento di nutrienti e la mucosa intestinale infiammata possono indurre un disturbo generale dell'immunit\ue0 mucosale che pu\uf2 portare allo sviluppo di malattie autoimmuni che coinvolgono altri organi ed apparati ed in alcuni casi possono favorire l\u2019insorgenza di linfomi. Questa malattia si sviluppa esclusivamente nei soggetti che presentano un complesso maggiore di istocompatibilit\ue0 (HLA) di classe II con aplotipo DQ2/DQ8 e dopo esposizione a cibi contenenti glutine. Questa \ue8 una condizione necessaria ma non sufficiente allo sviluppo della malattia, infatti circa il 24% dei soggetti sani presentano HLA-DQ2 e il 15% HLA-DQ8. Gli studi sulla celiachia degli ultimi vent\u2019anni, hanno focalizzato l\u2019attenzione della comunit\ue0 scientifica sulla genetica e sul ruolo della risposta immunitaria adattativa indotta nell\u2019organismo in seguito all\u2019assunzione del glutine nei pazienti CD. Il modello attuale della celiachia, derivato da questi studi, \ue8 in grado di spiegare molti aspetti della CD ma non \ue8 completo, non \ue8 infatti ancora in grado di chiarire perch\ue9 molte persone geneticamente predisposte non sviluppano mai la malattia Fino alla prima met\ue0 degli anno \u201990 sono state raccolte prove che inducono a sospettare un ruolo diretto del glutine nell\u2019insorgenza della CD. La Teoria lectinica ipotizza un\u2019attivit\ue0 citotossica della gliadina indipendente dal sistema immunitario adattativo. In questo campo d\u2019indagine si inserisce il lavoro discusso in questa tesi. Gli esperimenti condotti sui monociti e sulla linea di enterociti FHs74Int hanno dimostrato che il glutine digerito ha un effetto lectinico, svolge un\u2019azione diretta nell\u2019attivazione dei monociti e le cellule dell\u2019epitelio che ricoprono l\u2019intestino si contraggono in maniera transiente rendendo probabilmente pi\uf9 permeabile l\u2019intestino al passaggio di molecole come il DPT-G stesso. Non sono state individuate differenze significative nella risposta all\u2019esposizione al glutine tra soggetti CD e controlli sani. L\u2019unica differenza riscontrata \ue8 una minor produzione di TNF\u3b1 nei soggetti CD esposti al glutine. Ipotizziamo che questa differenza sia da attribuirsi ad una stimolazione cronica da parte dei peptidi tossici della gliadina, ipotizziamo inoltre che la ridotta risposta immunitaria innata possa portare ad una maggior disponibilit\ue0 di peptidi di gliadina nel sottomucosa in grado di attivare la risposta immunitaria adattativa. Questa tesi ha avuto come obiettivo l\u2019ampliamento delle conoscenze sulla patogenesi della CD ma i risultati qui esposti hanno permesso di chiarire ulteriormente il ruolo del glutine non solo nei celiaci ma nell\u2019intera popolazione. Il glutine ha dimostrato avere una tossicit\ue0 sulle cellule ed essere riconosciuto come un patogeno dal sistema immunitario innato

Fever tree revisited: From malaria to autoinflammatory diseases

Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin

Letter to the Editor: Acute Effects of Intravenous Administration of Pamidronate in Patients with Osteoporosis

We read the interesting article “Acute Effects of Intravenous Administration of Pamidronate in Patients with Osteoporosis” in the Journal of Korean Medical Science by Lim et al. (1). We would like to comment and compare these data to a study recently published by our research group (2). The two studies had different initial aims, but still they share the same results in determining the modulatory effect of inflammation of aminobisphosphonates, such as pamidronate. The pamidronate belongs to the family of aminobisphosphonates (N-BPs), currently the major class of drugs used for the treatment of osteoporosis and other diseases characterized by increased bone resorption. The immune modulation exerted by pamidronate has not yet fully been understood (3). In vitro experiments have shown an anti-inflammatory effect of this N-BP; (4, 5) as well as a pro-inflammatory one (6, 7). Moreover contrasting results were obtained when pamidronate was used for the treatment of different inflammatory or immunologic diseases, such as rheumatoid arthritis (8,9) or systemic sclerosis. The aminobiphosphonates act on farnesylpyrophosphate synthase (FPPS) and inhibit the mevalonate pathway, the latter being responsible for production of cholesterol and isoprenoid lipids. In particular we can hypothesize that the inflammatory phenotype is due to lack of enzymes downstream the FPPS, and in particular the lack of geranylgeranyl-pyrophosphate (GGPP) could be associated to the activation of caspase-1 and the high IL-1β release. Lim et al. (1) emphasized that in vivo infusion of pamidronate at a therapeutic dose of 30 mg increased production of two inflammatory cytokines, IL-6 and TNF-α in serum. The increase is an acute effect after intravenous injection (1). Recently, our group demonstrated that pamidronate is able to increase the sensitivity to bacterial compounds both in the murine macrophagic cell line (Raw 264.7) and in Balb/c mice, by an incremental release of IL1β. These findings are in agreement with published data concerning inflammatory modulation in alendronate treated-mice (2). Moreover the effect of pamidronate does not depend on its concentration, whereas it may be involved in the increase of susceptibility to pro-inflammatory compounds such as muramildipeptide or lipopolysaccaride (2). In summary, we agree with the study by Lim et al. (1) and we emphasize the pivotal role of pamidronate in the modulation of inflammatory response

Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study

Periodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS

An online tool for fetal fraction prediction based on direct size distribution analysis of maternal cell-free DNA

The discovery of circulating fetal DNA in the plasma of pregnant women has greatly promoted advances in noninvasive prenatal testing. Screening performance is enhanced with higher fetal fraction and analysis of samples whose fetal DNA fraction is lower than 4% are unreliable. Although current approaches to fetal fraction measurement are accurate, most of them are expensive and time consuming. Here we present a simple and cost-effective solution that provides a quick and reasonably accurate fetal fraction by directly evaluating the size distribution of circulating DNA fragments in the extracted maternal cell-free DNA. The presented approach could be useful in the presequencing stage of noninvasive prenatal testing to evaluate whether the sample is suitable for the test or a repeat blood draw is recommended

Novel Missense Mutation in the NOD2 Gene in a Patient with Early Onset Ulcerative Colitis: Causal or Chance Association?

Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn's disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G p.K953E) and two already described missense variants in the IL10RA gene (S159G and G351R). The new NOD2 missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. Although cumulative effect of these variations in the early onset of the disease can be only hypothesized, we demonstrated that family information and in silico studies can be used to predict association with the disease

HLA-G/C, miRNAs, and Their Role in HIV Infection and Replication

In recent years, a number of different mechanisms regulating gene expressions, either in normal or in pathological conditions, have been discovered. This review aims to highlight some of the regulatory pathways involved during the HIV-1 infection and disease progression, focusing on the novel discovered microRNAs (miRNAs) and their relation with immune system’s agents. Human leukocyte antigen (HLA) family of proteins plays a key role because it is a crucial modulator of the immune response; here we will examine recent findings, centering especially on HLA-C and -G, novel players lately discovered to engage in modulation of immune system. We hope to provide novel perspectives useful to find out original therapeutic roads against HIV-1 infection and AIDS progression

Database tools in genetic diseases research

The knowledge of the human genome is in continuous progression: a large number of databases have been developed to make meaningful connections among worldwide scientific discoveries. This paper reviews bioinformatics resources and database tools specialized in disseminating information regarding genetic disorders. The databases described are useful for managing sample sequences, gene expression and post-transcriptional regulation. In relation to data sets available from genome-wide association studies, we describe databases that could be the starting point for developing studies in the field of complex diseases, particularly those in which the causal genes are difficult to identify