No description available.

Cervical stenotic myelopathy (CSM) is an important musculoskeletal and neurologic disease of the horse. Clinical disease occurs due to malformations of the vertebrae in the neck causing stenosis of the cervical vertebral canal and subsequent spinal cord compression. The disease is multifactorial in nature, therefore a clearer understanding of the etiology and pathogenesis of CSM will allow for improved management and therapeutic practices. This thesis examines issues of equine CSM diagnosis, skeletal tissue pathology, and inherited genetic determinants utilizing advances in biomedical imaging technologies and equine genomics. Magnetic resonance imaging (MRI) data provided a more complete assessment of the cervical column through image acquisition in multiple planes. First, MRI was compared to standing cervical radiographs for detection of stenosis. Using canal area or the cord canal area ratio, MRI more accurately predicted sites of compression in CSM cases. Secondly, articular process skeletal pathology localized on MRI was found to be more frequent and severe in CSM horses compared to controls. In addition, lesions were generalized throughout the cervical column and not limited to the spinal cord compression sites. A subset of lesions identified on MRI was evaluated using micro-CT and histopathology. Osteochondrosis, osseous cyst-like structures, fibrous tissue replacement of bone, and osteosclerosis were observed. These lesions support likely developmental aberrations of vertebral bone and cartilage maturation with secondary biomechanical influences. Bone cyst-like structures are a novel finding in this disease. Finally, the long-standing question of the contribution of genetic determinants to CSM was investigated using a genome wide association study (GWAS). Multiple significant loci were identified supporting the influence of a complex genetic trait in clinical disease. A simple Mendelian trait controlled by one gene is unlikely given the detection of variants across multiple chromosomes. Major contributions from this research include documentation of articular process bone and cartilage pathology in horses with CSM, support for abnormal cervical vertebrae development being an important contributing factor in the etiology and/or pathogenesis of equine CSM, and evidence that multiple genetic loci contribute to the CSM disease phenotype.

No description available.

Αν και η Αυχενική Σπονδυλωτική Μυελοπάθεια (ΑΣΜ) αποτελεί την πιο κοινή αιτία δυσλειτουργίας νωτιαίου μυελού στους ενήλικες άνω των 55 ετών, οι μοριακοί μηχανισμοί παραμένουν άγνωστοι. Μέχρι σήμερα, πολλές προσπάθειες έχουν διενεργηθεί για την ανάπτυξη ενός αξιόπιστου πειραματικού μοντέλου AΣΜ. Ωστόσο, αρκετά μειονεκτήματα εμφανίζονται σε αυτές τις μελέτες. Στη παρούσα μελέτη έχουμε σκοπό τη δημιουργία ενός νέου, πρωτότυπου πειραματικού μοντέλου ΑΣΜ, το οποίο εξομοιώνει τα ιστολογικά και κλινικά χαρακτηριστικά της ανθρωπίνης νόσου. Mεθοδολογία: Μετά από αφαίερεση του πετάλου του έβδομου αυχενικού σπονδύλου, ένα λεπτό τεμάχιο αρωματικού πολυαιθέρα τοποθετήθηκε κάτω από το πέταλο του έκτου αυχενκού σπονδύλου σε κόνικλους Νέας Ζηλανδίας (Ομάδα ΧΠΠ). Σε μία άλλη ομάδα πειραματόζωων ο αρωματικός πολυαιθέρας αφαιρέθηκε 30 δευτερόλεπτα μετά την εμφύτευση (ομάδα ελέγχου). Νευρολογική εκτίμηση πραγματοποιήθηκε χρησιμοποιώντας τη κλίμακα του Tarlov μετά το πέρας της χειρουργικής διαδικασίας και ακολούθως εβδομαδιαίως. Ηλεκτροφυσιολογικές μελέτες πραγματοποιήθηκαν στις 20 εβδομάδες μετά το χειρουργείο και πριν από τη θυσία των πειραματόζωων. Ακολούθησαν ιστολογικές και ανοσοιστοχημικές μελέτες. Αποτελέσματα: Τα πειραματόζωα που άνηκαν στην ομάδα ελέγχου δεν εμφάνισαν νευρολογικά ελλείμματα κατά τη διάρκεια της μελέτης. Αντιθέτως τα πειραματόζωα που άνηκαν στη ΧΠΠ εμφάνισαν νευρολογικά ελλείματα. Στους νωτιαίους μυελούς προερχόμενους από την ΧΠΠ ομάδα ανεδείχθησαν οι χαρακτηριστικές ιστοπαθολογικές αλλοιώσεις της χρόνιας μυελοπάθειας. Ειδικότερα, ανεδείχθη σπογγώδης εκφύλιση της λευκής ουσίας, διάμεσο οίδημα και αποπλάτυνση των πρόσθιων κεράτων της φαιάς ουσίας. Επίσης ανεδείχθη κατακρήμνιση του μυελικού σάκου και διόγκωση του δακτυλίου της μυελίνης. Τέλος, η χρόνια πίεση του νωτιαίου οδήγησε σε ενεργοποίηση της απόπτωσης και διαταραχή της αρχιτεκτονικής του μικροαγγειακού συστήματος του νωτιαίου μυελού Συμπέρασμα: Το πρωτότυπο μοντέλο ΑΣΜ στους κονίκλους ποσομοιώνει το χωρικό και χρονικό προφίλ της ανθρώπινης νόσου στο σημείο της πίεσης του νωτιαίου μυελού. ΜΕΛΕΤΗ B Εισαγωγή: Η φλεγμονή, η δημιουργία ουλώδους ιστού και η διαταραχή του μικροαγγειακού συστήματος του νωτιαίου μυελού είναι ορισμένα από τα κύρια παθοφυσιολογικά φαινόμενα της ΑΣΜ. Ωστόσο οι μοριακοί μηχανισμοί που εμπλέκονται σε αυτά τα φαινόμενα κάτω από τη χρόνια και προοδευτική πίεση του νωτιαίου μυελού παραμένουν ανεξερεύνητα. Mεθοδολογία: Στη συγκεκριμένη μελέτη χρησιμοποιήθηκε το πειραματικό μοντέλο ΑΣΜ που περιγράφεται στη μελέτη Α με σκοπό να διερευνηθεί ο ρόλος του NF-κB και των πρωτεινών της εξωκυττάριας ουσίας στην ΑΣΜ. Εν συντομία, κόνικλοι Νέας Ζηλανδίας (διαφορετικά πειραματόζωα από εκείνα της μελέτης Α) χωρίστηκαν τυχαία σε δύο ομάδες: την ομάδα ΧΠΠ (n=15) και την ομάδα ελέγχου (n=15). Η έκφραση των πρωτεινών των υπομονάδων p50 και p65 του NF-kB, όπως επίσης και των ενζύμων διάσπασης της εξωκυττάριας ουσίας (MMP-2, MMP-9) και του ενεργοποιητή του πλασμινογόνου τύπου ουροκινάσης (urokinase-type plasminogen activator; u-PA) αξιολογήθηκαν σε τομές νωτιαίων μυελών προερχόμενων και από τις δύο ομάδες χρησιμοποιώντας ανοσοιστοχημική τεχνική. Στατιστική ανάλυση πραγματοποιήθηκε χρησιμοποιώντας SPSS για Windows, release 12.0 (SPSS Inc., Chicago, IL). Αποτελέσματα: Σε τομές νωτιαίων μυελών που προέρχονταν από πειραματόζωα που έπασχαν από ΑΣΜ αναδείχθηκε στατιστικά σημαντικά αυξημένη έκφραση των υπομονάδων του NF-κB (p50 & p65), όπως επίσης και των ενζύμων MMP-2, MMP-9, and u-PA σε σύγκριση με εκείνες που προέρχονταν από την ομάδα ελέγχου. Τέλος, σημαντικά θετική συσχέτιση παρατηρήθηκε μεταξύ των επιπέδων έκφρασης του NF-κB και εκείνων των MMP-9, MMP-2, and u-PA. Συμπέρασμα: Τα ευρήματα αυτά αποτελούν ισχυρές ενδείξεις πως η χρόνια και προοδευτική πίεση του αυχενικού νωτιαίου μυελού οδηγεί σε αυξημένη έκφραση των MMP-2, MMP-9 και u-PA πιθανόν μέσω της δράσης του μεταγραφικού παράγοντα NF-κB. Είναι βέβαιο ότι περισσότερες μελέτες απαιτούνται για την εξακρίβωση του ρόλου των πρωτεινών αυτών στην ΑΣΜ. / Although cervical spondylotic myelopathy (CSM) represents the most common cause of spinal cord impairment among individuals over 55 years old, the molecular mechanisms of the disease remain mainly unknown. To date, many experimental studies have been conducted to establish a reliable model of CSM, however most of them appear some limitations. In this study we aim to create a new animal model of CSM, which will reproduce the temporal course of the human disease and the local microenvironment at the site of spinal cord compression. Methods: Following C7 posterior laminectomy, a thin sheet of aromatic polyether was implanted underneath C5–C6 laminae of the New Zealand rabbits. A sham group in which the material was removed 30 sec after the implantation was also included. Motor function evaluation was performed after the material implantation and weekly thereafter using the Tarlov classification. At 20 weeks post-material implantation electrophysiological studies were also conducted. All the animals were sacrificed 20 weeks post-material implantation and histological and immunohistochemical studies were performed. Results: Clinical evaluation of animals after operation reveals no symptoms and signs of acute spinal cord injury. Moreover, no neurological deficits were noticed in the sham group during the course of the study. However, the animals which underwent implantation of compression material exhibited progressive neurological deficits throughout the study. Rabbits of the compression group experienced significant increased axonal swelling and demyelination, interstitial edema and myelin sheet fragmentation. Histological evaluation of C5 and C6 laminae (at the site of implantation) reveals osteophyte formation. Moreover, the chronic and progressive compression of the cervical spinal cord resulted in induction of apoptosis as well as in disruption of the basement membrane of vessels. Conclusion: The proposed rabbit CSM model reproduces the temporal evolution of the disease and creates a local microenvironment at the site of spinal cord compression, which shares similar features with that of human disease. STUDY B Introduction: Inflammation, glial scar formation and disruption of spinal cord microvasculature represent some of the principal neuropathological features of CSM. However, the molecular mechanisms which are implicated in these pathophysiological phenomena under the chronic and progressive compression of the cervical spinal cord remain interestingly unexplored. Methods: In this study (B) in order to evaluate the role of NF-κB and extracellular matrix proteins in cervical myelopathy we used the rabbit CSM model which was extensively characterized in study A. Briefly New Zealand rabbits (different cohort of animals than that of the study A) were randomly and blindly divided into the following two groups: CSM (n=15) and sham group (n=15). The expression pattern of p50 and p65 subunits of NF-kB, as well as that of MMP-2, MMP-9, and u-PA, was evaluated in spinal cord sections coming from both groups using immunohistochemistry technique. Statistical analysis was performed using SPSS for Windows, release 12.0 (SPSS Inc., Chicago, IL). Results: CSM animals exhibited statistically significant increased immuoreactivity in both NF-κB subunits, p50 and p65. Moreover, the levels MMP-2, MMP-9, and u-PA were found to be significantly increased in CSM animals compared to controls. Finally, strong positive correlation between NF-κB subunits immunoreactivity and that of MMP-9, MMP-2, and u-PA was demonstrated. Conclusion: The NF-κB pathway as well as the extracellular matrix proteins (MMP-2 and MMP-9) are involved in CSM. However, more studies are needed to clarify the functional role of these molecules in the pathobiology of CSM.

La myélopathie cervicale est une maladie chronique dégénérative de la moelle épinière dont la fréquence augmente avec l’âge. Elle est caractérisée par une compression mécanique menant à un endommagement de la structure médullaire et peut être source de handicaps sévères dégradant la qualité de vie. Néanmoins, la prise en charge clinique reste délicate.C’est pourquoi les travaux conduits dans le cadre de cette thèse se sont focalisés sur la compréhension des phénomènes biomécaniques à l’origine de cet endommagement (via des méthodes de simulation par éléments finis) et les conséquences microstructurelles pouvant être observées par IRM multi-paramétrique. Plus précisément, le but était d’établir un lien entre la cause mécanique et les conséquences structurelles menant aux déficits cliniques afin de mieux comprendre et prédire l’évolution de ces pathologies.Pour atteindre cela, une caractérisation de la morphologie et microstructure de la moelle épinière saine a été conduite par IRM, procurant à la fois une source de données normatives pour évaluer les atteintes chez patients mais aussi des données d’entrée pour raffiner les modèles numériques utilisés. D’un point de vue biomécanique, les phénomènes mécaniques observés lors d’une compression médullaire telle que pouvant être rencontrée dans une myélopathie cervicale ont été étudiés. Bien qu’à confirmer, les résultats obtenus au cours de ces travaux sont encourageants et posent une première pierre vers l’établissement de nouvelles méthodes permettant de mieux comprendre l’origine des déficits observés chez des patients souffrant de lésions médullaires en étudiant le lien entre mécanique, microstructure et fonction. / Cervical myelopathy is a chronic degenerative spinal cord pathology whose incidence increases with age. It is characterized by a mechanical compression leading to structural spinal cord damage. It can be at the origin of severe handicap hampering the quality of life. However, the clinical management remains challenging.This is why the work conducted in this thesis was focused on the comprehension of the biomechanics of the spinal cord damage (through numerical simulation finite element methods) and microstructural consequences that can be observed with multi-parametric MR imaging. More specifically, the final goal was to link the mechanical cause to the structural consequences at the origin of the clinical deficits in order to better understand and predict the pathology’s evolution.To reach that end, a characterization of the morphology and microstructure of the spinal cord was achieved using MRI, procuring on one side a normative database useful to study the alterations encountered in patients, and on another side to refine the numerical models employed. From a biomechanical perspective, the mechanisms of spinal cord compression as encountered in cervical myelopathy were studied using finite element analysis. The results obtained, which should be confirmed, are encouraging and represent a first stone towards the establishment of new methods in order to help in the clinical management of patients with spinal cord lesions by linking the mechanics, microstructure and function of the spinal cord.

Based on contemporary theoretical knowledge in this prospective study we outline the relationship between a chosen surgical approach (anterior or posterior approach) as it relates to the localization of spinal cord lesion (anterior or posterior spinal pathways) assessed by the use of evoked potentials (SEP, MEP) and the effect of this approach on the postoperative state of patients with cervical spondylotic myelopathy. Furthermore we evaluate clinical outcome of these patients according to several aspects of their MRI and X-ray findings. The study, from 2006 to 2010, comprised 65 patients with clinical signs of cervical myelopathy. These patients had been indicated for surgery, which subsequently was performed by using either the front (anterior - a) or back (posterior - p) approach. The patients were assessed using Nurick and mJOA scores before surgery, then at 12 months, and finally 24 months after surgery. In addition, they were preoperatively examined with a battery of evoked potentials (EP) - somatosensory evoked potential (SEP) and motor evoked potential (MEP) tests. Based on EP, principal spinal cord disability was determined: A - anterior (maximum changes in MEP), P - posterior - maximum change in SEP). The entire group was, on the basis of EP partitioning and the surgical approach used, divided...

Based on contemporary theoretical knowledge in this prospective study we outline the relationship between a chosen surgical approach (anterior or posterior approach) as it relates to the localization of spinal cord lesion (anterior or posterior spinal pathways) assessed by the use of evoked potentials (SEP, MEP) and the effect of this approach on the postoperative state of patients with cervical spondylotic myelopathy. Furthermore we evaluate clinical outcome of these patients according to several aspects of their MRI and X-ray findings. The study, from 2006 to 2010, comprised 65 patients with clinical signs of cervical myelopathy. These patients had been indicated for surgery, which subsequently was performed by using either the front (anterior - a) or back (posterior - p) approach. The patients were assessed using Nurick and mJOA scores before surgery, then at 12 months, and finally 24 months after surgery. In addition, they were preoperatively examined with a battery of evoked potentials (EP) - somatosensory evoked potential (SEP) and motor evoked potential (MEP) tests. Based on EP, principal spinal cord disability was determined: A - anterior (maximum changes in MEP), P - posterior - maximum change in SEP). The entire group was, on the basis of EP partitioning and the surgical approach used, divided...

RIPPLY2 is an essential part of the formation of somite patterning during embryogenesis and in establishment of rostro-caudal polarity. Here, we describe three individuals from two families with compound-heterozygous variants in RIPPLY2 (NM_001009994.2): c.238A > T, p.(Arg80*) and c.240-4 T > G, p.(?), in two 15 and 20-year-old sisters, and a homozygous nonsense variant, c.238A > T, p.(Arg80*), in an 8 year old boy. All patients had multiple vertebral body malformations in the cervical and thoracic region, small or absent rib involvement, myelopathies, and common clinical features of SCDO6 including scoliosis, mild facial asymmetry, spinal spasticity and hemivertebrae. The nonsense variant can be classified as likely pathogenic based on the ACMG criteria while the splice variants must be classified as a variant of unknown significance. With this report on two further families, we confirm RIPPLY2 as the gene for SCDO6 and broaden the phenotype by adding myelopathy with or without spinal canal stenosis and spinal spasticity to the symptom spectrum.

Le virus T-lymphotrope humain de type 1 (HTLV-1) est l’agent étiologique de deux principales pathologies : la leucémie/lymphome à cellules T de l’adulte (ATLL) et la paraparésie spastique tropicale/myélopathie associée à HTLV-1 (HAM/TSP). Ces deux maladies sont caractérisées par des phénotypes immunitaires opposés, puisque l’ATLL est associée à une immunosuppression et l’HAM/TSP à une réponse pro-inflammatoire. Les mécanismes qui déterminent l’évolution de l’infection chronique vers l’une ou l’autre de ces maladies sont peu connus. L’interféron de type 1 (IFN-I) a une fonction ambiguë dans l’organisme. Si cette cytokine contribue à la réponse immunitaire précoce, elle est également associée au développement de pathogenèses pour des infections virales persistantes. Les cellules dendritiques plasmacytoïdes (pDCs) ont la particularité de produire de grandes quantités d’IFN-I après la reconnaissance de cellules infectées par des virus. Nous avons montré que ceci était également vrai pour HTLV-1, puisque le contact entre une cellule infectée par HTLV-1 et la pDC est nécessaire à la production d’IFN-I. Cette production est induite par la particularité de HTLV-1 à s’accumuler en surface des cellules infectées, au sein d’une structure préalablement définie sous le terme de biofilm viral. La nature de la matrice extracellulaire dans laquelle est accumulée le virus régule la réponse IFN-I par les pDCs, la présence de l’antigène Galβ(1-3)GalNAc désialylé à la surface des cellules infectées contribuant à réduire cette réponse IFN-I. Nous avons également observé que des cellules infectées par le virus HTLV-2, virus phylogénétique proche de HTLV-1 mais peu pathogène, tendent à induire une plus faible production d’IFN-I, mais une meilleure maturation des pDCs. Nous avons enfin montré que la fréquence des pDCs dans le sang et leur capacité à répondre à un stimulus est similaire chez des patients HAM/TSP, des porteurs asymptomatiques et des individus sains. Ces résultats contrastent avec des études antérieures qui montrent une diminution de la fréquence des pDCs chez les patients ATLL et une diminution de leur activité chez les individus infectés. Le nombre et la fonction des pDCs pourraient ainsi contribuer à l’orientation de la pathogenèse vers l’ATLL ou l’HAM/TSP. / HTLV-1 (Human T-lymphotropic virus type 1) is the etiological agent of two main diseases: the adult T-cell leukemia/lymphoma (ATLL) and the HTLV-1 associated myelopathy/tropical spastic paraparesis, which are characterized by different immune phenotypes. While the ATLL is linked to an immunosuppressive state, the HAM/TSP is linked to a pro-inflammatory state in patients. The mechanisms contributing to the development of these two diseases in the HTLV-1 infected individuals are poorly understood. Type I interferon (IFN-I) has ambivalent functions in the organism. While this cytokine is an effector of early immune responses, several studies have reported a negative impact of this cytokine during chronic infections. The plasmacytoid dendritic cells (pDCs) are the main producers of IFN-I in vivo, and can produce high amounts of this cytokine after the recognition of virally infected cells. We have shown that pDCs are able to recognize HTLV-1-infected cells, thus leading to the production of IFN-I. pDCs’ triggering is mediated by the accumulated viral particles at the surface of the infected cells, within a carbohydrate-rich structure, previously described as the viral biofilm. The nature of the extracellular matrix itself seems to regulate IFN-I production by pDCs, since the exposition of an asialylated Galβ(1-3)GalNAc glycan at the surface of the HTLV-infected cells reduces the IFN-I production. We also observed that HTLV-2 (a close relative of HTLV-1)-infected cells, in contrast to HTLV-1-infected cells, tend to induce a lower production of IFN-I after being recognized by the pDCs but a greater maturation of the latter. Finally, we have shown that pDCs’ frequency in the blood and their ability to produce IFN-α after an ex vivo stimulation is equivalent in healthy donors, asymptomatic HTLV-1 carriers and HAM/TSP patients. This result contrasts with previous studies which demonstrated that blood circulating pDCs’ frequency is reduced in ATLL patients and that pDCs from HTLV-1 infected individuals have a reduced ability to produce IFN-α after stimulation. Thus, dysregulation of the frequency and functionality of pDCs could contribute to the development of one disease or the other.

Embora o vírus linfotrópico de células T humanas do tipo 1 (HTLV-1) seja reconhecido como o agente etiológico da leucemia/linfoma de células T do adulto (ATL) e da paraparesia espástica tropical/mielopatia associada ao HTLV-1 (HAM/TSP), cerca de 90% dos indivíduos infectados permanecem assintomáticos por toda a vida. Até o presente momento, os fatores associados ao desenvolvimento de doença relacionada ao HTLV-1 não foram totalmente elucidados. Sabe-se que o aumento da carga proviral e a expressão de genes virais estão envolvidos no desenvolvimento/progressão de doenças associadas ao HTLV-1. Assim, por exemplo, a proteína Tax modula genes envolvidos na patogênese da HAM/TSP e genes regulados por HBZ estimulam a proliferação de linfócitos T, induzindo a ATL. Desde a última década, diversos estudos têm demonstrado que células transformadas pelo HTLV-1 apresentam microRNAs do hospedeiro desregulados, o que poderia promover alteração na expressão de genes virais (tax e HBZ), com possível contribuição para o desenvolvimento de HAM/TSP e ATL. Diante desses indícios, o presente estudo teve como objetivos: i) quantificar a expressão de miRNAs humanos conhecidos em células T CD4+ e T CD8+ do sangue periférico de indivíduos assintomáticos infectados por HTLV-1 e de pacientes com HAM/TSP; ii) identificar padrões diferenciais de expressão de miRNAs desregulados que pudessem caracterizar os grupos de pacientes de acordo com sua condição clínica; iii) investigar associações dos padrões diferenciais de expressão de miRNAs com a carga proviral e com a expressão dos genes tax e HBZ de HTLV-1. Analisou-se o perfil de expressão de 754 miRNAs em células T CD4+ e TCD8+ infectadas por HTLV-1 em 19 indivíduos assintomáticos, 17 pacientes com HAM/TSP e 14 controles não infectados. Foram detectados 10 miRNAs diferencialmente expressos no grupo HAM, quando comparados ao grupo ASS (super-expressos: hsa-miR-133a, -148a, -211, -330, -369-5p, -486 e -889 e sub-expressos: hsa-miR-520b, -520e e -566). A expressão alterada dos hsa-miR-133a, -148a, -211, e -889 (super-expressos) e do hsa-miR-520b (sub-expresso) foi correlacionada à carga proviral e a do hsa-miR-211 (super-expresso) à expressão de tax. Além disso, ao analisar as vias canônicas geradas no estudo, identificaram-se as moléculas IL6ST, PTPN11, MAP2K5, ELK4, AKT1, BAD, FOSL1, IRAK 3, CDC42, STAT3 e CREB A como potencialmente afetadas pela expressão alterada de miRNAs no grupo HAM, quando comparado com o grupo ASS. Tais achados mostram-se úteis para o delineamento futuro de estudos longitudinais com indivíduos infectados por HTLV-1, com vistas à identificação de biomarcadores prognósticos de risco para o desenvolvimento de HAM/TSP. / Even though human lymphotropic virus type 1 (HTLV-1) is etiologically linked to adult T-cell leukemia (ATL) and to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), about 90% of infected individuals remain asymptomatic lifelong. So far, factors that are associated with development of HTLV-1-related disease have not been totally clarified. Increase in proviral load and expression of viral genes are recognized as involved in disease development and progression. For instance, the Tax protein is known to modulate genes that are involved in HAM/TSP pathogenesis and HBZ-regulated genes account for T lymphocyte proliferation that leads to ATL. In the last decade, several studies have shown that HTLV-1-transformed cells exhibit dysregulated human microRNA expression, which could result in altered viral gene expression (tax and HBZ), contributing to the development of HAM/TSP and ATL. Based on this evidence, our study aimed at: i) quantifying known human miRNA expression in CD4+ and CD8+ peripheral blood T-cells from HTLV-1 asymptomatic carriers and patients with HAM/TSP; ii) identifying distinctive dysregulated miRNA expression profiles that could distinguish patients according to their clinical status; iii) investigating associations between differential miRNA expression profiles with proviral load and with HTLV-1 tax and HBZ gene expression. We analysed the expression profile of 754 miRNAs in CD4+ e CD8+ peripheral blood T cells from 19 HTLV-1 asymptomatic carriers (AC), 17 patients with HAM/TSP (HAM) and in 14 non-infected controls. Ten differentially expressed miRNAs were found in HAM, as compared with AC (overexpressed: hsa-miR-133a, -148a, -211, -330, -369-5p, -486 and -889; and underexpressed: hsa-miR-520b, -520e and -566). Altered expression of hsa-miR-133a, -148a, -211, and -889 (overexpressed) and of hsa-miR-520b (underexpressed) was shown to be correlated with proviral load and that of hsa-miR-211 (overexpressed) with tax expression. Moreover, analysing the miRNA canonical pathways generated in this study, we identified IL6ST, PTPN11, MAP2K5, ELK4, AKT1, BAD, FOSL1, IRAK 3, CDC42, STAT3 and CREB A as molecules that are potentially affected by altered miRNA expression in HAM, as compared to AC. Our findings are useful for the future design of longitudinal studies of HTLV-1 infected cohorts, aiming at the recognition of prognostic biomarkers of risk for the development of HAM/TSP