16 research outputs found
The role of invariant natural killer T (iNKT) cells in bone omoiostasis and in multiple myeloma bone disease
Increased expression of RANKL on osteoblasts and T cells is central for osteoclast activation and development of bone disease in multiple myeloma. We tested the hypothesis that iNKT cells, a CD1d-restricted, glycolipid-specific subset of potent immunoregulatory T cells, are also an important source of RANKL in the myeloma microenvironment. First we established that iNKT cells ex vivo isolated from normal individuals express mRNA and membrane-bound RANKL at a significantly higher level than conventional T cells. Notably, iNKT cells upregulate surface RANKL more efficiently than T cells under activating conditions and their supernatants generate osteoclasts more efficiently under limiting conditions. Similarly, blood and bone marrow iNKT cells from myeloma patients express higher surface RANKL than conventional T cells and at a higher level compared to iNKT cells from age-matched controls. Interestingly, compared to PB, iNKT cells are enriched in the bone marrow of patients with myeloma and they upregulate surface RANKL, thus showing a tissue-specific effect. Finally, in MM patients but not in normal controls, iNKT RANKL expression correlates with β-C-terminal telopeptide, a sensitive and specific marker of bone resorption. We propose that increased RANKL expression defines an acquired, myeloma-specific dysfunctional iNKT cell phenotype that may contribute to osteoclast activation and myeloma bone disease.Η αυξημένη έκφραση της κυτταροκίνης RANKL στους οστεοβλάστες και τα Τ λεμφοκύτταρα είναι ουσιώδης για την ενεργοποίηση των οστεοκλαστών και την ανάπτυξη της οστικής νόσου του πολλαπλού μυελώματος. Στην παρούσα εργασία, ερευνήσαμε το ρόλο των iNKT λεμφοκυττάρων, μιας υποομάδας ισχυρών ανοσορρυθμιστικών, CD1d-εξαρτώμενων και ειδικών για λιπιδικά αντιγόνα Τ λεμφοκυττάρων, στην παραγωγή RANKL στο μικροπεριβάλλον του πολλαπλού μυελώματος. Αρχικά, αποδείξαμε ότι ex vivo τα iNKT λεμφοκύτταρα φυσιολογικών ατόμων εκφράζουν περισσότερο RANKL, τόσο σε επίπεδο mRNA όσο και σε πρωτεϊνικό επίπεδο, απ’ότι τα συμβατικά Τ λεμφοκύτταρα. Επιπρόσθετα, τα iNKT λεμφοκύτταρα αυξάνουν την παραγωγή RANKL μετά από ανοσοδιέγερση σε μεγαλύτερο βαθμό από τα Τ λεμφοκύτταρα ενώ έχουν την δυνατότητα να προάγουν το σχηματισμό οστεοκλαστών πιο αποτελεσματικά κάτω από περιοριστικές συνθήκες καλλιέργειας. Ομοίως, τα iNKT λεμφοκύτταρα από το περιφερικό αίμα και το μυελό των οστών ασθενών με πολλαπλούν μυέλωμα εκφράζουν επιφανειακό RANKL σε υψηλότερο ποσοστό απ΄ ότι τα Τ λεμφοκύτταρα αλλά και από iNKT λεμφοκύτταρα υγιών δοτών παρόμοιας ηλικίας. Αξιοσημείωτη είναι η παρατήρηση ότι, σε σχέση με το περιφερικό αίμα, τα iNKT λεμφοκύτταρα βρίσκονται σε αυξημένες συγκεντρώσεις στο μυελό των οστών όπου συμβάλλουν αποτελεσματικότερα στην παραγωγή RANKL, καταδεικνύοντας ένα ειδικό για το μυελό των οστών φαινόμενο. Τέλος, σε ασθενείς με πολλαπλούν μυέλωμα αλλά όχι σε υγιείς δότες, η έκφραση του RANKL στα iNKT λεμφοκύτταρα σχετίζεται στατιστικά με τα επίπεδα βCTx του ορού, έναν ειδικό και ευαίσθητο δείκτη οστικής απορρόφησης. Τα παραπάνω ευρήματα υποδεικνύουν ότι η αυξημένη έκφραση RANKL καθορίζει έναν επίκτητο, ειδικό για το μυέλωμα δυσλειτουργικό φαινότυπο των iNKT λεμφοκυττάρων, ο οποίος πιθανόν να συμβάλλει στην ενεργοποίηση των οστεοκλαστών και την οστική νόσο του πολλαπλού μυελώματος
Natural history of chronic hepatitis B virus infection in children of different ethnic origins: A cohort study with up to 12 years' follow-up in northern Greece
Aim: To investigate the mode of transmission and the natural history of
chronic hepatitis B virus (HBV) infection in children of different
ethnicities in Greece. This study was part of the Interreg I-II EC
project.
Patients and Methods: One hundred seventy-three hepatitis B surface
antigen (HBsAg)(+) carriers, median age 6.9 (5-12) y, were prospectively
followed-up for a mean period of 5.3 (1-12) y for serological markers of
HBV infection, serum alanine aminotransferase (ALT), HBV-DNA,
(x-fetoprotein levels and ultrasonography.
Results: Vertical transmission predominates (61.8%) in Moslem children
and horizontal (44%) in those born in Russia. At entry, 73 of 173
(42%) HBsAg(+) genotype D children were hepatitis B e antigen
(HBeAg)(+), ranging from 27% to 67% among ethnic groups; 55 of 173
(32%) had ALT > 2 x upper normal limit (UNL), ranging from 21% to
39%. Of 100 anti-HBe(+) children, 85 (85%) were inactive carriers.
During the follow-up period, seroconversion to anti-HBe was observed in
40 of 73 (55%) children with an annual rate of 11%; 35 of 40 (87.5%)
had biochemical remission, and 28 of 35 (80%) lost HBV-DNA. In the
anti-HBe(+) group, 27 of 100 (27%) lost HBV-DNA and 9 of 100 (9%) lost
HBsAg. The annual seroconversion rate for HBeAg was significantly lower:
in children with vertical transmission compared with horizontal (7.7%
vs 14.8%, respectively, P < 0.001) and in Muslim children compared with
both Christian children and those born in Russia (8.6% vs 12%,
respectively, P < 0.001). No differences were found among the ethnic
groups after adjusting for the mode of infection. Two of 173 children
had progression of liver disease.
Conclusions: The differences in HBeAg(+) status and seroconversion rate
among the ethnic groups are related to the time/mode of HBV infection.
The majority of children who developed anti-HBe immunity had biochemical
remission, and a substantial number of the inactive carriers lost
viremia during the observation period of up to 12 y
THE JAK2V617F POINT MUTATION INCREASES THE OSTEOCLAST FORMING ABILITY OF MONOCYTES IN PATIENTS WITH CHRONIC MYELOPROLIFERATIVE NEOPLASMS AND MAKES THEIR OSTEOCLASTS MORE SUSCEPTIBLE TO JAK2 INHIBITION
P706: RESISTANCE TO HYPOMETHYLATING AGENTS (HMA) IN HIGH-RISKMYELODYSPLASTIC SYNDROME (HR-MDS): THE ROLE OF THE ADENOSINEDEAMINASE ACTING ON RNA 1 (ADAR1) ENZYME
Over-expression of RANKL in invariant NKT cells is characteristic of active myeloma but not of MGUS or asymptomatic myeloma
Over-expression of RANKL in invariant NKT cells is characteristic of active myeloma but not of MGUS or asymptomatic myeloma
Common cardiovascular biomarkers can independently predict outcome of patients with Myelodysplastic syndromes
Risk factors for cardiovascular disease mortality in patients with myelodysplastic syndromes: A nationwide, registry‐based cohort study
Abstract Cardiovascular disease (CVD) emerges as a major cause of death in patients with myelodysplastic syndrome (MDS), but predictors of fatal CVD and the effect of MDS‐specific treatments on CVD mortality remain largely unknown. In an analysis involving 831 patients with MDS with known causes of death, we noted an independent association of lower risk MDS, age >70 years, pre‐existing CVD, and treatment with erythropoiesis‐stimulating agents with a higher risk of death from CVD. If externally validated, these simple risk factors could increase clinicians’ awareness toward CVD complications and guide early introduction of intensive monitoring and preventive interventions in MDS patients