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Teramo, Antonella (2009) Meccanismi patogenetici della malattia linfoproliferativa dei linfociti granulati. [Tesi di dottorato]

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Abstract (inglese)

The lymphoproliferative disease of granular lymphocytes (LDGL) is a rare disease characterized by chronic proliferation of granular lymphocytes (GLs). According to the immunologic analysis, the proliferating lymphocytes belong to the T cell lineage, T-LDGL (CD3+), or are represented by natural killer cells, NK-LDGL (CD3- CD16+).
The pathogenesis of this disorder is still a matter of debate.
To better define its pathogenetic mechanisms, still a matter of debate, in our laboratory several lines of investigation have been pursued both on T and NK LDGLs.
Regarding NK-LDGL, we studied the Killer Immunoglobulin-like Receptors (KIRs) expressed on the surface of NK-cells. By PCR on genomic DNA, we found an higher presence of activating KIR genes in LDGL patients as compared to controls. This result suggested that a genetic predisposition would exist. In agreement with this result, our preliminary data indicated the tendency of patients to express the activating gene KIR3DS1 rather than the equivalent inhibitory KIR3DL1. When we evaluated if DNA methylation could be responsible of KIR3DL1 silencing, we found an altered methylation of KIR3D1 promoter, that explained the silencing of KIR3DL1 in the GLs.
Regarding T-LDGL, we examined the molecular pathway JAK/STAT (Janus kinase/signal transductor and transcription activator). It is reported in literature that GLs of T-LDGL patients present high levels of activated STAT3. Considering these findings, by Real Time-PCR, we evaluated the expression pattern of SOCS3 protein, i.e. the principal STAT3 inhibitor. We found that in pathological cells SOCS3 exhibited low mRNA levels, as commonly occurs in quiescent cells where STAT3 is expressed at low levels. Moreover, SOCS3 resulted unable to increase its expression after IL-6 stimulus, showing a defect on regulatory mechanisms of JAK/STAT pathway.
Finally, our previous observations, by flow cytometry analysis, that DCs of a small group of LDGL patients overexpressed the chemokine CXCL16, mostly in bone marrow, prompted us to investigate the putative function of this chemokine in LDGL and the role of its receptor CXCR6, expressed by GLs, in DC-GL cross-talk. The data obtained on a large group of patients confirmed the high expression of this chemokine in bone marrow, demonstrating its positive influence on the prolonged survival of GLs. Moreover, by confocal microscopy, we found CXCL16 with its receptor CXCR6 in the contact site between DC and GL, suggesting an important role of CXCL16 in DCs activity and DC-GL cross-talk.
Overall, these results confirm and complete our previously published data and contribute to get new insights into the pathogenesis and development of LDGL.

Abstract (italiano)

La malattia linfoproliferativa dei linfociti granulati (LDGL) è una malattia rara caratterizzata da una linfocitosi cronica dei linfociti granulati (GL). Da un punto di vista immunologico, si distinguono due forme di LDGL, la T-LDGL, caratterizzata dalla proliferazione di GL CD3+ CD16+, e la NK-LDGL caratterizzata dalla proliferazione di GL CD3- CD16+.
L’eziopatogenesi della LDGL rimane attualmente materia di dibattito.
Per quanto riguarda la NK-LDGL, un primo oggetto di studio sono stati i Killer Immunoglobulin-like Receptor (KIR). Tramite PCR su DNA, abbiamo rilevato nei pazienti un’aumentata presenza di geni KIR attivatori rispetto ai controlli sani e la presenza di genotipi KIR caratteristici dei pazienti. I risultati ottenuti hanno evidenziato nei pazienti una predisposizione genica alla malattia.
In linea con questo risultato, i nostri dati preliminari indicavano la tendenza dei pazienti ad esprimere il recettore attivatorio KIR3DS1 rispetto al corrispondente inibitorio KIR3DL1. Abbiamo quindi indagato se il principale meccanismo epigenetico dell’espressione genica, la metilazione, fosse responsabile dello sbilanciamento a favore dell’espressione del recettore KIR3DS1 attivatore su quello inibitore 3DL1 nei GL dei pazienti. I risultati hanno rilevato un’alterazione della metilazione che risulta nella tendenza dei GL patologici a silenziare in maniera molto intensa il KIR3DL1.
Nell’ambito della LDGL sostenuta dalle cellule T, abbiamo preso in esame il pathway molecolare JAK/STAT (Janus chinasi/trasduttore di segnale e attivatore di trascrizione). È riportato in letteratura che i GL dei pazienti hanno alti livelli d’espressione di STAT3 in forma attivata. L’obiettivo è stato quello di analizzare, tramite Real Time-PCR, il pattern d’espressione della proteina SOCS3, principale inibitore di STAT3. I risultati hanno indicato che la proteina SOCS3 nei GL patologici, non solo esibisce bassi livelli di mRNA, come avviene nelle cellule quiescenti dove STAT3 risulta poco espresso, ma dimostra anche di non essere in grado di aumentare i propri livelli di mRNA in risposta allo stimolo dell’IL-6, manifestando una mancanza d’efficienza dei meccanismi regolatori del pathway JAK/STAT nei pazienti.
Un ultimo obiettivo di ricerca che coinvolge entrambe le forme di LDGL, si è sviluppato dal riscontro, tramite osservazione citofluorimetrica, di una peculiare over-espressione di CXCL16 sulle DC di un piccolo gruppo di pazienti, soprattutto a livello midollare. Lo scopo è stato, quindi, quello di indagare una possibile funzione di questa chemochina nella LDGL e quello di verificare il suo coinvolgimento, insieme al suo recettore CXCR6 presente sui GL, nel cross-talk tra DC e GL. I dati raccolti hanno confermato su un ampio gruppo di pazienti la elevata espressione di questa chemochina a livello midollare e la sua positiva influenza sul prevenire l’apoptosi dei GL. Inoltre, tramite osservazioni al microscopio confocale, abbiamo rilevato la sua localizzazione con CXCR6 nel sito di contatto tra DC e GL suggerendo che le DC giochino il loro ruolo chiave nella LDGL tramite CXCL16.
L’insieme dei risultati prodotti durante questo progetto di ricerca sono in linea con i dati precedentemente pubblicati dal nostro gruppo e contribuiscono a definire nuovi aspetti nella comprensione della patogenesi e del decorso della LDGL.

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Tipo di EPrint:Tesi di dottorato
Relatore:Semenzato, Gianpietro
Correlatore:Zambello, Renato
Dottorato (corsi e scuole):Ciclo 21 > Corsi per il 21simo ciclo > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:30 Gennaio 2009
Anno di Pubblicazione:Febbraio 2009
Parole chiave (italiano / inglese):LDGL; KIR; STAT3; SOCS3; CXCL16; CXCR6.
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/15 Malattie del sangue
Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Medicina Clinica e Sperimentale
Codice ID:1701
Depositato il:30 Gen 2009
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