Objective: CD38 is a type II glycoprotein highly expressed on plasmablasts and on short- and long- lived plasma cells, but weakly expressed by lymphoid, myeloid, and non-hematopoietic cells. CD38 is a target for therapies aimed at depleting antibody-producing plasma cells. Systemic sclerosis (SSc) is an immune-mediated disease with a well-documented pathogenic role of B cells. We therefore analyzed CD38 expression in different subsets of peripheral blood mononuclear cells (PBMCs) from a cohort of SSc patients. Methods: Cell surface expression of CD38 was evaluated on PBMCs from SSc patients using eight- color flow cytometry analysis performed with a FacsCanto II (BD). Healthy individuals were used as controls (HC). Results: Forty-six SSc patients (mean age 60, range 23-79 years; 38 females and 8 males), and thirty- two age- and sex-matched HC were studied. Twenty-eight patients had the limited cutaneous form and eighteen the diffuse cutaneous form of SSc. The mean disease duration was 7 years. Fourteen patients were on immunosuppressive therapy (13 MMF, 5 RTX). The total percentages of T, B and NK cells were not different between SSc and HC. Compared to HC, SSc patients had higher levels of CD3+CD38+ T cells (p<0.05), higher percentage (p<0.001) of CD3+CD4+CD25+FOXP3+ regulatory T cells, lower percentage (p<0.05) of CD3+CD56+ NK cells. Moreover, SSc patients had higher levels of CD24highCD19+CD38high regulatory B cells than HC (p<0.01), while the amount of CD24+CD19+CD38+CD27+ memory B cells was lower (p<0.001). Finally, the percentages of circulating CD38highCD27+ plasmablasts and CD138+CD38high plasma cells were both higher in the SSc group than in HC (p<0.001). We did not observe any correlations between these immunophenotypes and disease subsets or duration, and ongoing immunosuppressive treatment. Conclusions: The increased expression of CD38 in peripheral blood plasmablasts and plasma cells of SSc patients may suggest this ectoenzyme as a candidate therapeutic target, under the hypothesis that depletion of these cells may beneficially downregulate the chronic immune response in SSc patients. Validation of this data in multicenter cohorts shall be obtained prior to clinical trials with existing anti- CD38 drugs.
Obiettivo: CD38 è una glicoproteina di tipo II altamente espressa sui plasmablasti e sulle plasmacellule, ma debolmente espressa dalle cellule linfoidi, mieloidi e non ematopoietiche. Il CD38 è un bersaglio per le terapie mirate alla deplezione delle plasmacellule produttrici di anticorpi. La sclerosi sistemica (SSc) è una malattia immuno-mediata con un ruolo patogenetico ben documentato delle cellule B. Abbiamo quindi analizzato l'espressione di CD38 in diversi sottoinsiemi di cellule mononucleate del sangue periferico (PBMC) da una coorte di pazienti con SSc. Metodi: L'espressione della superficie cellulare di CD38 è stata valutata su PBMC di pazienti con SSc utilizzando l'analisi della citometria a flusso a otto colori eseguita con un FacsCanto II (BD). Individui sani sono stati usati come controlli (HC). Risultati: Sono stati studiati quarantasei pazienti con SSc (età media 60 anni, range 23-79 anni; 38 femmine e 8 maschi) e trentadue HC abbinati per età e sesso. Ventotto pazienti avevano la forma cutanea limitata e diciotto la forma cutanea diffusa di SSc. La durata media della malattia è stata di 7 anni. Quattordici pazienti erano in terapia immunosoppressiva (13 MMF, 5 RTX). Le percentuali totali di cellule T, B e NK non erano diverse tra SSc e HC. Rispetto all'HC, i pazienti con SSc avevano livelli più elevati di cellule T CD3+CD38+ (p<0,05), percentuale più alta (p<0,001) di cellule T regolatorie CD3+CD4+CD25+FOXP3+, percentuale inferiore (p<0,05) di cellule T regolatorie CD3+ cellule NK CD56+. Inoltre, i pazienti con SSc avevano livelli più elevati di cellule B regolatorie CD24highCD19+CD38high rispetto a HC (p<0,01), mentre la quantità di cellule B di memoria CD24+CD19+CD38+CD27+ era inferiore (p<0,001). Infine, le percentuali di plasmablasti circolanti ad alto CD38+CD27+ e di plasmacellule ad alto CD138+CD38 erano entrambe più alte nel gruppo SSc che in HC (p<0,001). Non abbiamo osservato alcuna correlazione tra questi immunofenotipi e sottoinsiemi o durata della malattia e il trattamento immunosoppressivo in corso. Conclusioni: L'aumentata espressione di CD38 nei plasmablasti del sangue periferico e nelle plasmacellule dei pazienti con SSc può suggerire questo ectoenzima come bersaglio terapeutico, nell'ipotesi che la deplezione di queste cellule possa ridurre la risposta immunitaria cronica nei pazienti con SSc. E' necessario validare questi dati in coorti multicentriche prima di condurre sperimentazioni cliniche con i farmaci anti-CD38 esistenti.
Increased expression of the ectoenzyme CD38 in peripheral blood plasmablasts and plasma cells of patients with systemic sclerosis / Benfaremo, Devis. - (2023 Mar 27).
Increased expression of the ectoenzyme CD38 in peripheral blood plasmablasts and plasma cells of patients with systemic sclerosis
BENFAREMO, Devis
2023-03-27
Abstract
Objective: CD38 is a type II glycoprotein highly expressed on plasmablasts and on short- and long- lived plasma cells, but weakly expressed by lymphoid, myeloid, and non-hematopoietic cells. CD38 is a target for therapies aimed at depleting antibody-producing plasma cells. Systemic sclerosis (SSc) is an immune-mediated disease with a well-documented pathogenic role of B cells. We therefore analyzed CD38 expression in different subsets of peripheral blood mononuclear cells (PBMCs) from a cohort of SSc patients. Methods: Cell surface expression of CD38 was evaluated on PBMCs from SSc patients using eight- color flow cytometry analysis performed with a FacsCanto II (BD). Healthy individuals were used as controls (HC). Results: Forty-six SSc patients (mean age 60, range 23-79 years; 38 females and 8 males), and thirty- two age- and sex-matched HC were studied. Twenty-eight patients had the limited cutaneous form and eighteen the diffuse cutaneous form of SSc. The mean disease duration was 7 years. Fourteen patients were on immunosuppressive therapy (13 MMF, 5 RTX). The total percentages of T, B and NK cells were not different between SSc and HC. Compared to HC, SSc patients had higher levels of CD3+CD38+ T cells (p<0.05), higher percentage (p<0.001) of CD3+CD4+CD25+FOXP3+ regulatory T cells, lower percentage (p<0.05) of CD3+CD56+ NK cells. Moreover, SSc patients had higher levels of CD24highCD19+CD38high regulatory B cells than HC (p<0.01), while the amount of CD24+CD19+CD38+CD27+ memory B cells was lower (p<0.001). Finally, the percentages of circulating CD38highCD27+ plasmablasts and CD138+CD38high plasma cells were both higher in the SSc group than in HC (p<0.001). We did not observe any correlations between these immunophenotypes and disease subsets or duration, and ongoing immunosuppressive treatment. Conclusions: The increased expression of CD38 in peripheral blood plasmablasts and plasma cells of SSc patients may suggest this ectoenzyme as a candidate therapeutic target, under the hypothesis that depletion of these cells may beneficially downregulate the chronic immune response in SSc patients. Validation of this data in multicenter cohorts shall be obtained prior to clinical trials with existing anti- CD38 drugs. File | Dimensione | Formato | |
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