The emergence of circulating activated autoreactive desmoglein 3-specific follicular regulatory T cells is associated with long-term efficacy of rituximab in patients with pemphigus vulgaris.
Br J Dermatol
; 191(4): 605-615, 2024 Sep 18.
Article
em En
| MEDLINE
| ID: mdl-38848544
ABSTRACT
BACKGROUND:
Pemphigus vulgaris (PV) is characterized by autoantibodies targeting keratinocyte adhesion proteins desmoglein (Dsg) 1 and 3, and by the human leukocyte antigen (HLA) predisposition allele HLA-DRB1*0402. Treatment using rituximab (RTX) combined with short-term corticosteroids (CS) allows disease control and long-lasting remission.OBJECTIVES:
The principal aim of this study was to evaluate the impact of RTX on the circulating subpopulations of Dsg3-specific T lymphocytes that specifically regulate B-cell responses follicular helper T (Tfh) and follicular regulatory T (Tfr) lymphocytes.METHODS:
Using the HLA-DRB1*0402 tetramer loaded with the Dsg3 immunodominant peptide, we used flow cytometry to analyse the frequency, polarization and activation status of blood Dsg3-specific follicular T-cell populations at baseline, month (M) 6 and long-term follow-up (M60-90) from patients with PV.RESULTS:
At baseline, we observed a predominance of Tfh1* and Tfh17 subsets and an underrepresentation of the Tfh2 subset among autoreactive Dsg3-specific Tfh cells compared with nonautoreactive Tfh cells. RTX treatment induced a decrease of autoreactive Tfh cells with no effect on their polarization during follow-up. In parallel, we observed the emergence of a Dsg3-specific Tfr subpopulation with a significant overexpression of the surface activation markers PD1, ICOS and CD25 that was not observed at the surface of autoreactive Tfh and nonautoreactive Tfr cells of the same patients with PV. In contrast, very few Dsg3-specific Tfr cells were observed in patients with PV who were treated with CS alone.CONCLUSIONS:
Here we show that the emergence of circulating autoreactive Dsg3-specific Tfr cells is associated with the long-term efficacy of RTX in patients with PV.
Pemphigus vulgaris (PV) is an autoimmune disease mediated by pathogenic antibodies directed against the body's own tissues (called autoantibodies). In this condition, autoantibodies bind to and inhibit a protein called desmoglein 3 (Dsg3), which is responsible for the adhesion of keratinocytes (cells that make up the superficial layers of the skin and mucous membranes). As a result, PV causes painful blistering. People with PV are commonly treated with low doses of oral corticosteroids (prednisone) and rituximab (administered via infusions), which have significantly improved patient outcomes. Rituximab temporarily (for 69 months) depletes B lymphocytes, which are immune cells that differentiate into cells producing anti-Dsg3 antibodies. While autoimmune diseases can be lifelong, this study looked at why some people achieve long-lasting remissions without ongoing treatment, even after the return of B lymphocytes. We analysed anti-Dsg3 follicular T cells, which regulate B-cell differentiation. Among these, we observed the emergence of regulatory (or inhibiting) T cells over time following treatment, accompanied by a decrease in conventional (or activating) follicular T cells. We also found that these autoimmune follicular regulatory T cells were more activated compared with conventional follicular T cells or other T cells not directed against the Dsg3 protein. Overall, our findings suggest that the emergence of these follicular regulatory T cells may be responsible for the sustained remission observed in some people with PV and could be promoted by the use of rituximab.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autoanticorpos
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Pênfigo
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Linfócitos T Reguladores
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Desmogleína 3
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Rituximab
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article