RESUMEN
Pemphigus are B-cell-mediated autoimmune diseases affecting skin and mucous membranes. They are characterized by the production of pathogenic autoantibodies directed against desmogleins (Dsg). In this prospective study, we treated 21 pemphigus patients with rituximab and analyzed immunological modifications induced by anti-CD20 immunotherapy. The total depletion of peripheral B cells led to a significant decrease of total serum IgM but not IgG levels. The B-cell depletion was followed by a progressive re-emergence of naive blood B lymphocytes, with one-third of them expressing a transitional CD19+CD38(high)CD24(high) phenotype. In most patients, clinical response to rituximab was closely related to the evolution of anti-Dsg autoantibodies that decreased in patients who achieved complete remission, whereas they remained unchanged or reincreased in relapsing patients. In contrast, serum antimicrobial IgG remained stable after rituximab treatment. B-cell repertoire analysis of three patients using immunoscope showed distortions of VH-IgM and VH-IgG immunoscope profiles before treatment, particularly clonal and oligoclonal expansions in some VH families, which were not found after B-cell reconstitution, following anti-CD20 immunotherapy. The depletion of autoreactive B cells leading to the elimination of anti-Dsg autoantibodies in most remitted patients and the restoration of a diverse B-cell repertoire by naive B lymphocytes may provide an explanation for the long-lasting efficacy of rituximab in pemphigus patients.
Asunto(s)
Linfocitos B/inmunología , Inmunoterapia/métodos , Pénfigo/inmunología , ADP-Ribosil Ciclasa 1/biosíntesis , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales de Origen Murino , Formación de Anticuerpos , Antígenos CD19/biosíntesis , Antígenos CD20/química , Antígeno CD24/biosíntesis , Citometría de Flujo , Humanos , Inmunoglobulina G/química , Inmunoglobulina M/química , Fenotipo , Polisacáridos/química , RituximabRESUMEN
Transitional B cells have been recently identified in human peripheral blood. However, their precise role in human B cell differentiation has not been established. Therefore, besides characterizing them further in the blood of healthy adults and children and cord blood, we used the immune reconstitution after hematopoietic stem cell transplantation (HSCT) model to define their role in human B cell development. Human transitional B cells are reliably identified as CD19(+) CD24(high) CD38(high) lymphocytes and represent approximately 4% of B cells in healthy adult peripheral blood. In contrast, they are abundant in cord blood (near 50% of B cells) and their percentage progressively decreases during infancy. Similarly, after HSCT, all B cells first appearing in peripheral blood are transitional B cells; afterwards, the transitional B cell percentage progressively decreases while the mature naïve B cell proportion rises. Our results now formally demonstrate that transitional B cells are necessary developmental intermediates for human mature B cell generation.