title: Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab.
abstract: Primary warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease in which red blood cells are eliminated by IgG autoantibodies. We analyzed the antibody-secreting cells in the spleen and the peripheral blood of wAIHA patients in various contexts of treatment. Plasmablasts were observed in peripheral blood of newly diagnosed wAIHA patients and, accordingly, active germinal center reactions were present in the spleen of patients receiving short-term corticosteroid therapy. Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro. In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive. By using a set of diagnostic genes that allowed us to assess the plasma cell maturation stage, we observed that these cells displayed a long-lived program, differing from the one of plasma cells from healthy donors or from wAIHA patients with various immunosuppressant treatments, and more similar to the one of normal long-lived bone-marrow plasma cells. Interestingly, an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients. These results suggest, in line with our previous report on primary immune thrombocytopenia, that the B-cell depletion induced by rituximab promoted a suitable environment for the maturation and survival of auto-immune long-lived plasma cells in the spleen.
authors.affiliation: Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine-Site Broussais, Paris, France; Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France; Etablissement Français du Sang, Ile de France, Institut Mondor Recherche Biomédicale, Inserm U955, équipe 2, Université Paris-Est Créteil, Créteil, France. Electronic address: matthieu.mahevas@hmn.aphp.fr.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Mahévas
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France; Etablissement Français du Sang, Ile de France, Institut Mondor Recherche Biomédicale, Inserm U955, équipe 2, Université Paris-Est Créteil, Créteil, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Michel
authors.affiliation: Etablissement Français du Sang, Ile de France, Institut Mondor Recherche Biomédicale, Inserm U955, équipe 2, Université Paris-Est Créteil, Créteil, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Vingert
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Moroch
authors.affiliation: Service d'Immunologie Clinique, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Boutboul
authors.affiliation: Service de Médecine Interne et d'immunologie Clinique, Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Audia
authors.affiliation: Plateforme Bio-informatique, Université Paris Descartes-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.affiliation: Etablissement Français du Sang, Ile de France, Institut Mondor Recherche Biomédicale, Inserm U955, équipe 2, Université Paris-Est Créteil, Créteil, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Ripa
authors.affiliation: INSERM U917, Université de Rennes 1, Hôpital Universitaire de Rennes, Rennes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Menard
authors.affiliation: INSERM U917, Université de Rennes 1, Hôpital Universitaire de Rennes, Rennes, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
authors.affiliation: Plateforme de cytométrie en flux, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Mégret
authors.affiliation: Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine-Site Broussais, Paris, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Le Gallou
authors.affiliation: Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine-Site Broussais, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Patin
authors.affiliation: Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine-Site Broussais, Paris, France.
authors.forename: Lan
authors.initials: L
authors.lastname: Thai
authors.affiliation: Service d'Immunologie Clinique, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Galicier
authors.affiliation: Service de Médecine Interne et d'immunologie Clinique, Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Bonnotte
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Godeau
authors.affiliation: Etablissement Français du Sang, Ile de France, Institut Mondor Recherche Biomédicale, Inserm U955, équipe 2, Université Paris-Est Créteil, Créteil, France.
authors.forename: France
authors.initials: F
authors.lastname: Noizat-Pirenne
authors.affiliation: Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine-Site Broussais, Paris, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Weill
authors.affiliation: Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine-Site Broussais, Paris, France.
authors.forename: Claude-Agnès
authors.initials: CA
authors.lastname: Reynaud
mesh_terms: D000328:Adult; D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000601:surgery; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity; D053264:B-Cell Activating Factor / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D000069283:Rituximab / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013156:Splenectomy; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D007155:Immunologic Factors; D000069283:Rituximab
keywords: Anti-CD20; Antibody-secreting cells; B-cell depletion; Long-lived plasma cells; Warm autoimmune hemolytic anemia