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High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura
Pablo Canales-Herrerias, … , Matthieu Mahevas, Pierre Bruhns
Pablo Canales-Herrerias, … , Matthieu Mahevas, Pierre Bruhns
Published May 3, 2022
Citation Information: J Clin Invest. 2022;132(12):e153580. https://doi.org/10.1172/JCI153580.
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Research Article Autoimmunity Article has an altmetric score of 11

High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura

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Abstract

The major therapeutic goal for immune thrombocytopenic purpura (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. Eighty percent of patients with ITP possess anti–integrin αIIbβ3 IgG autoantibodies that cause platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in approximately 50% of patients to recover a normal platelet count after anti-CD20 rituximab-mediated B cell depletion and splenectomy suggests that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SCs) reside in other anatomical compartments. We analyzed more than 3,300 single IgG-SCs from spleen, bone marrow, and/or blood of 27 patients with ITP, revealing high interindividual variability in affinity for αIIbβ3, with variations over 3 logs. IgG-SC dissemination and range of affinities were, however, similar for each patient. Longitudinal analysis of autoreactive IgG-SCs upon treatment with the anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti–αIIbβ3 IgG-SCs in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.

Authors

Pablo Canales-Herrerias, Etienne Crickx, Matteo Broketa, Aurélien Sokal, Guilhem Chenon, Imane Azzaoui, Alexis Vandenberghe, Angga Perima, Bruno Iannascoli, Odile Richard-Le Goff, Carlos Castrillon, Guillaume Mottet, Delphine Sterlin, Ailsa Robbins, Marc Michel, Patrick England, Gael A. Millot, Klaus Eyer, Jean Baudry, Matthieu Mahevas, Pierre Bruhns

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Figure 2

Autoreactive ASCs with high and low affinity are present in the spleen, blood, and bone marrow (BM) of patients with ITP.

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Autoreactive ASCs with high and low affinity are present in the spleen, ...
(A) IgG secretion rate and (B) affinity for αIIbβ3 of single ASCs from pooled data of patients with ITP and healthy donors (HD) for spleen (ITP, n = 14; HD, n = 6), BM (ITP, n = 17; HD, n = 4), and blood (ITP, n = 14; HD, n = 10). Single-cell values and medians are plotted. Total numbers of IgG-SCs analyzed per compartment are indicated in A. In B, affinities are classified into high (red), medium (orange), and low (yellow) affinity, with dotted lines separating these categories. (C) Frequency of αIIbβ3-reactive IgG-SCs among mononuclear cells (MCs) classified into high, medium, and low affinity from patients (ITP) and HD according to B. (D–F) Frequency of αIIbβ3-reactive IgG-SCs among MCs classified into high, medium, and low affinity represented for individual patients (ITP) and HD for (D) spleen, (E) BM, and (F) blood. (D–F) The dotted line marks the highest frequency found in an HD. **P < 0.01; ****P < 0.0001 using post hoc contrast analysis after linear (A and B) or logistic (C) modeling and multiple-testing P-value adjustment. NS, not significant. See Supplemental Table 2 for further details.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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