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

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 α IIb β 3 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 α IIb β 3, 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– α IIb β 3 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.

Regulation of CD8 T cell by B-cells: A narrative review

“…Response to B-cell depletion with Rituximab is frequent but inconsistent (~60%). One current explanation is that Rituximab refractoriness is characterized by the persistence of long-lived autoreactive plasma cells in the spleen and in other sites, the emergence of which may even be promoted by B-cell depletion itself ( 12 , 13 ). However, alternative and nonexclusive mechanisms may be involved.…”

Antibodies as drugs—a Keystone Symposia report

“…All three compartments produced autoreactive antibodies with low, medium, and high affinities, though there was significant variability between patients in both the level of antibody‐producing cells and the distribution of antibody affinity. Treatment with the anti‐CD38 antibody daratumumab for the depletion of antibody‐secreting cells led to ITP remission in some patients, but no others 38 . Bruhns's group, in collaboration with Matthieu Mahévas’ group (Institut Necker Enfants Malades, Paris, France) is now investigating clonal relationships between high‐affinity autoreactive cells from different organs in these patients.…”

“…Treatment with the anti-CD38 antibody daratumumab for the depletion of antibody-secreting cells led to ITP remission in some patients, but no others. 38 Bruhns's group, in collaboration with Matthieu Mahévas' group (Institut Necker Enfants Malades, Paris, France) is now investigating clonal relationships between high-affinity autoreactive cells from different organs in these patients. Matteo Broketa from Bruhns's group presented unpublished work using DropMap to characterize the affinities of SARS-CoV-2 RBD-specific antibody-secreting cells after vaccination, in collaboration with the Mahévas group.…”

Daratumumab for the treatment of refractory ANCA-associated vasculitis

“…Different approaches have been investigated in order to specifically target plasma cells in autoantibody-mediated diseases such as immunoablation followed by autologous stem cell transplantation 5 or the proteasome inhibitor bortezomib. 6 7 The monoclonal anti-CD38 antibody daratumumab, licensed for use in multiple myeloma, also depletes non-malignant plasma cells and its successful use has been reported in cases of refractory autoimmune haemolytic anaemia, 8 autoimmune encephalitis, 9 immune thrombocytopenia 10 and systemic lupus erythematosus (SLE). 11 Here we report two cases of refractory AAV successfully treated with daratumumab.…”