Anti-CD20–mediated B-cell depletion in autoimmune diseases: successes, failures and future perspectives

Crickx, Étienne; Weill, Jean‐Claude; Reynaud, Claude‐Agnès; Mahévas, Matthieu

doi:10.1016/j.kint.2019.12.025

Cited by 43 publications

(46 citation statements)

References 110 publications

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“…This work extends [45][46][47][48] our knowledge of autoreactive IgG-SC in human ITP. We demonstrate the homogenous dissemination of platelet autoreactive ASC into multiple anatomical compartments that could explain splenectomy failure in some patients.…”

Section: Discussionsupporting

confidence: 67%

Single-cell analyses of immune thrombocytopenic patients reveal multiorgan dissemination of high-affinity autoreactive plasma cells

Herrerias

Crickx

Broketa

et al. 2021

Preprint

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The major therapeutic goal for immune thrombocytopenia (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. 80% of patients possess anti-integrin αIIbβ3 (GPIIbIIIa) IgG autoantibodies causing 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 ~50% of patients to recover a normal platelet count after anti-CD20 Rituximab-mediated B cell depletion and splenectomy suggest that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SC) reside in other anatomical compartments. We analyzed >3,300 single IgG-SC from spleen, bone marrow and/or blood of 27 patients with ITP revealing high inter-individual variability in affinity for GPIIbIIIa with variations over 3 logs. IgG-SC dissemination and range of affinities were however similar per patient. Longitudinal analysis of autoreactive IgG-SC upon treatment with anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti-GPIIbIIIa IgG-SC 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.

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Section: Discussionsupporting

confidence: 67%

Single-cell analyses of immune thrombocytopenic patients reveal multiorgan dissemination of high-affinity autoreactive plasma cells

Herrerias

Crickx

Broketa

et al. 2021

Preprint

Self Cite

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“…These nonproliferating plasma cells lacking CD19 and CD20 markers provide the basis for humoral memory and refractory autoimmune diseases. They may explain the limited rate of sustained complete remission in patients treated with rituximab [30]. Because these cells are targeted by anti-CD38 antibodies, the results of ongoing trials using anti-CD38 antibodies are eagerly awaited.…”

Section: Improving the Use Of Anti-cd20 Antibodiesmentioning

confidence: 99%

Advances in Membranous Nephropathy

Ronco

Plaisier

Dębiec

2021

JCM

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Membranous nephropathy (MN) is a rare auto-immune disease where the glomerulus is targeted by circulating auto-antibodies mostly against podocyte antigens, which results in the formation of electron-dense immune complexes, activation of complement and massive proteinuria. MN is the most common cause of nephrotic syndrome in adults leading to severe thrombotic complications and kidney failure. This review is focused on the recent therapeutic and pathophysiological advances that occurred in the last two years. For a long time, we were lacking a head-to-head comparison between cyclophosphamide considered as the gold standard therapy and other medications, notably rituximab. Substantial progress has been achieved owing to three randomized controlled trials. MENTOR (Membranous Nephropathy Trial of Rituximab) and STARMEN (Sequential Therapy with Tacrolimus and Rituximab in Primary Membranous Nephropathy) conclusively established that calcineurin inhibitor-based regimens are slower to result in an immunologic response than rituximab or cyclophosphamide, achieve fewer complete clinical remissions, and are less likely to maintainremission. Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO) suggested that competition between cyclophosphamide and rituximab remains open. Given the technological leapcombining laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins, four “new antigens” were discovered including NELL-1 and Semaphorin 3B in so-called primary MN, and exostosins 1 and 2 and NCAM 1 in lupus MN. NELL-1 is associated with about 8% of primary MN and is characterized by segmental immune deposits and frequent association with cancer (30%). Semaphorin 3B-associated MN usually occurs in children, often below the age of two years, where it is the main antigen, representing about 16% of non-lupus MN in childhood. Exostosins 1/2 and NCAM 1 are associated with 30% and 6% of lupus MN, respectively. Exostosins 1/2 (EXT1/2) staining is associated with a low rate of end-stage kidney disease (ESKD) even in mixed classes III/IV+V. These findings already lead to revisiting the diagnostic and therapeutic algorithms toward more personalized medicine.

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“…The diagnosis of autoimmune diseases often relies on the identification of characteristic autoantibody profiles, emphasizing their association with the activation of autoreactive B cells. Furthermore, B cell depletion therapy can have beneficial effects in patients with these disorders 1 , highlighting the importance of B cells in the pathogenesis of autoimmune diseases. In autoimmune diseases B cells have been regarded almost exclusively for their role in autoantibody production, although we now know that they also mediate deleterious functions through antibody-independent activities, including: the presentation of antigen to T cells, co-stimulatory functions via the expression of accessory molecules engaging stimulatory receptors on T cells and the production of cytokines 2 .…”

mentioning

confidence: 99%