Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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MatthieuMAHEVAS

ABSTRACT: Splenic tissues from immune thrombocytopenia purpura (ITP) patients splenectomized after primary failure of treatment with the B-cell depleting agent rituximab were analyzed, and antibody-secreting cells were identified as the major B-cell population resisting the treatment. The phenotype, antibody specificity and gene expression profile of these cells were characterized and compared to antibody-secreting cells from untreated ITP spleens and from healthy tissues. Anti-platelet-specific plasma cells (PC) were detected in the spleen of ITP patients up to 6 months after rituximab treatment, and the PC population displayed a long-lived program similar to the one of bone marrow PC, thus explaining for most of these patients the absence of response to rituximab and the response to splenectomy. When analyzed by multiplex PCR at the singlecell level, normal splenic PC showed a markedly different gene expression profile, with an intermediate signature including genes characteristic of both long-lived PC and proliferating plasmablasts. Surprisingly, long-lived PC were not detected either in the inflammatory environment of the untreated ITP spleen. These results suggest that neither the normal nor the auto-immune splenic environment favors the differentiation and residence of long-lived PC, and that it is most probably the milieu generated by B-cell depletion that promotes their local settlement.

ORGANISM(S): Homo sapiens

SUBMITTER: Nicolas Cagnard

PROVIDER: E-MEXP-3711 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells.

Mahévas Matthieu M Patin Pauline P Huetz François F Descatoire Marc M Cagnard Nicolas N Bole-Feysot Christine C Le Gallou Simon S Khellaf Mehdi M Fain Olivier O Boutboul David D Galicier Lionel L Ebbo Mikael M Lambotte Olivier O Hamidou Mohamed M Bierling Philippe P Godeau Bertrand B Michel Marc M Weill Jean-Claude JC Reynaud Claude-Agnès CA

The Journal of clinical investigation 20121217 1

Primary immune thrombocytopenia (ITP) is a disorder caused by autoantibody-mediated platelet destruction and decreased platelet production. Rituximab, a B cell-depleting agent, has become the first-line treatment for ITP; however, patients with refractory disease usually require splenectomy. We identified antibody-secreting cells as the major splenic B cell population that is resistant to rituximab. The phenotype, antibody specificity, and gene expression profile of these cells were characterize ...[more]

PMID: 23241960

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Project description:Rituximab (RTX) is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Primary immune thrombocytopenia (ITP) is a prototypic B cell mediated autoimmune disease in which pathogenic antibodies directed against the platelet membrane glycoprotein IIb-IIIa (GPIIbIIIa) lead to platelet destruction by macrophages in the spleen. In ITP, RTX-mediated B-cell depletion leads to an immediate clinical response in 50% of patients but 80% of patients will subsequently relapse in the next following months. Patients failing to respond or relapsing after RTX treatment are splenectomized when alternative therapies are inefficient or unavailable. Therapeutic splenectomy, resulting in a durable platelet response in 60-70 % of ITP patients, offers a unique access to study the autoimmune response in the spleen. To understand the cellular basis of disease's relapse in secondary lymphoid organs in humans, memory B cells were sorted and analyzed by scRNAseq from the spleen of three different groups of splenectomized ITP patients: 1) Patients that achieved a complete response after a course of RTX and relapsed during B-cell reconstitution (hereafter referred to as “RTX relapse” patients), 2) patients with primary failure of RTX, i.e. who did not respond to treatment at the time of B-cell depletion (“RTX failure” patients), 3) patients with active ITP that were not treated with RTX (“ITP” patients). All were compared with sorted splenic memory B cells from organ donors with no immune disease who died from stroke or head trauma, hereafter referred to as healthy donors (“HD” patients). We also included in this analysis splenic memory B cells from children with sickle cell disease that underwent splenectomy and are known to have a high frequency of B cell activation secondary to classical childhood infections and vaccinations, reflected by an increased number of GC. Single-cell mRNA sequencing was performed according to an adapted version of the SORT-seq protocol (Muraro et al., 2016, Cell Systems 3, 385–394), with cDNA libraries generation, sequencing and reads alignment performed at Single Cell Discoveries (Utrecht, Netherlands).

Dataset Information

MatthieuMAHEVAS

Publications

B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells.

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