Immunopathologie de la Maladie de Castleman Multicentrique associée à l'infection par HHV-8. Altérations des Cellules iNKT et Lymphocytes B

Abstract : Human Herpesvirus-8 is a B-lymphotropic \γ-herpesvirus closely related to the Epstein-Barr virus (EBV). He is specifically associated with monotypic (IgM/λ) plasmablasts in Multicentric Castleman disease (HHV-8 MCD), which is a B lymphoproliferative disorder. These cells express transcription factors suggesting they are at the plasmablast or pre-pasma cell stage of differentiation. Invariant natural killer T (iNKT) cells are innate-like T cells that play a role in antiviral immunity, specifically in controlling viral replication in EBV-infected B cells. Decline of iNKT cells is associated with age or HIV infection, both situations associated with HHV-8-related diseases. We demonstrated that iNKT cell abnormalities are associated with HHV-8 MCD. These iNKT cell alterations were found to be associated with an imbalance in the frequency of circulating and splenic B cell subsets, and results of Coculturing experiments indicate that iNKT cells may be required for maintaining this cell population. In the second part of our work thesis, we demonstrate that HHV-8 MCD is associated with a unique population of circulating plasmablasts detected during the flare of the disease, with the typical phenotype of the MCD HHV-8-infected plasmablasts in MCD lesions. Then, we used gene expression profile analysis (about 48 000 genes) to further define the phenotype of this MCD HHV-8-infected cells and to investigate the lymphoma relationship to normal B cell subpopulations. The results showed that MCD HHV-8-infected cells displayed a common gene expression profile that is clearly distinct from all the normal B cell subpopulations. The gene expression profile of MCD HHV-8-infected cells was defined as plasmablastic. Moreover, the transcriptomic pattern of MCD HHV-8-infected cells demonstrates that these cells are proliferating and escaping the immune system. Finally, we determined the clonality and the cellular origin of the monotypic circulating plasmablasts by studying the rearranged immunoglobulin heavy genes in LANA+ HHV-8-infected B cells from patients with HHV-8 MCD. Our results show that these cells are polyclonal without somatic mutation. Altogether our results allowed us to elaborate a model of MCD physiopathology.
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Zineb Sbihi. Immunopathologie de la Maladie de Castleman Multicentrique associée à l'infection par HHV-8. Altérations des Cellules iNKT et Lymphocytes B. Immunologie. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066221⟩. ⟨tel-02298576⟩

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