Intriguingly, large clones of pathogenic B cells persist in the blood of many MC patients long after the clearance of HCV infection by antiviral therapy ( 16), and probably underlie the HCV-independent relapses of vasculitis observed in a significant proportion of patients ( 8, 9). Phenotypically and functionally similar CD21 lowCD11c pos B cells accumulate in HIV infection ( 12), in Sjögren’s syndrome ( 13), in a subset of common variable immunodeficiency (CVID) ( 14), and in aged mice where they are called age-associated B cells ( 15). The pathogenic B cells of MC patients display a peculiar phenotype characterized by low expression of CD21 (CD21 low B cells), by atypical expression of CD11c and of an array of homing and inhibitory surface receptors, and by impaired BCR signaling also, proliferative responses to the triggering of BCR and of TLR9 are defective ( 10, 11). Nevertheless, cryoglobulins remain detectable in a substantial proportion of HCV-cured patients ( 6) and relapse of vasculitis occurs in about 12% of them ( 8), even many years after the clearance of virus and often in association with events characterized by increased production of immune complexes (ICs) such as infections or solid tumors ( 9). The strongest evidence for the dependence of these lymphoproliferative disorders on stimulation by HCV comes from the fact that the cure of infection with direct-acting antivirals (DAAs) leads in most patients to clinical improvement ( 6, 7). The specificity for HCV is indicated by sequence homologies with human antibodies recognizing the E2 envelope protein of the virus ( 3, 4), although the reactivity of antibodies cloned from HCV-associated lymphomas with E2 or other HCV proteins has not been demonstrated so far ( 5). These stereotyped BCRs are endowed with both rheumatoid factor (RF) activity and specificity for HCV. In both cases, monoclonal B cells express a restricted repertoire of stereotyped, or quasi-identical, B cell antigen receptors (BCRs) often encoded by the V H1-69/Vκ3-20 variable genes ( 3, 4). Hepatitis C virus (HCV) causes monoclonal B cell lymphoproliferative disorders that include type 2 mixed cryoglobulinemia (MC) ( 1) and non-Hodgkin lymphomas ( 2). BCR/TLR9 crosstalk might represent a more general mechanism enhancing systemic autoimmunity by the rescue of exhausted autoreactive CD21low B cells. Our findings indicate that autoantigen and CpG of microbial or cellular origin may unite to foster persistence of pathogenic RF B cells in HCV-cured MC patients. The signaling mechanism for this BCR/TLR9 crosstalk remains elusive, since TLR9 mRNA and protein as well as MyD88 mRNA were normally expressed and CpG-induced phosphorylation of p65 NF-kB was intact in MC clonal B cells, whereas BCR-induced p65 NF-kB phosphorylation was impaired and PI3K/Akt signaling was intact. TLR9 was quantified by qPCR and by intracellular flow cytometry, and MyD88 isoforms were analyzed using RT-PCR.ĭiscussion: We found that dual triggering with autoantigen and CpG restored the capacity of exhausted VH1-69pos B cells to proliferate. Phosphorylation of AKT and of the p65 NF-kB subunit were measured by flow cytometry. Methods: Clonal B cells from patients with HCV-associated type 2 MC or healthy donors were stimulated with CpG or heath-aggregated IgG (as surrogate immune complexes) alone or in combination proliferation and differentiation were then evaluated by flow cytometry. Although antiviral therapy is effective on MC vasculitis, pathogenic B cell clones persist long thereafter and can cause virus-independent disease relapses. These cells display an atypical CD21low phenotype and functional exhaustion evidenced by unresponsiveness to BCR and Toll-like receptor 9 (TLR9) stimuli. Introduction: Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of B cells expressing B cell receptors (BCRs), often encoded by the VH1-69 variable gene, endowed with both rheumatoid factor (RF) and anti-HCV specificity.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |