Small-vessel vasculitis
Rheumatoid factor-producing CD21low anergic clonal B-cells in essential mixed cryoglobulinaemia: a model for autoantigen-driven pathogenesis of infectious and non-infectious cryoglobulinaemias
M. Del Padre1, Y.A. Minafò2, R. Marrapodi3, G. Radicchio4, M. Granata5, A. Camponeschi6, M. Fiorilli7, L. Quartuccio8, S. De Vita9, M. Casato10, S. Colantuono11, M. Visentini12
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
- Department of Rheumatology and Inflammation Research, University of Gothenburg, Sweden.
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
- Department of Medical and Biological Sciences, Rheumatology Clinic, University of Udine, Italy.
- Department of Medical and Biological Sciences, Rheumatology Clinic, University of Udine, Italy.
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
- Department of Translational and Precision Medicine, Sapienza University of Rome, and Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy. marcella.visentini@uniroma1.it
CER12578
2020 Vol.38, N°2 ,Suppl.124
PI 0139, PF 0147
Small-vessel vasculitis
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PMID: 31969220 [PubMed]
Received: 08/07/2019
Accepted : 09/09/2019
In Press: 14/01/2020
Published: 21/05/2020
Abstract
OBJECTIVES:
Essential mixed cryoglobulinaemia (EMC) is a disorder of B-cells producing rheumatoid factor (RF), and is clinically and immunologically similar to mixed cryoglobulinaemia (MC) related to hepatitis C virus (HCV-MC). We report here the first comprehensive analysis of B-cell clonality, phenotype and function in EMC.
METHODS:
The study population included 16 patients with EMC and 24 patients with HCV-MC. Molecular analysis was done for the detection of circulating clonal B cells and for B cell receptor sequencing. B-cell phenotype, proliferative response, apoptosis and ERK signaling were analysed by flow cytometry.
RESULTS:
Molecular analysis of immunoglobulin genes rearrangements revealed circulating B-cell clones in about half of patients, on average of smaller size than those found in HCV-MC patients. Sequence analysis showed usage of the same stereotyped RF-encoding B-cell receptors frequently expressed in HCV-MC and in primary Sjögren’s syndrome. B-cells with low expression of CD21 (CD21low) and unusual homing and inhibitory receptors were increased in EMC and in HCV-MC, but at a significantly lower extent in the former. The CD21low B-cells of EMC and HCV-MC patients shared functional features of exhaustion and anergy, namely reduced proliferation upon ligation of Toll-like receptor 9, high constitutive expression of phosphorylated ERK, and proneness to spontaneous apoptosis.
CONCLUSIONS:
Our findings suggest a common pathogenetic mechanism in EMC, HCV-MC and primary Sjögren’s syndrome, consisting of autoantigen-driven clonal expansion and exhaustion of selected RF-producing B-cells. The more massive clonal expansion in HCV-MC may be due to co-stimulatory signals provided by the virus.
