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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


1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12

 

  1. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
  2. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
  3. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
  4. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
  5. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
  6. Department of Rheumatology and Inflammation Research, University of Gothenburg, Sweden.
  7. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
  8. Department of Medical and Biological Sciences, Rheumatology Clinic, University of Udine, Italy.
  9. Department of Medical and Biological Sciences, Rheumatology Clinic, University of Udine, Italy.
  10. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
  11. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
  12. 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.

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