Giovanni Almanzar1, Marc Schmalzing2, Raimund Trippen3, Kerstin Höfner3, Benedikt Weißbrich4, Eva Geissinger5, Thomas Meyer6, Johannes Liese3, Hans-Peter Tony2, Martina Prelog3. 1. Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany. Electronic address: Almanzar_G@ukw.de. 2. Department of Internal Medicine II, Rheumatology and Immunology, University Hospital Würzburg, Würzburg, Germany. 3. Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany. 4. Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany. 5. Institute of Pathology, University of Würzburg, Würzburg, Germany. 6. Pediatric Surgery Unit, Department of Surgery, University Hospital Würzburg, Würzburg, Germany.
Abstract
BACKGROUND: Latent Cytomegalovirus (CMV) infection accelerates immunosenescence in elderly with reactivations reported in Rheumatoid Arthritis (RA) and abnormal responses towards CMV in Juvenile Idiopathic Arthritis (JIA). OBJECTIVES: Considering the signs of premature T-cell immunosenescence in arthritis patients, the known effect of CMV latency on speeding up many of these signs in an age-dependent manner and the role of CMV on IFNγ-mediated inflammation in healthy elderly and RA, we hypothesized that latent CMV infection accelerates TCR repertoire restriction, loss of CD28, peripheral T-cell proliferation and aberrant IFNγ responses in arthritis patients. STUDY DESIGN: Unspecific and CMVpp65-specific IFNγ responses were investigated in peripheral CD8+ T-cells in RA or JIA patients and healthy, age-matched controls. RESULTS: Despite higher prevalence and concentrations of IgG-anti-CMV, arthritis patients showed lower unspecific IFNγ production, lower CD69-mediated activation and lower CD8+ T-cell proliferation. CMV-seropositive RA patients showed higher intracellular IFNγ production and increased proportions of CD28-CD8+ T-cells after specific CMVpp65 long-term stimulation which was not altered by in vitro blockade of TNFα or IL-6. A skewed TCR repertoire towards oligoclonality and less polyclonality was found in JIA. DISCUSSION: CMVpp65-specific IFNγ production with expansion of CD28-CD8+ T-cells suggests an efficient control of latent CMV regardless of immunosuppressive therapy or in vitro blockade of TNFα or IL-6 in CMV-seropositive arthritis patients. Increased IgG-anti-CMV antibody concentrations and increased proportions of intracellular IFNγ-producing CMVpp65-specific CD8+ T-cells in long-term cultures propose a possibly role of endogenous CMV reactivations boosting antibody levels and a higher possibly CMV-driven IFNγ-mediated inflammatory potential of CD8+ T-cells in arthritis patients.
BACKGROUND: Latent Cytomegalovirus (CMV) infection accelerates immunosenescence in elderly with reactivations reported in Rheumatoid Arthritis (RA) and abnormal responses towards CMV in Juvenile Idiopathic Arthritis (JIA). OBJECTIVES: Considering the signs of premature T-cell immunosenescence in arthritispatients, the known effect of CMV latency on speeding up many of these signs in an age-dependent manner and the role of CMV on IFNγ-mediated inflammation in healthy elderly and RA, we hypothesized that latent CMV infection accelerates TCR repertoire restriction, loss of CD28, peripheral T-cell proliferation and aberrant IFNγ responses in arthritispatients. STUDY DESIGN: Unspecific and CMVpp65-specific IFNγ responses were investigated in peripheral CD8+ T-cells in RA or JIA patients and healthy, age-matched controls. RESULTS: Despite higher prevalence and concentrations of IgG-anti-CMV, arthritispatients showed lower unspecific IFNγ production, lower CD69-mediated activation and lower CD8+ T-cell proliferation. CMV-seropositive RApatients showed higher intracellular IFNγ production and increased proportions of CD28-CD8+ T-cells after specific CMVpp65 long-term stimulation which was not altered by in vitro blockade of TNFα or IL-6. A skewed TCR repertoire towards oligoclonality and less polyclonality was found in JIA. DISCUSSION: CMVpp65-specific IFNγ production with expansion of CD28-CD8+ T-cells suggests an efficient control of latent CMV regardless of immunosuppressive therapy or in vitro blockade of TNFα or IL-6 in CMV-seropositive arthritispatients. Increased IgG-anti-CMV antibody concentrations and increased proportions of intracellular IFNγ-producing CMVpp65-specific CD8+ T-cells in long-term cultures propose a possibly role of endogenous CMV reactivations boosting antibody levels and a higher possibly CMV-driven IFNγ-mediated inflammatory potential of CD8+ T-cells in arthritispatients.
Authors: Laura E Petersen; Jaqueline B Schuch; Lucas A de Azeredo; Talita S A Baptista; Julia G Motta; Aline D do Prado; Moisés Evandro Bauer Journal: Clin Rheumatol Date: 2019-06-11 Impact factor: 2.980
Authors: Cara L Hrusch; Michelle M Stein; Justyna Gozdz; Mark Holbreich; Erika von Mutius; Donata Vercelli; Carole Ober; Anne I Sperling Journal: J Allergy Clin Immunol Date: 2019-08-08 Impact factor: 10.793