Elvis Hysa1, Emanuele Gotelli1, Silvia Sammorì1, Marco Amedeo Cimmino1, Sabrina Paolino2, Carmen Pizzorni3, Alberto Sulli4, Vanessa Smith5, Maurizio Cutolo6. 1. Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Italy - IRCCS San Martino Polyclinic, Genoa, Italy. 2. Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Italy - IRCCS San Martino Polyclinic, Genoa, Italy. Electronic address: sabrina.paolino@unige.it. 3. Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Italy - IRCCS San Martino Polyclinic, Genoa, Italy. Electronic address: carmen.pizzorni@unige.it. 4. Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Italy - IRCCS San Martino Polyclinic, Genoa, Italy. Electronic address: albertosulli@unige.it. 5. Department of Internal Medicine, Ghent University, Department of Rheumatology, Ghent University Hospital; Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address: vanessa.smith@ugent.be. 6. Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Italy - IRCCS San Martino Polyclinic, Genoa, Italy. Electronic address: mcutolo@unige.it.
Abstract
BACKGROUND AND AIM: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease that is common in elderly people. Its classification in the spectrum of autoinflammatory and autoimmune diseases is difficult because of its only partially understood immune-mediated mechanisms. The literature concerning the innate and adaptive immune system activation in PMR was systematically reviewed highlighting the relative weight of autoinflammation and autoimmunity in its pathogenesis and disease progression. METHODS: A literature search on PubMed Central and Embase scientific databases was performed by two independent reviewers. To be eligible, the studies needed to fully satisfy our initial PICO framework: a primary diagnosis of PMR as a population, the search for immune/inflammatory cells, cytokines and autoantibodies as an intervention, a control group consisting in healthy controls, patients with other inflammatory rheumatic diseases or PMR patients in remission after treatment and as outcomes the results of the investigations in the analyzed tissue samples. The most relevant data of the included papers were extracted by using a standardized template. RESULTS: Of the 933 screened abstracts, 52 papers were included in the systematic review and categorized depending on their primary research objectives. The hyper-activity of neutrophils and monocytes, expressing toll-like receptor 7 in active disease, an impaired phagocytosis and endothelial dysfunction, as well as an increased count of innate T cells in patients with remission emerged among the major derangements of the innate immune response in PMR. Among the cytokines profile, interleukin-6 plays a key role but other pro-inflammatory mediators and angiogenesis markers such as chemokines, B-cell activating factor, vascular endothelial growth factor and angiopoietins seem to be involved in refractory or glucocorticoid-resistant PMR. The aberrant adaptive immune response was documented by tissue and serum findings of polarized T cells towards T helper 1 and 17 phenotypes, an increased expression of immunosenescent surface markers and a downregulated immunoregulatory response. The altered distribution of peripheral B cells, detected during active disease, suggested their peripheral migration towards unidentified sites. The interaction between innate and adaptive immune response was documented by a synovial infiltrate of macrophages and T cells. Despite multiple autoantibodies have been detected in PMR patients, none proved to correlate with disease activity seeming to be reactive to the marked inflammation or antigenic determinants provided by environmental triggers or tissue/cell damage. CONCLUSIONS: The complex network between innate and adaptive immune system in PMR is supported by findings at molecular and cellular levels. By considering both the ends of the pathophysiological spectrum of immune-mediated rheumatic diseases, PMR may be regarded as an inflammatory immune-mediated disease with mixed mechanisms in a background of genetic and epigenetic factors together with immunological and endocrine senescence.
BACKGROUND AND AIM: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease that is common in elderly people. Its classification in the spectrum of autoinflammatory and autoimmune diseases is difficult because of its only partially understood immune-mediated mechanisms. The literature concerning the innate and adaptive immune system activation in PMR was systematically reviewed highlighting the relative weight of autoinflammation and autoimmunity in its pathogenesis and disease progression. METHODS: A literature search on PubMed Central and Embase scientific databases was performed by two independent reviewers. To be eligible, the studies needed to fully satisfy our initial PICO framework: a primary diagnosis of PMR as a population, the search for immune/inflammatory cells, cytokines and autoantibodies as an intervention, a control group consisting in healthy controls, patients with other inflammatory rheumatic diseases or PMR patients in remission after treatment and as outcomes the results of the investigations in the analyzed tissue samples. The most relevant data of the included papers were extracted by using a standardized template. RESULTS: Of the 933 screened abstracts, 52 papers were included in the systematic review and categorized depending on their primary research objectives. The hyper-activity of neutrophils and monocytes, expressing toll-like receptor 7 in active disease, an impaired phagocytosis and endothelial dysfunction, as well as an increased count of innate T cells in patients with remission emerged among the major derangements of the innate immune response in PMR. Among the cytokines profile, interleukin-6 plays a key role but other pro-inflammatory mediators and angiogenesis markers such as chemokines, B-cell activating factor, vascular endothelial growth factor and angiopoietins seem to be involved in refractory or glucocorticoid-resistant PMR. The aberrant adaptive immune response was documented by tissue and serum findings of polarized T cells towards T helper 1 and 17 phenotypes, an increased expression of immunosenescent surface markers and a downregulated immunoregulatory response. The altered distribution of peripheral B cells, detected during active disease, suggested their peripheral migration towards unidentified sites. The interaction between innate and adaptive immune response was documented by a synovial infiltrate of macrophages and T cells. Despite multiple autoantibodies have been detected in PMR patients, none proved to correlate with disease activity seeming to be reactive to the marked inflammation or antigenic determinants provided by environmental triggers or tissue/cell damage. CONCLUSIONS: The complex network between innate and adaptive immune system in PMR is supported by findings at molecular and cellular levels. By considering both the ends of the pathophysiological spectrum of immune-mediated rheumatic diseases, PMR may be regarded as an inflammatory immune-mediated disease with mixed mechanisms in a background of genetic and epigenetic factors together with immunological and endocrine senescence.
Authors: Kornelis S M van der Geest; Maria Sandovici; Pieter H Nienhuis; Riemer H J A Slart; Peter Heeringa; Elisabeth Brouwer; William F Jiemy Journal: Front Med (Lausanne) Date: 2022-06-06
Authors: Rosanne D Reitsema; William F Jiemy; Lieske Wekema; Annemieke M H Boots; Peter Heeringa; Minke G Huitema; Wayel H Abdulahad; Yannick van Sleen; Maria Sandovici; Caroline Roozendaal; Arjan Diepstra; Thomas Kwee; Bhaskar Dasgupta; Elisabeth Brouwer; Kornelis S M van der Geest Journal: Front Immunol Date: 2022-08-11 Impact factor: 8.786