SP0103 T LYMPHOCYTES AND INNATE IMMUNE CELLS BALANCE MUSCLE REGENERATION AND AUTOIMMUNITY
Authors: Patrizia Rovere-Querini
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The skeletal muscle is the largest cellular compartment of the organism. It represents an immunologically unique or a "non classical" immunological privileged site, being normally protected from the noxious effects of inflammation. The molecular events that control the homeostatic response to acute muscle injury are however poorly understood. The available information indicates that it involves the cross-talk among various cell populations, which i) perceive the muscle damage and release alert signals, which attract and activate inflammatory cells and progenitor cells ii) organize and maintain regeneration and tissue repair. The scenario is possibly even more complex during inflammatory idiopathic myositis (IIM) in which the immune privilege fails to proctect the environment and muscle cells undergo continuous cycles of death and regeneration as a consequence of the pressure of the immune respose targeting antigens preferentially expressed within regenerating fibers (1, 2). <h3>Objectives:</h3> I will review recent evidence on the relative role of unconventional cellular and molecular pathways activated in the tissues of subjects with IMM and in relevant experimental models of skeletal muscle regeneration and autoimmunity, focusing on the action of antigen-specific and regulatory T cells and immune cells populations of innate cells. <h3>Methods:</h3> Review of available published data and of data recently generated on the topic. <h3>Results:</h3> Muscle necrosis and the ensuing inflammation was consistently associated in mice with up-regulated expression of bona fide autoantigens targeted in patients with IIM, in particular of histidyl-transfer RNA synthetase (HisRS). Phagocytosis of HisRS-expressing apoptotic myoblasts and appropriate inflammatory costimuli are necessary to elicit the production of anti-HisRS autoantibodies and to jeopardize muscle regeneration. Soluble pattern recognition receptors, and in particular the prototypic long pentraxin PTX3 play a critical role in preventing the accumulation of cell debris in the inflamed skeletal muscle, restricting the immunogenic potential of dying and regenerating myofibers. Conversely the local expression of type I IFN is necessary for the prolonged autoantibody response and for the maintenance and spreading of the immune-mediated muscle damage, as demonstrated using IFNα/βR-null mice (3-5). A specialized population of regulatory T (Treg) cells, has been recently characterized in the inflamed and regenerating muscle, which influence both the immune response, by promoting the M1-to-M2 switch, and the activation of precursor/stem muscle cells. Treg cells control the efficacy of muscle repair and might be involved in preventing the systemic effects of the autoimmune response generated as a consequence of the disruption of the immunologically protected environment of the skeletal muscle (6, 7). <h3>Conclusion:</h3> Identification of the pathways that are physiologically involved in restricting the onset and accelerating the termination of autoimmune reponses targeting the skeletal muscle might be valuable for the identification of novel targets for molecular intervention in patients with IIM. <h3>References:</h3> [1] Mammen AL, Casciola-Rosen LA, Hall JC, Christopher-Stine L, Corse AM, Rosen A. Expression of the dermatomyositis autoantigen Mi-2 in regenerating muscle. Arthritis Rheum. 2009 Dec;60(12):3784-93. [2] Sciorati C, Rigamonti E, Manfredi AA, Rovere-Querini P. Cell death, clearance and immunity in the skeletal muscle. Cell Death Differ. 2016 Jun;23(6):927-37.3. [3] Sciorati C, Monno A, Ascherman DP, Seletti E, Manfredi AA, Rovere-Querini P. Required role of apoptotic myogenic precursors and toll-like receptor stimulation for the establishment of autoimmune myositis in experimental murine models. Arthritis Rheumatol. 2015 Mar;67(3):809-22. [4] Vezzoli M, Sciorati C, Campana L, Monno A, Doglio MG, Rigamonti E, Corna G, Touvier T, Castiglioni A, Capobianco A, Mantovani A, Manfredi AA, Garlanda C, Rovere-Querini P. The clearance of cell remnants and the regeneration of the injured muscle depend on soluble pattern recognition receptor PTX3. Mol Med. 2017 Jan;22:809-820. [5] Sciorati C, Monno A, Doglio MG, Rigamonti E, Ascherman DP, Manfredi AA, Rovere-Querini P. Exacerbation of Murine Experimental Autoimmune Myositis by Toll-Like Receptor 7/8. Arthritis Rheumatol. 2018 Aug;70(8):1276-1287. [6] Schiaffino S, Pereira MG, Ciciliot S, Rovere-Querini P.Regulatory T cells and skeletal muscle regeneration. FEBS J. 2017 Feb;284(4):517-524. doi: 10.1111/febs.13827 [7] DiSpirito JR, Zemmour D, Ramanan D, Cho J, Zilionis R, Klein AM, Benoist C, Mathis D. Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci Immunol. 2018 Sep 14;3(27). [8] Panduro M, Benoist C, Mathis D. Treg cells limit IFN-γ production to control macrophage accrual and phenotype during skeletal muscle regeneration. Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):E2585-E2593. <h3>Disclosure of Interests:</h3> Patrizia Rovere-Querini Grant/research support from: Adienne Pharma &amp; Biotech