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The underlying mechanisms driving immune dysfunction and lung injury, however, remain poorly understood. The study aims to gain insights into the disrupted immune landscape in peripheral and pulmonary compartments of severe anti\u2010MDA5+ DM and explore potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed single\u2010cell RNA sequencing to examine cellular constituents within five patients\u2019 bronchoalveolar lavage fluid and paired peripheral blood mononuclear cells. Luminex assay and flow cytometry were further applied to validate the results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis revealed starkly contrasting immune landscapes between the periphery and lungs, with peripheral immune suppression juxtaposed against pulmonary immune hyperactivation. Central to this dysregulation was the monocyte\u2013macrophage lineage. Circulating monocytes exhibited an immunosuppressive phenotype, characterised by diminished cytokine production, reduced MHC II expression, and features resembling myeloid\u2010derived suppressor cells. These monocytes were recruited to the lungs, where they differentiated into monocyte\u2010derived alveolar macrophages (Mo\u2010AMs) with robust proinflammatory and profibrotic activities. Mo\u2010AMs drove cytokine storms and produced chemokines that amplified inflammatory cell recruitment and lung tissue remodelling. Additionally, peripheral T and NK cells exhibited increased cell death and active migration into the lungs, which may be the cause of lymphopenia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study underscores the pivotal role of monocyte\u2013macrophage dynamics in the immunopathogenesis of anti\u2010MDA5+\u2010associated RP\u2010ILD, offering critical insights into compartment\u2010specific immune dysregulation. These findings suggest potential therapeutic strategies targeting monocyte recruitment and macrophage activation to mitigate disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Peripheral immune suppression and pulmonary immune hyperactivation characterise the distinct immune landscapes in anti\u2010MDA5+DM with RP\u2010ILD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Circulating monocytes transition from an immunosuppressive phenotype in the periphery to proinflammatory and profibrotic Mo\u2010AMs in the lungs.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Chemokines produced by Mo\u2010AMs drive monocyte and other immune cell recruitment to the lungs, amplifying pulmonary inflammation.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70226","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T06:59:41Z","timestamp":1738652381000},"source":"Crossref","is-referenced-by-count":20,"title":["Monocyte\u2013macrophage dynamics as key in disparate lung and peripheral immune responses in severe anti\u2010melanoma differentiation\u2010associated gene 5\u2010positive dermatomyositis\u2010related interstitial lung disease"],"prefix":"10.1002","volume":"15","author":[{"given":"Jia","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union 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