By Christopher Nelke

Publication

Antibody internalisation could link clinical phenotypes to subcellular dysfunctions in myositis

Iago Pinal-Fernandez, Sandra Muñoz-Braceras, Maria Casal-Dominguez, Katherine Pak, Jiram Torres-Ruiz, Jon Musai, Stefania Dell'Orso, Faiza Naz, Shamima Islam, Gustavo Gutierrez-Cruz, Maria Dolores Cano, Ana Matas-Garcia, Joan Padrosa, Ester Tobias-Baraja, Gloria Garrabou, Iban Aldecoa, Gerard Espinosa, Carmen Pilar Simeon-Aznar, Alfredo Guillen-Del-Castillo, Albert Gil-Vila, Ernesto Trallero-Araguás, Lisa Christopher-Stine, Thomas E Lloyd, Teerin Liewluck, Elie Naddaf, Werner Stenzel, Steven A Greenberg, Josep Maria Grau, Albert Selva-O'Callaghan, Jose Cesar Milisenda, Andrew Lee Mammen.

PMID: 38902010, PMCID: PMC11493519 (available on 2025-10-21), DOI: 10.1136/ard-2024-225773

https://pubmed.ncbi.nlm.nih.gov/38902010/

Summary

In idiopathic inflammatory myopathies (IIM), antibodies have evolved as key markers that define distinct clinical phenotypes with varying patterns of muscle weakness, skin involvement, and systemic symptoms. Despite their diagnostic importance, a central question has remained unanswered: How are these autoantibodies linked to distinct clinical presentations? And why do different antibodies cause similar disease subtypes with distinct patterns of organ involvement?

To address this question, Pinal-Fernadez and his team have studied a previously unrecognised mechanism by which antibodies may infiltrate muscle cells and disrupt intracellular targets, thereby shaping the disease phenotype.

The researchers employed a combination of transcriptomic analysis and advanced immunological techniques to investigate this mechanism in detail. By analysing muscle biopsies from 669 patients, including those with myositis-specific autoantibodies, disease controls, and healthy individuals, they uncovered distinct associations between autoantibodies and cellular dysfunction. Notably, they focused on two well-characterised autoantibodies: anti-Mi2, which targets the Mi2/NuRD chromatin remodelling complex, and anti-PM/Scl, which targets components of the nuclear RNA exosome complex. Both antibodies were found to localise within muscle cells, accumulating in the specific subcellular compartments where their respective autoantigens reside: anti-Mi2 in the nuclei and anti-PM/Scl in the nucleoli.

This localisation appears to not be incidental. Instead, the study provides evidence that antibodies may directly disrupt the function of the targeted autoantigens. For example, in patients with anti-PM/Scl autoantibodies, the dysfunction of the nuclear RNA exosome complex led to an accumulation of aberrant transcripts and long non-coding RNAs that are normally degraded by this machinery. These effects were confirmed in vitro, where introducing patient-derived autoantibodies into cultured myoblasts reproduced the transcriptomic changes observed in human muscle tissue.

This study introduces a novel paradigm in understanding myositis pathology, challenging the long-standing assumption that autoantibodies act only extracellularly. It also highlights the importance of exploring how different autoantibodies selectively target intracellular proteins and drive specific transcriptomic and functional changes. By linking autoantibody activity to distinct cellular dysfunctions, the findings provide a mechanistic basis for the clinical diversity observed in IIM.

Still, while antibodies have been uncovered to be the culprit behind the distinct clinical phenotypes observed in IIM patients, there remains one piece of the puzzle missing: How can antibodies enter muscle cells in vivo? Possible mechanisms have been suggested, such as Fc receptor mediated internalisation; however, understanding these mechanisms remains a current research question.

About the author

Iago Pinal-Fernandez, M.D., Ph.D., Ph.D. is a Staff Clinician in the Muscle Disease Unit of the NIAMS/NIH. He joined in 2015 as a visiting fellow, then transitioned to a clinical fellowship before becoming a staff clinician in 2021. Dr. Pinal-Fernandez is also an adjunct assistant professor in the Department of Neurology at Johns Hopkins University School of Medicine. Dr. Pinal-Fernandez graduated from the Santiago de Compostela School of Medicine and completed his five-year internal medicine residency in the Vall d’Hebron Hospital in Barcelona.

 About the reviewer

Christopher Nelke, M.D., is a clinician scientist in the Department of Neurology at the University Hospital Düsseldorf. He completed medical school at the University of Saarland, Saarbrücken, in 2018, followed by a residency in neurology at the University Hospitals Münster and Düsseldorf. Dr. Nelke is focused on translational biostatistics with a particular emphasis on large-scale data analysis in neuromuscular diseases.