. 2024 Oct 21;83(11):1549-1560.

doi: 10.1136/ard-2024-225773.

Pathological autoantibody internalisation in myositis

Iago Pinal-Fernandez^{1

2}, Sandra Muñoz-Braceras³, Maria Casal-Dominguez^#^{3

2}, Katherine Pak^#³, Jiram Torres-Ruiz^#^{3

4}, Jon Musai³, Stefania Dell'Orso³, Faiza Naz³, Shamima Islam³, Gustavo Gutierrez-Cruz³, Maria Dolores Cano⁵, Ana Matas-Garcia^{5

6

7}, Joan Padrosa⁷, Ester Tobias-Baraja^{5

6

7}, Gloria Garrabou^{5

6

7}, Iban Aldecoa⁸, Gerard Espinosa^{6

9}, Carmen Pilar Simeon-Aznar^{10

11}, Alfredo Guillen-Del-Castillo^{10

11}, Albert Gil-Vila^{10

11}, Ernesto Trallero-Araguás^{10

11

12}, Lisa Christopher-Stine^{2

13}, Thomas E Lloyd², Teerin Liewluck¹⁴, Elie Naddaf¹⁴, Werner Stenzel¹⁵, Steven A Greenberg¹⁶, Josep Maria Grau^{5

6

7}, Albert Selva-O'Callaghan^{10

11}, Jose Cesar Milisenda^{5

6

7}, Andrew Lee Mammen^{1

2

13}

Affiliations

¹ Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA andrew.mammen@nih.gov iago.pinalfernandez@nih.gov.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³ Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
⁵ Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain.
⁶ Barcelona University, Barcelona, Spain.
⁷ CIBERER and IDIBAPS, Barcelona, Spain.
⁸ Pathology, Neurological Tissue Bank, Hospital Clinic of Barcelona-CDB-IDIBAPS/FCRB-University of Barcelona, Barcelona, Spain.
⁹ Department of Autoimmune Diseases, Reference Centre for Systemic Autoimmune Diseases (UEC/CSUR) of the Catalan and Spanish Health Systems-Member of ERN-ReCONNET, Hospital Clinic, Barcelona, Spain.
¹⁰ Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain.
¹¹ Autonomous University of Barcelona, Barcelona, Spain.
¹² Rheumatology Department, Vall d'Hebron Hospital, Barcelona, Spain.
¹³ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁴ Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
¹⁶ Department of Neurology, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

^# Contributed equally.

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

Pathological autoantibody internalisation in myositis

Iago Pinal-Fernandez et al. Ann Rheum Dis. 2024.

. 2024 Oct 21;83(11):1549-1560.

doi: 10.1136/ard-2024-225773.

Authors

Affiliations

¹ Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA andrew.mammen@nih.gov iago.pinalfernandez@nih.gov.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³ Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
⁵ Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain.
⁶ Barcelona University, Barcelona, Spain.
⁷ CIBERER and IDIBAPS, Barcelona, Spain.
⁸ Pathology, Neurological Tissue Bank, Hospital Clinic of Barcelona-CDB-IDIBAPS/FCRB-University of Barcelona, Barcelona, Spain.
⁹ Department of Autoimmune Diseases, Reference Centre for Systemic Autoimmune Diseases (UEC/CSUR) of the Catalan and Spanish Health Systems-Member of ERN-ReCONNET, Hospital Clinic, Barcelona, Spain.
¹⁰ Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain.
¹¹ Autonomous University of Barcelona, Barcelona, Spain.
¹² Rheumatology Department, Vall d'Hebron Hospital, Barcelona, Spain.
¹³ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁴ Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
¹⁶ Department of Neurology, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

^# Contributed equally.

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

Abstract

Objectives: Autoantibodies targeting intracellular proteins are common in various autoimmune diseases. In the context of myositis, the pathologic significance of these autoantibodies has been questioned due to the assumption that autoantibodies cannot enter living muscle cells. This study aims to investigate the validity of this assumption.

Methods: Confocal immunofluorescence microscopy was employed to localise antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to examine the transcriptomic profiles of 669 samples, including those from patients with myositis, disease controls and healthy controls. Additionally, antibodies from myositis patients were introduced into cultured myoblasts through electroporation, and their transcriptomic profiles were analysed using RNA sequencing.

Results: In patients with myositis autoantibodies, antibodies accumulated inside myofibres in the same subcellular compartment as the autoantigen. Bulk RNA sequencing revealed that muscle biopsies from patients with autoantibodies targeting transcriptional regulators exhibited transcriptomic patterns consistent with dysfunction of the autoantigen. For instance, in muscle biopsies from patients with anti-PM/Scl autoantibodies recognising components of the nuclear RNA exosome complex, an accumulation of divergent transcripts and long non-coding RNAs was observed; these RNA forms are typically degraded by the nuclear RNA exosome complex. Introducing patient antibodies into cultured muscle cells recapitulated the transcriptomic effects observed in human disease. Further supporting evidence suggested that myositis autoantibodies recognising other autoantigens may also disrupt the function of their targets.

Conclusions: This study demonstrates that, in myositis, autoantibodies are internalised into living cells, causing biological effects consistent with the disrupted function of their autoantigen.

Keywords: Antibodies; Autoantibodies; Dermatomyositis; Polymyositis.

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Conflict of interest statement

Competing interests: None declared.

Update of

Pathogenic autoantibody internalization in myositis.
Pinal-Fernandez I, Muñoz-Braceras S, Casal-Dominguez M, Pak K, Torres-Ruiz J, Musai J, Dell'Orso S, Naz F, Islam S, Gutierrez-Cruz G, Cano MD, Matas-Garcia A, Padrosa J, Tobías-Baraja E, Garrabou G, Aldecoa I, Espinosa G, Simeon-Aznar CP, Guillen-Del-Castillo A, Gil-Vila A, Trallero-Araguas E, Christopher-Stine L, Lloyd TE, Liewluck T, Naddaf E, Stenzel W, Greenberg SA, Grau JM, Selva-O'Callaghan A, Milisenda JC, Mammen AL. Pinal-Fernandez I, et al. medRxiv [Preprint]. 2024 Jan 17:2024.01.15.24301339. doi: 10.1101/2024.01.15.24301339. medRxiv. 2024. Update in: Ann Rheum Dis. 2024 Oct 21;83(11):1549-1560. doi: 10.1136/ard-2024-225773. PMID: 38313303 Free PMC article. Updated. Preprint.

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References

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Pathological autoantibody internalisation in myositis

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