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Publications scientifiques

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Pathogenic roles of autoantibodies in systemic sclerosis: Current understandings in pathogenesis

Journal of Scleroderma and Related Disorders
29 July 2019

Jean-Luc Senécal 1,2,3, Sabrina Hoa 2,3, Roger Yang 2 and Martial Koenig 3,4

1. Scleroderma Research Chair, Université de Montréal, Montreal, QC, Canada
2. Division of Rheumatology, Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada
3. Autoimmunity Research Laboratory, Research Centre of the Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada
4. Division of Internal Medicine, Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada


The potential pathogenic role for autoantibodies in systemic sclerosis has captivated researchers for the past 40 years. This review answers the question whether there is yet sufficient knowledge to conclude that certain serum autoantibodies associated with systemic sclerosis contribute to its pathogenesis. Definitions for pathogenic, pathogenetic and functional autoantibodies are formulated, and the need to differentiate these autoantibodies from natural autoantibodies is emphasized. In addition, seven criteria for the identification of pathogenic autoantibodies are proposed. Experimental evidence is reviewed relevant to the classic systemic sclerosis antinuclear autoantibodies, anti-topoisomerase I and anticentromere, and to functional autoantibodies to endothelin 1 type A receptor, angiotensin II type 1 receptor, muscarinic receptor 3, platelet-derived growth factor receptor, chemokine receptors CXCR3 and CXCR4, estrogen receptor α, and CD22. Pathogenic evidence is also reviewed for anti-matrix metalloproteinases 1 and 3, anti-fibrillin 1, anti-IFI16, anti-eIF2B, anti-ICAM-1, and anti-RuvBL1/RuvBL2 autoantibodies. For each autoantibody, objective evidence for a pathogenic role is scored qualitatively according to the seven pathogenicity criteria. It is concluded that anti-topoisomerase I is the single autoantibody specificity with the most evidence in favor of a pathogenic role in systemic sclerosis, followed by anticentromere. However, these autoantibodies have not been demonstrated yet to fulfill completely the seven proposed criteria for pathogenicity. Their contributory roles to the pathogenesis of systemic sclerosis remain possible but not yet conclusively demonstrated. With respect to functional autoantibodies and other autoantibodies, only a few criteria for pathogenicity are fulfilled. Their common presence in healthy and disease controls suggests that major subsets of these immunoglobulins are natural autoantibodies. While some of these autoantibodies may be pathogenetic in systemic sclerosis, establishing that they are truly pathogenic is a work in progress. Experimental data are difficult to interpret because high serum autoantibody levels may be due to polyclonal B-cell activation. Other limitations in experimental design are the use of total serum immunoglobulin G rather than affinity-purified autoantibodies, the confounding effect of other systemic sclerosis autoantibodies present in total immunoglobulin G and the lack of longitudinal studies to determine if autoantibody titers fluctuate with systemic sclerosis activity and severity. These intriguing new specificities expand the spectrum of autoantibodies observed in systemic sclerosis. Continuing elucidation of their potential mechanistic roles raises hope of a better understanding of systemic sclerosis pathogenesis leading to improved therapies. Read more…


Ellezam B, Leclair V, Troyanov Y, et al.
Capillary pathology with prominent basement membrane reduplication is the hallmark histopathological feature of scleromyositis. Neuropathol Appl Neurobiol. 2022;e12840. doi:10.1111/nan.12840

Benjamin Ellezam 1 | Valérie Leclair 2 | Yves Troyanov 3 | Imane Bersali 4 | Margherita Giannini 4 | Sabrina Hoa 5 | Josiane Bourré-Tessier 5 | Valérie Nadon 6 | Julie Drouin 7 | Jason Karamchandani 8 | Erin O’Ferrall 9 | Béatrice Lannes 10 | Minoru Satoh 11 | Marvin J. Fritzler 12 | Jean-Luc Senécal 5 | Marie Hudson 2 | Alain Meyer 4 | Océane Landon-Cardinal 5

1. Division of Pathology, CHU Sainte-Justine, Department of Pathology and Cell Biology, Université de Montréal, Montréal, Québec, Canada
2. Division of Rheumatology, Jewish General Hospital, Department of Medicine, McGill University, Montréal, Québec, Canada
3. Division of Rheumatology, Hôpital du Sacré-Coeur, Department of Medicine, Université de Montréal, Montréal, Québec, Canada
4. Service de physiologie – explorations fonctionnelles musculaires, service de rhumatologie et Centre de référence des maladies autoimmunes rares, Hôpitaux
universitaires de Strasbourg, Strasbourg, France
5. Division of Rheumatology, Centre hospitalier de l’Université de Montréal (CHUM), Autoimmunity Research Laboratory, CHUM Research Center; Department of
Medicine, Université de Montréal, Montréal, Québec, Canada
6. Division of Rheumatology, Hôpital Notre-Dame, Department of Medicine, Université de Montréal, Montréal, Québec, Canada
7. Division of Rheumatology, Centre Hospitalier Affilié Universitaire Régional (CHAUR) du CIUSSS Mauricie Centre-du-Québec, Department of Medicine, Université de
Montréal, Montréal, Québec, Canada
8. Department of Pathology, Montreal Neurological Institute and Hospital, Montréal, Québec, Canada
9. Department of Neurology and Neurosurgery and Department of Pathology, McGill University and the Montreal Neurological Institute and Hospital, Montréal,
Québec, Canada
10. Service de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
11. Department of Clinical Nursing, University of Occupational and Environmental Health, Kitakyushu, Japan
12. Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada


Aims: We aim to perform ultrastructural and histopathological analysis of muscle biopsies from a large group of systemic sclerosis (SSc) patients, including some with early/mild SSc features, and examine whether capillary pathology differentiates ‘scleromyositis’ (SM) from other auto-immune myositis (AIM) subsets. Methods: Muscle biopsies from a total of 60 SM patients and 43 AIM controls from two independent cohorts were examined by electron microscopy, collagen-4 immunofluorescence (Col4IF) and routine light microscopy. Results: Ultrastructural examination revealed prominent capillary basement membrane (BM) reduplication (4+ layers in >50% of capillaries) in 65% of SM vs 0% of AIM controls (p < 0.001). In SM cases without prominent BM reduplication, capillary dilation was the most distinctive feature, present in 8% of capillaries in SM vs 2% in controls (p = 0.001). Accumulation of ensheathed pericyte processes was another characteristic feature of SM and closely correlated with the degree of BM reduplication (r = 0.833, p < 0.001). On light microscopy, BM marker Col4IF revealed more frequent capillary enlargement in SM than in controls (84% vs 21%, p < 0.001). SM cases were classified as noninflammatory myopathy (36%), non-specific myositis (33%) or immune-mediated necrotizing myopathy (31%), but despite this histopathological heterogeneity, prominent BM reduplication remained a constant finding. In the 16 SM patients with early/mild SSc features, 63% showed prominent BM reduplication. Conclusions: These results show that capillary pathology, and in particular prominent capillary BM reduplication, is the hallmark histopathological feature of SM even in patients with early/mild SSc and support the concept of SM as an organ manifestation of SSc and a distinct subset of AIM. Read more…