Characterization of immune specificities in idiopathic inflammatory myopathies
Author: Galindo-Feria, Angeles Shunashy
Date: 2022-09-23
Location: Center of Molecular Medicine, Lecture Hall L08:01, Visionsgatan 18, Karolinska Institutet, Solna
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
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Thesis (9.520Mb)
Abstract
Idiopathic inflammatory myopathies (IIM or myositis) are a group of rheumatic autoimmune diseases characterised by skeletal muscle inflammation and weakness, and are associated with high morbidity and mortality. The diagnosis integrates several subgroups of muscular disorders with autoimmune backgrounds, where identifying myositis-specific and associated autoantibodies play an essential role. The spectrum of these autoantibodies may reflect different clinicopathological mechanisms involved in the disease for the various subgroups of IIM. The high heterogeneity and complexity in myositis represent a clinical challenge and due to the rarity of the disease, the pathophysiological mechanism behind IIM remains elusive.
The aims of this thesis were to 1) study the mechanisms of disease associated with the group of IIM and anti-Jo-1 autoantibodies in terms of T cell functionality and local autoantibody production; 2) to gain a deeper understanding of T cell infiltrate in the muscle tissue at a single-cell level; 3) to characterise the autoantibody subgroups and identify new associations of risk HLA alleles, and 4) to study the prevalence of anti-FHL1 autoantibody and clinical manifestations in cross-sectional and longitudinal cohorts.
In Paper I, we identified histidyl–tRNA synthetase (HisRS) reactive CD4+ T cells in the bronchoalveolar lavage fluid and germinal centre-like structures in the lungs of patients with IIM/anti-synthetase syndrome and the HLA-DRB1*03 allele. Thereby, we identified a potential link between autoreactive T cells and the formation of autoantibodies originating from the lung. In Paper II and V, we detected anti-four-and-a-half-LIM domain 1 (FHL1) autoantibodies in patients with IIM from Australia and Sweden in a cross-sectional and longitudinal approach. In Paper V, we also evaluated the autoantibody levels against FHL1 over time and reported the correlation between FHL1 levels and disease severity. We found that anti-FHL1 autoantibodies were present in patients with IIM who were previously autoantibody-negative, thus adding a novel autoantibody that supports IIM diagnosis. In Paper III, we classified IIM autoantibody co-expression patterns and determined the underlying HLA allele variations. In Paper IV, we used single-cell mRNA sequencing to explore T cell infiltration in the muscle of patients with IIM. We identified a muscle T cell signature containing genes associated with tissue homing and tissue residency. Moreover, we identified immunosuppression-resistant T cell clones in blood and muscle.
In conclusion, this thesis contributes to the understanding of the pathophysiology of IIM from the perspective of the tissue-specific T cells, HLA variations, and autoantibodies diversity. Our findings also propose new avenues for further research, which could facilitate the development of a personalised treatment or new biomarkers.
The aims of this thesis were to 1) study the mechanisms of disease associated with the group of IIM and anti-Jo-1 autoantibodies in terms of T cell functionality and local autoantibody production; 2) to gain a deeper understanding of T cell infiltrate in the muscle tissue at a single-cell level; 3) to characterise the autoantibody subgroups and identify new associations of risk HLA alleles, and 4) to study the prevalence of anti-FHL1 autoantibody and clinical manifestations in cross-sectional and longitudinal cohorts.
In Paper I, we identified histidyl–tRNA synthetase (HisRS) reactive CD4+ T cells in the bronchoalveolar lavage fluid and germinal centre-like structures in the lungs of patients with IIM/anti-synthetase syndrome and the HLA-DRB1*03 allele. Thereby, we identified a potential link between autoreactive T cells and the formation of autoantibodies originating from the lung. In Paper II and V, we detected anti-four-and-a-half-LIM domain 1 (FHL1) autoantibodies in patients with IIM from Australia and Sweden in a cross-sectional and longitudinal approach. In Paper V, we also evaluated the autoantibody levels against FHL1 over time and reported the correlation between FHL1 levels and disease severity. We found that anti-FHL1 autoantibodies were present in patients with IIM who were previously autoantibody-negative, thus adding a novel autoantibody that supports IIM diagnosis. In Paper III, we classified IIM autoantibody co-expression patterns and determined the underlying HLA allele variations. In Paper IV, we used single-cell mRNA sequencing to explore T cell infiltration in the muscle of patients with IIM. We identified a muscle T cell signature containing genes associated with tissue homing and tissue residency. Moreover, we identified immunosuppression-resistant T cell clones in blood and muscle.
In conclusion, this thesis contributes to the understanding of the pathophysiology of IIM from the perspective of the tissue-specific T cells, HLA variations, and autoantibodies diversity. Our findings also propose new avenues for further research, which could facilitate the development of a personalised treatment or new biomarkers.
List of papers:
I. Pro-inflammatory histidyl-tRNA synthetase-specific CD4+ T cells in the blood and lung of patients with idiopathic inflammatory myopathies. Galindo-Feria AS*, Albrecht I*, Fernandes-Cerqueira CS, Notarnicola A, James E, Herrath J,Dastmalchi M, Sandalova T, Ronnblom L, Jakobsson P, Fathi M, Achour A, Grunewald J, Malmstrom V, Lundberg IE. Arthritis & Rheumatology. 2020 Jan; 72 (1): 179-191. *Equal contribution
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II. Autoantibodies against four-and-a-half-LIM domain 1 (FHL1) in inflammatory myopathies: results from an Australian single-centre cohort. Galindo-Feria AS, Horuluoglu B, Day J, Fernandes-Cerqueira CS, Wigren E, Gräslund S, Proudman S, Lundberg IE, Limaye V. Rheumatology. (Oxford). 2022 Jan 12: keac003.
Fulltext (DOI)
Pubmed
III. HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies. Leclair V, Galindo-Feria AS, Rothwell S, Krystufkova O, Mann H, Diederichsen L, Andersson H, Klein M, Tansley S, McHugh N, Lamb J, Jiri Vencovzky, Chinoy H, Holmqvist M, Padyukov L, Lundberg IE, Diaz-Gallo LM. [Manuscript]
IV. Single cell sequencing uncovers muscle T cell signatures and clonally expanded tissue resident memory T cells in myositis. Argyriou A*, Galindo-Feria AS*, Horuluoglu B*, Diaz-Boada JS, Notarnicola A, Dani L, van Vollenhoven A, Ramsköld D, Nennesmo I, Dastmalchi M, Lundberg IE, Diaz-Gallo LM°, Chemin K°. *Equal contribution, °Equal contribution [Manuscript]
V. Anti-FHL1 autoantibodies in adult myositis: a longitudinal follow-up analysis. Galindo-Feria AS*, Lodin K*, Horuluoglu B, Sarrafzadeh-Zargar S, Edvard Wigren E, Gräslund S, Danielsson O, Wahren-Herlenius M, Maryam D, Lundberg IE and the SweMyoNet consortium. *Equal contribution [Manuscript]
I. Pro-inflammatory histidyl-tRNA synthetase-specific CD4+ T cells in the blood and lung of patients with idiopathic inflammatory myopathies. Galindo-Feria AS*, Albrecht I*, Fernandes-Cerqueira CS, Notarnicola A, James E, Herrath J,Dastmalchi M, Sandalova T, Ronnblom L, Jakobsson P, Fathi M, Achour A, Grunewald J, Malmstrom V, Lundberg IE. Arthritis & Rheumatology. 2020 Jan; 72 (1): 179-191. *Equal contribution
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Autoantibodies against four-and-a-half-LIM domain 1 (FHL1) in inflammatory myopathies: results from an Australian single-centre cohort. Galindo-Feria AS, Horuluoglu B, Day J, Fernandes-Cerqueira CS, Wigren E, Gräslund S, Proudman S, Lundberg IE, Limaye V. Rheumatology. (Oxford). 2022 Jan 12: keac003.
Fulltext (DOI)
Pubmed
III. HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies. Leclair V, Galindo-Feria AS, Rothwell S, Krystufkova O, Mann H, Diederichsen L, Andersson H, Klein M, Tansley S, McHugh N, Lamb J, Jiri Vencovzky, Chinoy H, Holmqvist M, Padyukov L, Lundberg IE, Diaz-Gallo LM. [Manuscript]
IV. Single cell sequencing uncovers muscle T cell signatures and clonally expanded tissue resident memory T cells in myositis. Argyriou A*, Galindo-Feria AS*, Horuluoglu B*, Diaz-Boada JS, Notarnicola A, Dani L, van Vollenhoven A, Ramsköld D, Nennesmo I, Dastmalchi M, Lundberg IE, Diaz-Gallo LM°, Chemin K°. *Equal contribution, °Equal contribution [Manuscript]
V. Anti-FHL1 autoantibodies in adult myositis: a longitudinal follow-up analysis. Galindo-Feria AS*, Lodin K*, Horuluoglu B, Sarrafzadeh-Zargar S, Edvard Wigren E, Gräslund S, Danielsson O, Wahren-Herlenius M, Maryam D, Lundberg IE and the SweMyoNet consortium. *Equal contribution [Manuscript]
Institution: Karolinska Institutet
Supervisor: Lundberg, Ingrid E
Co-supervisor: Dastmalchi, Maryam; Chemin, Karine; Albrecht, Inka
Issue date: 2022-09-01
Rights:
Publication year: 2022
ISBN: 978-91-8016-578-5
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