Antibody-associated inflammation in and outside the joint in rheumatoid arthritis
Author: Joshua, Vijay
Date: 2017-09-07
Location: Lecture hall, L8:00, Center for Molecular Medicine (CMM), Karolinska University Hospital, Solna
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
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Thesis (3.758Mb)
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by pain, chronic inflammation and joint destruction. Epidemiological investigations in large populationbased cohorts have identified both genetic (such as HLA-DRB1 Shared epitope, SE) and environmental (such as smoking) risk factors for the development of RA. One of the hallmarks of the disease is the presence of antibodies against a large array of citrullinated proteins (anti citrullinated protein antibodies, ACPA), which are present years before the onset of clinical symptoms. These findings suggest that RA-associated autoimmunity might be initiated somewhere else than the joints, possibly at the mucosal surfaces of the lungs. In the current thesis we aimed to investigate immunological events in the lungs contributing to ACPA generation and to identify novel targets for these antibodies.
Presence of ACPA associates with parenchymal lung abnormalities (as detected by high resolution computed tomography, HRCT) in early-untreated RA. Recognition of more than one citrullinated target by ACPA and specifically recognition of citrullinated fibrinogen peptides increases the odds of detecting HRCT lung abnormalities. Beside HRCT abnormalities, significantly decreased microbial richness and diversity is present in the bronchoalveolar lavage of early-untreated RA patients as compared to healthy volunteers. Interestingly, a similar microbiota dysbiosis is also detected in the presence of overt lung inflammation in the bronchoalveolar lavage of patients with lung sarcoidosis, suggesting that similar inflammatory mechanisms might be active in both lung sarcoidosis and RA. To further explore the possibility that changes in the lungs contribute to generation of autoimmunity in RA, we investigated the presence of citrullinated targets in the mucosal biopsies of early-untreated RA. We identified several novel citrullinated targets, with two citrullinated vimentin peptides detected in a majority of the biopsies. Interestingly these two peptides were also identified in the inflamed synovial tissues of RA patients showing that shared immunological targets are present in the lungs and joints in RA patients. Antibodies against these novel targets were detectable in RA patients suggesting that they could act as immunological targets during disease development. Using a similar approach, we further screened for antibody-reactivity against novel citrullinated targets identified in the synovial fluid of RA patients. Several citrullinated fibrinogen peptides specifically reacted with the antibodies in RA serum, with varying proportion of reactivity for each of these peptides. Interestingly, these antibodies differ from the classical ACPA being associated with the PTPN22 risk allele but not with the HLA-DRB1 SE. As such RA patients carrying the PTPN22 risk allele displayed higher proportion of B cells reacting with citrullinated fibrinogen loaded B cell antigen tetramers than those lacking the risk allele.
In conclusion, we provide evidence for a pathogenic link between early events in the lungs and autoimmunity in RA and identify several novel immunological targets for this autoimmunity. Our studies contribute to the understanding of the longitudinal development of RA, opening the possibility for future targeting of early pathogenic events in order to delay and/or prevent the disease.
Presence of ACPA associates with parenchymal lung abnormalities (as detected by high resolution computed tomography, HRCT) in early-untreated RA. Recognition of more than one citrullinated target by ACPA and specifically recognition of citrullinated fibrinogen peptides increases the odds of detecting HRCT lung abnormalities. Beside HRCT abnormalities, significantly decreased microbial richness and diversity is present in the bronchoalveolar lavage of early-untreated RA patients as compared to healthy volunteers. Interestingly, a similar microbiota dysbiosis is also detected in the presence of overt lung inflammation in the bronchoalveolar lavage of patients with lung sarcoidosis, suggesting that similar inflammatory mechanisms might be active in both lung sarcoidosis and RA. To further explore the possibility that changes in the lungs contribute to generation of autoimmunity in RA, we investigated the presence of citrullinated targets in the mucosal biopsies of early-untreated RA. We identified several novel citrullinated targets, with two citrullinated vimentin peptides detected in a majority of the biopsies. Interestingly these two peptides were also identified in the inflamed synovial tissues of RA patients showing that shared immunological targets are present in the lungs and joints in RA patients. Antibodies against these novel targets were detectable in RA patients suggesting that they could act as immunological targets during disease development. Using a similar approach, we further screened for antibody-reactivity against novel citrullinated targets identified in the synovial fluid of RA patients. Several citrullinated fibrinogen peptides specifically reacted with the antibodies in RA serum, with varying proportion of reactivity for each of these peptides. Interestingly, these antibodies differ from the classical ACPA being associated with the PTPN22 risk allele but not with the HLA-DRB1 SE. As such RA patients carrying the PTPN22 risk allele displayed higher proportion of B cells reacting with citrullinated fibrinogen loaded B cell antigen tetramers than those lacking the risk allele.
In conclusion, we provide evidence for a pathogenic link between early events in the lungs and autoimmunity in RA and identify several novel immunological targets for this autoimmunity. Our studies contribute to the understanding of the longitudinal development of RA, opening the possibility for future targeting of early pathogenic events in order to delay and/or prevent the disease.
List of papers:
I. Association between number and type of different ACPA fine specificities with lung abnormalities in early, untreated rheumatoid arthritis. Vijay Joshua, Aase Haj Hensvold, Gudrun Reynisdottir, Monika Hansson, Martin Cornillet, Leonor Nogueira, Guy Serre, Sven Nyren, Reza Karimi, Anders Eklund, Carl Magnus Sköld, Johan Grunewald, Katerina Chatzidionysiou and Anca I. Catrina. [Submitted]
II. The lung microbiota in early rheumatoid arthritis and autoimmunity. Jose U. Scher, Vijay Joshua, Alejandro Artacho, Shahla Abdollahi-Roodsaz, Johan Öckinger, Susanna Kullberg, Magnus Sköld, Anders Eklund, Johan Grunewald, Jose C. Clemente, Carles Ubeda, Leopoldo N. Segal and Anca I. Catrina. Microbiome. 2016, 4(1):60.
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III. Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. A Jimmy Ytterberg, Vijay Joshua, Gudrun Reynisdottir, Nataliya K Tarasova, Dorothea Rutishauser, Elena Ossipova, Aase Haj Hensvold, Anders Eklund, C Magnus Sköld, Johan Grunewald, Vivianne Malmström, Per Johan Jakobsson, Johan Rönnelid, Leonid Padyukov, Roman A Zubarev, Lars Klareskog and Anca I Catrina. Annals of Rheumatic Diseases. 2015 Sep, 74(9):1772-7.
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IV. Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells. Vijay Joshua, Loes Schobers, Philip J. Titcombe, Lena Israelsson, Johan Rönnelid, Monika Hansson, Anca I. Catrina, Ger J. M. Pruijn and Vivianne Malmström. Arthritis Research & Therapy. 2016, 18(1): 284.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Association between number and type of different ACPA fine specificities with lung abnormalities in early, untreated rheumatoid arthritis. Vijay Joshua, Aase Haj Hensvold, Gudrun Reynisdottir, Monika Hansson, Martin Cornillet, Leonor Nogueira, Guy Serre, Sven Nyren, Reza Karimi, Anders Eklund, Carl Magnus Sköld, Johan Grunewald, Katerina Chatzidionysiou and Anca I. Catrina. [Submitted]
II. The lung microbiota in early rheumatoid arthritis and autoimmunity. Jose U. Scher, Vijay Joshua, Alejandro Artacho, Shahla Abdollahi-Roodsaz, Johan Öckinger, Susanna Kullberg, Magnus Sköld, Anders Eklund, Johan Grunewald, Jose C. Clemente, Carles Ubeda, Leopoldo N. Segal and Anca I. Catrina. Microbiome. 2016, 4(1):60.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. A Jimmy Ytterberg, Vijay Joshua, Gudrun Reynisdottir, Nataliya K Tarasova, Dorothea Rutishauser, Elena Ossipova, Aase Haj Hensvold, Anders Eklund, C Magnus Sköld, Johan Grunewald, Vivianne Malmström, Per Johan Jakobsson, Johan Rönnelid, Leonid Padyukov, Roman A Zubarev, Lars Klareskog and Anca I Catrina. Annals of Rheumatic Diseases. 2015 Sep, 74(9):1772-7.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells. Vijay Joshua, Loes Schobers, Philip J. Titcombe, Lena Israelsson, Johan Rönnelid, Monika Hansson, Anca I. Catrina, Ger J. M. Pruijn and Vivianne Malmström. Arthritis Research & Therapy. 2016, 18(1): 284.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Catrina, Anca
Co-supervisor: Malmström, Vivianne; Wähämaa, Heidi; Klareskog, Lars
Issue date: 2017-08-17
Rights:
Publication year: 2017
ISBN: 978-91-7676-768-9
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