The role of autoantibodies in inflammatory myopathies
Author: Barbasso Helmers, Sevim
Date: 2007-11-23
Location: Föreläsningssalen Loben, Thorax, 6 tr, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Institutionen för medicin / Department of Medicine
View/ Open:
thesis.pdf (855.9Kb)
Abstract
Polymyositis (PM), dermatomyositis (DM) and inclusion body myositis
(IBM), collectively called myositis, are chronic inflammatory myopathies.
These disease subsets are heterogeneous but share some features, such as
skeletal muscle weakness and inflammatory cell infiltrates in muscle
tissue. In many patients involvement of other organs, in particular skin
and lung, also occurs. Another characteristic feature is the presence of
autoantibodies which are (1) myositis specific, e.g.
anti-histidyl-transfer ribonucleic acid (RNA) synthetase (Jo-1) and
anti-Mi-2, and (2) myositis associated e.g. anti-Ro52/SSA, anti-Ro60/SSA,
anti-PM/Scl and anti-U1sn ribonucleoprotein (RNP) autoantibodies.
Presence of anti-Jo-1 autoantibodies is specifically associated with
interstitial lung disease (ILD). Despite the clinical associations it is
not known whether these autoantibodies have a pathogenic role or are
merely an epiphenomenon in the disease mechanism.
Aim: The overall goal of this thesis was to evaluate the role of specific
and associated autoantibodies in myositis pathogenesis by combining in
vivo and in vitro approaches.
Results: We demonstrated in vitro that immune complexes containing
anti-Jo-1 or anti-Ro52/Ro60 autoantibodies and RNA may act as endogenous
type I interferon (IFNalpha/beta) inducers via plasmacytoid dendritic
cells (PDCs). Patients also had increased expression of
IFNalpha/beta-inducible human myxovirus resistance 1 (MX-1) protein in
muscle tissue which correlated with number of blood dendritic cell
antigen (BDCA)-2 positive PDCs. DM patients characterized by skin rash
also had increased MX-1 expression in muscle tissue but this was located
to capillaries, suggesting another induction mechanism and cellular
IFNalpha source such as the skin. The same groups of patients displayed
elevated levels of B cell activating factor (BAFF), suggesting an
induction by a local (muscle and skin) type I IFN system. Sera from PM
patients with anti-Jo-1 autoantibodies and ILD exhibited induced
intracellular adhesion molecule (ICAM)-1 expression in lung endothelial
cells in vitro, which has clinical relevance as ICAM-1 is upregulated in
vivo in endothelial cells of capillaries in muscle tissue.
The effects of high dose intravenous immunoglobulin (IVIG) treatment on
endothelial cell activation and other immunological molecules
investigated in muscle tissue varied between patients and were not
correlated with improved muscle function. This could be due to the
heterogeneity of the disease mechanisms in myositis. The effects of IVIG
treatment were thus considered as being limited.
Conclusion: There seems to be a role for anti-Jo-1 autoantibodies in the
pathogenesis of myositis patients with lung and skin involvement. The
findings in this thesis suggest that this role is related to the
endogenous production of type I IFN, which perpetuates disease. Sera with
anti-Jo-1 autoantibodies are capable of inducing endothelial cell
activation, enabling the influx of inflammatory cells into the muscle
tissue. An inflammatory condition sustained by inflammatory cells and
their mediators may induce changes in muscle fiber metabolism which can
lead to muscle damage.
List of papers:
I. Eloranta ML, Helmers SB, Ulfgren AK, Rönnblom L, Alm GV, Lundberg IE (1970). "A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies." Arthritis Rheum 56(9): 3112-24
Pubmed
II. Helmers SB, Englund P, Åhlin E, Heimburger M, Fathi M, Rönnelid J, Lundberg IE (2007). "Anti-Jo-1 positive sera from polymyositis patients with interstitial lung disease induce ICAM-1 expression in human lung endothelial cells." (Submitted)
III. Krystufkova O, Vallerskog T, Helmers SB, Mann H, Putova I, Belacek J, Malmström V, Trollmo C, Vencovsky J, Lundberg IE (2007). "Increased serum levels of B cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies." (Submitted)
IV. Helmers SB, Dastmalchi M, Alexanderson H, Nennesmo I, Esbjörnsson M, Lindvall B, Lundberg IE (2007). "Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies." Ann Rheum Dis 66(10): 1276-83. Epub 2007 Feb 2
Pubmed
I. Eloranta ML, Helmers SB, Ulfgren AK, Rönnblom L, Alm GV, Lundberg IE (1970). "A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies." Arthritis Rheum 56(9): 3112-24
Pubmed
II. Helmers SB, Englund P, Åhlin E, Heimburger M, Fathi M, Rönnelid J, Lundberg IE (2007). "Anti-Jo-1 positive sera from polymyositis patients with interstitial lung disease induce ICAM-1 expression in human lung endothelial cells." (Submitted)
III. Krystufkova O, Vallerskog T, Helmers SB, Mann H, Putova I, Belacek J, Malmström V, Trollmo C, Vencovsky J, Lundberg IE (2007). "Increased serum levels of B cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies." (Submitted)
IV. Helmers SB, Dastmalchi M, Alexanderson H, Nennesmo I, Esbjörnsson M, Lindvall B, Lundberg IE (2007). "Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies." Ann Rheum Dis 66(10): 1276-83. Epub 2007 Feb 2
Pubmed
Issue date: 2007-11-02
Rights:
Publication year: 2007
ISBN: 978-91-7357-312-2
Statistics
Total Visits
Views | |
---|---|
The ...(legacy) | 671 |
The ... | 125 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
The ... | 2 | 1 | 1 | 0 | 0 | 2 | 0 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 759 |
thesis.pdf | 400 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 328 |
Sweden | 87 |
Germany | 57 |
China | 56 |
South Korea | 16 |
Russia | 15 |
Finland | 14 |
United Kingdom | 13 |
Ireland | 9 |
Denmark | 7 |
Top cities views
Views | |
---|---|
Sunnyvale | 39 |
Romeo | 21 |
Beijing | 17 |
Kiez | 17 |
Stockholm | 17 |
Seoul | 15 |
Dublin | 9 |
Helsinki | 8 |
London | 7 |
Moscow | 7 |