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Mixed connective tissue disease, myositis and systemic lupus erythematosus : immunological and genetic studies in three related rheumatic autoimmune studies

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posted on 2024-09-03, 01:45 authored by Adla Bakri Hassan

Mixed connective tissue disease (MCTD), polymyositis (PM)/ dermatomyositis (DM) and systemic lupus erythematosus (SLE) are chronic, rheumatic, systemic inflammatory disorders. The disorders depend on several factors of both genetic and environmental origin. They are heterogeneous diseases but all are characterized by the presence of various autoantibodies directed to nuclear and/or cytoplasmic components. Neither the pathogenic role nor the mechanisms driving the autoantibody production in these diseases are fully understood.

The main objective of my thesis was to get an increased knowledge of the mechanisms driving autoantibody production and their importance in disease mechanisms. Therefore, 1 studied the relation of autoantibody production to disease activity and furthermore to serum levels of cytokines and also to certain genetic markers that could be of interest in these aspects in three different but related autoimmune rheumatic diseases such as MCTD, PM/DM and SLE.

The anti-U1snRNP (68 kDa, RNP-A and RNP-C) autoantibodies in MCTD patients and the anti-Ro and anti-La autoantibodies in SLE patients had a coordinated expression indicating that these groups of autoantibodies are driven by a similar mechanism in the same disease. Nevertheless, the anti-U1 RNP autoantibodies levels were highly fluctuating with time in MCTD patients, while anti-Ro and anti-La autoantibodies levels in SLE patients were fixed early in the disease and hardly changed with time indicating that autoantibodies are derived and maintained by different mechanisms in different diseases. Correlations between autoantibodies and overall disease activity or specific clinical features in different diseases were observed.

Increased serum levels of the cytokines TNF-alpha and EL-10 were demonstrated in patients with PM/DM and MCTD compared to controls, but not in SLE. There were no correlations between individual cytokine levels and disease activity in any of the investigated disorders. In MCTD patients correlations between anti-U1 snRNP antibody levels and cytokines levels particularly for TNF-alpha were demonstrated. A high TNF-alpha/IL-10 ratio was associated with presence of anti-Jo-1 autoantibodies in PM/DM patients. This ratios seemed to have a genetic basis. An association between certain MHC and non-MHC genes and development of disease, cytokine production and presence of autoantibodies in patients with MCTD and P~ has been determined. In particular TNF2 allele of the -308TNFA gene was associated with PM/DM diagnoses.

In conclusion, these inummological studies in MCTD, SLE and PM/DM provided information about immunological factors and some mechanisms that could drive these factors in these diseases. The diverse autoantibody patterns in MCTD and SLE could indicate that different mechanisms drive and maintain various autoantibodies, while the co-ordinated expression indicates that autoantibodies within one disorder could be driven by the same mechanism. The current studies imply that upregulation of cytokine production is likely to be part of the mechanisms underlying autoantibody production. Variations in cytokines and autoantibody production may have a genetic basis. The genetic studies suggest that the HLADRB1*04 and -DRB1*03 positive haplotypes rather than the separate markers in the HLA region are important factors in the disease susceptibility for MCTD and PM/DM, respectively. Finally, these genetic studies were the first to enlighten the role of cytokine gene polymorphisms and also to provide the basis for haplotype analysis in patients with MCTD and adult PM/DM.

List of scientific papers

I. Bakri Hassan A, Ronnelid J, Gunnarsson I, Karlsson G, Berg L, Lundberg I (1998). Increased serum levels of immunoglobulins, C-reactive protein, type 1 and type 2 cytokines in patients with mixed connective tissue disease. J Autoimmun. 11(5): 503-8.
https://pubmed.ncbi.nlm.nih.gov/9802936

II. Hassan AB, Gunnarsson I, Karlsson G, Klareskog L, Forslid J, Lundberg IE (2001). Longitudinal study of interleukin-10, tumor necrosis factor-alpha, anti-U1-snRNP antibody levels and disease activity in patients with mixed connective tissue disease. Scand J Rheumatol. 30(5): 282-9.
https://pubmed.ncbi.nlm.nih.gov/11727843

III. Hassan AB, Nikitina-Zake L, Padyukov L, Karlsson G, Gupta M, Lundberg IE, Sanjeevi CB (2002). MICA/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease (MCTD) in Swedish patients. Human Immunology.

IV. Hassan AB, Lundberg IE, Isenberg D, Wahren-Herlenius M (2002). Serial analysis of Ro/SSA and La/SSB antibody levels and correlation with clinical disease activity in patients with systemic lupus erythematosus. Scand J Rheumatol. 31(3): 133-9.
https://pubmed.ncbi.nlm.nih.gov/12195626

V. Hassan AB, Nikitina-Zake L, Sanjeevi CB, Lundberg IE, Padyukov L (2002). Proinflammatory haplotype (MICA5.1/TNF2/TNFa2/DRB1*03) is associated with poly- and dermatomyositis. [Submitted]

VI. Hassan AB, Fati M, Dastmalchi M, Lundberg IE, Padyukov L (2002). Relative production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 is associated with cytokine gene polymorphisms and with presence of anti-Jo-1 antibodies in patients with poly- and dermatomyosistis. [Manuscript]

History

Defence date

2002-12-19

Department

  • Department of Medicine, Solna

Publication year

2002

Thesis type

  • Doctoral thesis

ISBN-10

91-7349-388-0

Number of supporting papers

6

Language

  • eng

Original publication date

2002-11-28

Author name in thesis

Bakri Hassan, Adla

Original department name

Department of Medicine

Place of publication

Stockholm

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