BAFF (B-cell Activating Factor of the TNF Family) in patients with idiopathic inflammatory myopathieswith respect to autoantibody profile.

Souhrn Idiopatické zánětlivé myopatie (IZM) jsou heterogenní skupinou chronických zánětlivých onemocnění svalů s vážnou prognózou. Přítomnost autoprotilátek a složení svalových infiltrátů svědčí o jejich autoimunitní povaze a o roli B lymfocytů v patogeneze IZM. Kromě tradičních diagnostických podjednotek byly identifikovány autoprotilátkově- fenotypové podskupiny s podobným patogenetickým mechanismem. Nejznámější z nich je antisyntetázový syndrom, charakterizovaný myozitidou, protilátkami proti tRNA syntetázám (z nichž nejčastější jsou anti-Jo-1), intersticiálním plicním onemocněním a dalšími extramuskulárními projevy. BAFF (B cell-Activating Factor of the TNF Family) je klíčovým faktorem v modulaci B buněčné homeostázy. Ve vysokých hladinách umožňuje přežití autoreaktivních klonů a účastní se tak v patogeneze autoimunitních onemocnění. Jeho exprese je indukována interferony I. typu (IFN-1). Cílem doktorské práce bylo studium cytokinu BAFF v patogeneze IZM analýzou sérových hladin BAFF, jeho receptorů ve svalech ve vztahu k IFN-1 a exprese mRNA transkripčních variant BAFF genu v periferní krvi. Dalším aspektem byla možná synergie BAFF a visfatinu (PBEF; pre-B cell colony-enhancing factor), který stimuluje časná stadia diferenciace B lymfocytů. Studovali jsme asociace těchto aspektů s autoprotilátkami,...The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of chronic muscle diseases with frequent extramuscular organ involvement that contributes to serious prognosis. The presence of autoantibodies and composition of muscle infiltrates both support autoimmune nature of the disease and pathogenic role of B lymphocytes. Besides the traditional diagnostic subgroups, autoantibody characterised phenotype subsets have been identified with presumed similar pathogenic mechanisms. The best known is the antisynthetase syndrome which is characterised by presence of myositis, antisynthetase autoantibodies (with anti-Jo-1 being the most frequent), interstitial lung disease and other extramuscular manifestations. BAFF (B cell-Activating Factor of the TNF Family) is a key factor in B cell homeostasis modulation. In high levels, it allows survival of autoreactive B cell clones and thus participates in the pathogenesis of autoimmune diseases. Its expression is induced by type I interferons (IFN-1). The aim of the PhD thesis was to explore the role of BAFF in pathogenesis of IIMs by analysis of its serum levels, the receptors for BAFF in muscle tissue, their associations to IFN-1 and expression of BAFF gene mRNA transcription variants in peripheral blood cells. Further aspect was to study a possible...Revmatologická klinika 1. LF UK v Praze a Revmatologický ústavDepartment of Rheumatology First Faculty of Medicine and Rheumatology InstituteFirst Faculty of Medicine1. lékařská fakult

Serum levels of B-cell activating factor of the TNF family (BAFF) correlate with anti-Jo-1 autoantibodies levels and disease activity in patients with anti-Jo-1positive polymyositis and dermatomyositis

Abstract Background B-cell activating factor of the tumour necrosis factor family (BAFF) plays a role in autoantibody production and is elevated in dermatomyositis (DM) and anti-Jo-1-positive polymyositis (PM). We investigated the inter-relationships between serum levels of BAFF, anti-Jo-1 autoantibodies, and disease activity. Methods Serum levels of BAFF and anti-Jo-1 antibodies measured by enzyme-linked immunosorbent assay (ELISA) were compared to levels of myoglobin, creatine kinase (CK), aminotransferases (alanine (ALT) and aspartate (AST)), C-reactive protein (CRP), and disease activity assessed by the Myositis Disease Activity Assessment Tool in 63 anti-Jo-1 antibody-positive DM/PM patients. Serial serum samples collected at 2 (46 cases) and 3–5 time points (23 cases) were included. Relationships between BAFF, anti-Jo-1, disease activity, CRP, and their longitudinal changes were evaluated using correlation analysis, multiple regression (MR), path analysis (PA), and hierarchical linear models (HLM). Results Cross-sectional assessment demonstrated significant correlations between the levels of BAFF and anti-Jo-1 antibodies which were associated with levels of CK, myoglobin, AST, and CRP, as well as multivariate associations between BAFF, anti-Jo-1 antibodies, and CK levels. PA revealed direct effects of anti-Jo-1 antibodies on CK (β = 0.41) and both direct (β = 0.42) and indirect (through anti-Jo-1 antibodies; β = 0.17) effects of BAFF on CK. Changes in levels of both BAFF and anti-Jo-1 between two time points (Δ) were associated with Δmyoglobin and Δaminotransferases and changes of BAFF correlated with ΔCK, Δcutaneous, Δmuscle, Δglobal, and Δskeletal disease activities. The longitudinal analysis showed a high intra-individual variability of serum levels of BAFF over time (97%) which could predict 79% of the variance in anti-Jo-1 levels. The anti-Jo-1 variability was explained by inter-individual differences (68%). The close longitudinal relationship between levels of BAFF, anti-Jo-1, and disease activity was supported by high proportions of their variance explained with serum levels of CK and CRP or pulmonary and muscle activities. Conclusion Our findings of associations between levels of BAFF and anti-Jo-1 antibodies in serum and myositis activity suggest a role of this cytokine in disease-specific autoantibody production as part of disease mechanisms, and support BAFF as a potential target for intervention in anti-Jo-1-positive myositis patients

Additional file 5: of Serum levels of B-cell activating factor of the TNF family (BAFF) correlate with anti-Jo-1 autoantibodies levels and disease activity in patients with anti-Jo-1positive polymyositis and dermatomyositis

The scatter plots of source data for correlational analysis presented in Table 3. Changes between first two visits (Δ = 1st visit – 2nd visit) of (A) BAFF plotted against Δanti-Jo-1, changes in both BAFF and anti-Jo-1 plotted in columns against parameters of activity in rows. These are: (B) changes in markers of muscle impairment (ΔCK, Δmyoglobin, ΔALT and ΔAST) and (C) changes in clinical disease activity assessments (Δmuscle, Δglobal, Δskeletal within the entire patient group, Δcutaneous within patients with dermatomyositis (DM), and Δpulmonary within patients with lung involvement (ILD)). Statistics are: r = Spearman’s correlation coefficient; p = p value. A single outlying value of Δanti-Jo-1 is highlighted by a red circle. The graphs with exclusion of the outlier are plotted in the right column. The significance of some correlations became even stronger after exclusion of the outlier. (PDF 535 kb

Additional file 3: of Serum levels of B-cell activating factor of the TNF family (BAFF) correlate with anti-Jo-1 autoantibodies levels and disease activity in patients with anti-Jo-1positive polymyositis and dermatomyositis

The scatter plots of source cross-sectional data for correlational analysis presented in Table 2. The values of levels of BAFF, anti-Jo-1 antibodies, and CRP in serum are plotted in columns against the serum levels of markers of muscle impairment (CK, myoglobin, and AST) and CRP in rows. Based on the non-normal distribution, the logarithmically transformed data are plotted. Statistics are: r = Spearman’s correlation coefficient; p = p value. (PDF 540 kb

Additional file 2: of Serum levels of B-cell activating factor of the TNF family (BAFF) correlate with anti-Jo-1 autoantibodies levels and disease activity in patients with anti-Jo-1positive polymyositis and dermatomyositis

The application method of the hierarchical linear model (HLM). Detailed explanation of HLM principles, its use for the unbalanced designs, and interpretation of results. (PDF 199 kb