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Autoantibodies directed to novel components of the PM/Scl complex, the human exosome
Rick Brouwer1, Wilma T M Vree Egberts, Gerald J D Hengstman
1Department of Biochemistry, University of Nijmegen, NL-6500 HB Nijmegen, The Netherlands.
Abstract:
The autoantigenic polymyositis/scleroderma (PM/Scl) complex was recently shown to be the human homologue of the yeast exosome, which is an RNA-processing complex. Our aim was to assess whether, in addition to targeting the known autoantigens PM/Scl-100 and PM/Scl-75, autoantibodies also target recently identified components of the PM/Scl complex. The prevalence of autoantibodies directed to six novel human exosome components (hRrp4p, hRrp40p, hRrp41p, hRrp42p, hRrp46p, hCsl4p) was determined in sera from patients with idiopathic inflammatory myopathy (n = 48), scleroderma (n = 11), or the PM/Scl overlap syndrome (n = 10). The sera were analyzed by enzyme-linked immunosorbent assays and western blotting using the affinity-purified recombinant proteins. Our results show that each human exosome component is recognized by autoantibodies. The hRrp4p and hRrp42p components were most frequently targeted. The presence of autoantibodies directed to the novel components of the human exosome was correlated with the presence of the anti-PM/Scl-100 autoantibody in the sera of patients with idiopathic inflammatory myopathy (IIM), as was previously found for the anti-PM/Scl-75 autoantibody. Other clear associations between autoantibody activities were not found. These results further support the conception that the autoimmune response may initially be directed to PM/Scl-100, whereas intermolecular epitope spreading may have caused the autoantibody response directed to the associated components.
Insights
Autoantibodies target novel components of the polymyositis/scleroderma (PM/Scl) complex, which is the human exosome RNA-processing complex. This suggests an autoimmune response may initially target PM/Scl-100, with spreading to other exosome components.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmunity
Background:
- The polymyositis/scleroderma (PM/Scl) complex is an autoantigen associated with autoimmune diseases.
- The PM/Scl complex is the human homologue of the yeast exosome, an RNA-processing complex.
- Previous studies identified autoantibodies targeting PM/Scl-100 and PM/Scl-75.
Purpose of the Study:
- To investigate autoantibody reactivity against newly identified components of the human exosome (PM/Scl complex).
- To determine the prevalence of autoantibodies targeting six novel human exosome components in patients with idiopathic inflammatory myopathy (IIM), scleroderma, and PM/Scl overlap syndrome.
Main Methods:
- Sera from patients were analyzed using enzyme-linked immunosorbent assays (ELISAs) and western blotting.
- Affinity-purified recombinant proteins of six novel human exosome components were used as targets.
- Prevalence of autoantibodies was assessed in patient cohorts (IIM, n=48; scleroderma, n=11; PM/Scl overlap, n=10).
Main Results:
- All six novel human exosome components were recognized by autoantibodies in patient sera.
- Human exosome component hRrp4p and hRrp42p were the most frequently targeted.
- Autoantibodies to novel exosome components correlated with anti-PM/Scl-100 autoantibodies in IIM patients.
Conclusions:
- The findings support the hypothesis that the autoimmune response initially targets PM/Scl-100.
- Intermolecular epitope spreading likely contributes to the autoantibody response against other associated exosome components.
- This expands the understanding of the antigenic targets in PM/Scl-associated autoimmune diseases.