title: Immunogenicity of autoantigens.
abstract: BACKGROUND
  Autoantibodies against self-antigens have been associated not only with autoimmune diseases, but also with cancer and are even found in healthy individuals. The mechanism causing the autoantibody response remains elusive for the majority of the immunogenic antigens. To deepen the understanding of autoantibody responses, we ask whether natural-occurring, autoimmunity-associated and tumor-associated antigens have structural or biological features related to the immune response. To this end, we have carried out the most comprehensive in-silicio study of different groups of autoantigens including large antigen sets identified by our groups combined with publicly available antigen sets.
  
  
  RESULTS
  We found evidence for an enrichment of genes with a larger exon length increasing the probability of the occurrence of potential immunogenic features such as mutations, SNPs, immunogenic sequence patterns and structural epitopes, or alternative splicing events. While SNPs seem to play a more central role in autoimmunity, somatic mutations seem to be stronger enriched in tumor-associated antigens. In addition, antigens of autoimmune diseases are different from other antigen sets in that they appear preferentially secreted, have frequently an extracellular location, and they are enriched in pathways associated with the immune system. Furthermore, for autoantibodies in general, we found enrichment of sequence-based properties including coiled-coils motifs, ELR motifs, and Zinc finger DNA-binding motifs. Moreover, we found enrichment of proteins binding to proteins or nucleic acids including RNA and enrichment of proteins that are part of ribosome or spliceosome. Both, homologies to proteins of other species and an enrichment of ancient protein domains indicate that immunogenic proteins are evolutionary conserved and that mimicry might play a central role.
  
  
  CONCLUSIONS
  Our results provide evidence that proteins which i) are evolutionary conserved, ii) show specific sequence motifs, and iii) are part of cellular structures show an increased likelihood to become autoimmunogenic.
authors: Center for Bioinformatics, Saarland University, 66041 Saarbrücken, Germany. cbackes@bioinf.uni-sb.de
authors: Christina
authors: C
authors: Backes
authors: Nicole
authors: N
authors: Ludwig
authors: Petra
authors: P
authors: Leidinger
authors: Christian
authors: C
authors: Harz
authors: Jana
authors: J
authors: Hoffmann
authors: Andreas
authors: A
authors: Keller
authors: Eckart
authors: E
authors: Meese
authors: Hans-Peter
authors: HP
authors: Lenhof
mesh_terms: D020816:Amino Acid Motifs; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D030541:Databases, Genetic; D005091:Exons; D018716:Molecular Mimicry; D009696:Nucleic Acids / Q000737:chemistry / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016335:Zinc Fingers
chemical_list: D001324:Autoantigens; D009696:Nucleic Acids