Single nucleotide polymorphisms as a prerequisite for autoantigens

Stadler, Michael; Arnold, Diana; Frieden, Sara; Luginbühl, Sarah; Stadler, Beda M.

doi:10.1002/eji.200425481

Cited by 16 publications

(20 citation statements)

References 40 publications

(46 reference statements)

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“…This enrichment was detected for all SNP types, including (non)-synonymous SNPs and (non)-synonymous SNPs normalized. This observation is in line with published data also reporting an enrichment of SNPs in autoantigens associated with autoimmune diseases [36]. For tumor antigens, we obtained ambivalent results.…”

Section: Resultssupporting

confidence: 87%

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Immunogenicity of autoantigens

et al. 2011

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BackgroundAutoantibodies 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.ResultsWe 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.ConclusionsOur 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.

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Section: Resultssupporting

confidence: 87%

“…The antigen set Lit-AAG that is online available contains 348 genes associated with autoimmune diseases http://www.wiley-vch.de/contents/jc_2040/2005/25481_s.pdf. This set was initially collected to analyze the occurrences of SNPs (single nucleotide polymorphisms) in autoantigens [36]. …”

Section: Methodsmentioning

confidence: 99%

Immunogenicity of autoantigens

et al. 2011

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“…The occurrence of autoimmune diseases implies a failure of this distinction of self and non-self. These aberrations have many potential causes, some related to the immune system itself, and some related to the autoantigen targets, as is argued by Stadler et al in the current issue [5].…”

Section: Introductionmentioning

confidence: 84%

“…This concept is certainly consistent with the demonstrated genetic complexity that has been found in most autoimmune conditions. At least some of the proposed mechanisms of failure of self tolerance require that autoantigens be altered or perceived in a way that would make them immunogenic, as described by Stadler et al in the present issue of the European Journal of Immunology [5]. In the most extreme version, these antigen-specific processes would interact with a normal immune system.…”

Section: Mechanisms Of Autoimmunitymentioning

confidence: 93%

“…Autoantigens in general have been found to have peculiarities of charge or of secondary structure [16]; or genetic polymorphisms, as in the paper by Stadler et al [5]. Particular autoantigens may have particular features: they may be mimicked by prokaryotic sequences [17]; they may have biological activities such as chemoattraction [18]; they may bind secondary receptors such as TLR9 [19]; they may traffic to apoptotic blebs [20]; they may be cleaved by apoptosis enzymes [21]; or they may undergo posttranslational modifications [22].…”

Section: Autoantigen Selectionmentioning

confidence: 99%

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Do autoantigens define autoimmunity or vice versa?

Eisenberg

2005

Eur J Immunol

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The basic function of the adaptive immune system is to distinguish self from foreign. The failure of self tolerance can result in autoimmunity, which comes in many forms but still targets a limited selection of the total available autologous determinants. This selectivity must reflect the underlying mechanisms of the autoimmune reaction, as well as the particular features of the autoantigens that are targeted. Here I discuss the overall paradigm of autoimmunity, and what kinds of mechanisms might play a role. It is likely that multiple different pathways are critical in various diseases, and even in a single condition.

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